Journal articles on the topic 'IgA'
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Hall, R. P., and T. J. Lawley. "Characterization of circulating and cutaneous IgA immune complexes in patients with dermatitis herpetiformis." Journal of Immunology 135, no. 3 (September 1, 1985): 1760–65. http://dx.doi.org/10.4049/jimmunol.135.3.1760.
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Abstract Dermatitis herpetiformis (DH) is a chronic, blistering skin disease characterized in part by deposits of IgA at the dermal-epidermal junction. Eighty-five percent of DH patients have granular IgA deposits and have an associated gluten-sensitive enteropathy (GSE). In contrast, 15% of DH patients have a linear pattern of IgA deposits and no associated intestinal abnormality. Although circulating IgA antibodies against skin are not present in these patients, 40% of DH patients do have IgA-containing circulating immune complexes (IgA-CIC). The role and origin of the cutaneous IgA and the IgA-CIC in patients with DH are unknown; however, the association of GSE with the granular IgA deposits suggests that a mucosal immune response may be important in the pathogenesis of DH. We have characterized the IgA subclass composition of the cutaneous IgA deposits in patients with DH, and have isolated and characterized the IgA-CIC from these patients. Twenty-nine of 29 patients with DH and granular IgA deposits were found to have only IgA1 deposits. Ten of 11 patients with linear IgA deposits also had only IgA1 deposits; one of 11 had IgA2 deposits. Isolated IgA-CIC from the sera of eight patients with DH and granular IgA deposits were found to contain both IgA1 (58% +/- 5, mean percent of total IgA +/- SEM) and IgA2 (42% +/- 5), as were IgA-CIC from two patients with ordinary GSE without cutaneous IgA deposits. The IgA subclass composition of the isolated immune complexes was significantly different from the serum IgA1 and IgA2 composition (serum IgA1 = 76% +/- 6; IgA2 = 24% +/- 5, p less than 0.025, Student's t-test), and suggests that the IgA-CIC may arise from gut-associated lymphoid tissue (GALT). Sequential anti-IgA1 absorption of serum which contained IgA-CIC did not remove all the IgA-CIC, suggesting that the complexes circulate as separate IgA1 and IgA2 complexes. The finding of IgA1 alone in the skin of patients with DH suggests that the cutaneous IgA may not arise from GALT, or that IgA1, possibly arising in GALT, is preferentially bound to DH skin. Because IgA-containing CIC which contain both IgA1 and IgA2 were found in the serum of patients with DH and with ordinary GSE, it seems unlikely that IgA-containing CIC are responsible for the cutaneous IgA deposits seen in DH.
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Chevailler, A., R. C. Monteiro, H. Kubagawa, and M. D. Cooper. "Immunofluorescence analysis of IgA binding by human mononuclear cells in blood and lymphoid tissue." Journal of Immunology 142, no. 7 (April 1, 1989): 2244–49. http://dx.doi.org/10.4049/jimmunol.142.7.2244.
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Abstract The nature of IgA-binding cells and their tissue distribution was examined by an indirect immunofluorescence assay with the use of IgA1 and IgA2 paraproteins and fluorochrome- or biotin-labeled F(ab')2 fragments of idiotype-specific antibodies. The frequency of IgA-binding mononuclear cells was approximately 13% in blood and spleen samples but less than 1% in tonsil samples. IgA binding could be visualized by flow immunocytometry on monocyte/macrophages, but not on T and B cells. IgA polymers were bound better than IgA dimers and monomers. Nonhomologous IgA myelomas of both IgA1 and IgA2 subclasses inhibited the IgA-binding to monocytes, whereas aggregated normal serum IgG, IgM paraproteins, and an IgG myeloma did not. IgA binding was relatively insensitive to changes in temperature or cation concentration. IgA-binding monocytes were found in IgA-deficient patients at the same frequency as in normal individuals. The results indicate that monocytes constitutively express class-specific binding sites for both IgA1 and IgA2 molecules.
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Derksen, V., C. Allaart, A. van der Helm-van Mil, T. Huizinga, R. Toes, and D. van der Woude. "AB0077 IN RHEUMATOID ARTHRITIS PATIENTS, TOTAL IgA1 AND IgA2 LEVELS ARE ELEVATED: IMPLICATIONS FOR THE MUCOSAL ORIGIN HYPOTHESIS." Annals of the Rheumatic Diseases 81, Suppl 1 (May 23, 2022): 1170.2–1171. http://dx.doi.org/10.1136/annrheumdis-2022-eular.2829.
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BackgroundMucosal surfaces may be involved in the pathophysiology of rheumatoid arthritis (RA) (1). IgA is the most abundant class of immunoglobulin at mucosal sites. Therefore, it is worthwhile to study this isotype in RA patients in more detail. Humans have two IgA subclasses, IgA1 and IgA2, which are not evenly distributed. IgA1 is dominant in serum, whereas IgA1 and IgA2 are more balanced at mucosal surfaces (2). Besides these differences in location, IgA2 has also been ascribed pro-inflammatory properties (3).ObjectivesAs IgA subclasses might provide new insights into mucosal involvement and potential pro-inflammatory mechanisms, we investigated total and autoantibody-specific IgA subclasses responses in sera of rheumatoid arthritis patients.MethodsSera from two cohorts of RA patients, the IMPROVED (baseline visit) and the EAC (1-year visit), were selected based on previous autoantibody measurements. All patients fulfilled the 1987 (EAC) or 2010 (IMPROVED) ACR criteria for RA. Total IgA subclasses and IgA subclasses of rheumatoid factor (RF) and anti-citrullinated protein antibodies (ACPA) were measured using (in-house) ELISA’s, and compared to healthy donors. Associations between these IgA subclass levels and markers of inflammation (CRP and disease activity score (DAS)) were investigated using Spearman’s rank correlation. Mann–Whitney U tests were performed to investigate the association between IgA1 and IgA2 levels and smoking, a proxy for chronic mucosal inflammation. To correct for confounders, a multivariate linear model including age, gender, CRP and smoking was used.ResultsTotal IgA1 and IgA2 levels were increased in RA patients compared to healthy donors in both cohorts (Figure 1A-C, data IMPROVED). This increase was more pronounced in seropositive RA versus seronegative RA. Both total IgA subclasses were raised to the same extent, since the percentage of IgA2 of total IgA in serum did not differ between patients and healthy donors. In seropositive patients, RF and anti-CCP2 IgA1 and IgA2 could be detected, but measurements of anti-CCP2 IgA2 levels proved challenging due to interference of RF IgA. Although IgA2 has been postulated to be more proinflammatory, no correlations were found between total, RF and ACPA IgA subclass levels and DAS. An association between CRP and RF IgA2 was observed, but the effect size was small and did not remain significant after correction for multiple testing in the EAC. In smoking seropositive RA patients, a trend towards a selective increase in total IgA2 and RF IgA1 and IgA2 was observed (Figure 1D, data IMPROVED seropositive RA).Figure 1.ConclusionSeropositive RA patients have raised IgA1 and IgA2 levels and can also harbor RF and ACPA IgA subclasses. No shift towards IgA2 was observed, indicating that the increase in total IgA is not due to translocation of mucosal IgA into the bloodstream. However, chronic mucosal inflammation might be one of the mechanisms involved in the raise in IgA(2) levels in RA, given the association between smoking and total IgA2 levels. Despite its’ pro-inflammatory properties, no strong associations between IgA2 and markers of inflammation were found, which suggests that IgA2 does not play a essential role in the ongoing pro-inflammatory processes in RA patients.References[1]Holers VM, Demoruelle MK, Kuhn KA, et al. Rheumatoid arthritis and the mucosal origins hypothesis: protection turns to destruction. Nature Reviews Rheumatology. 2018;14(9):542-57.[2]Woof JM, Russell MW. Structure and function relationships in IgA. Mucosal Immunol. 2011;4(6):590-7.[3]Steffen U, Koeleman CA, Sokolova MV, et al. IgA subclasses have different effector functions associated with distinct glycosylation profiles. Nat Commun. 2020;11(1):120.Disclosure of InterestsNone declared
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Pakkanen, Sari H., Jussi M. Kantele, Zina Moldoveanu, Spencer Hedges, Miikka Häkkinen, Jiri Mestecky, and Anu Kantele. "Expression of Homing Receptors on IgA1 and IgA2 Plasmablasts in Blood Reflects Differential Distribution of IgA1 and IgA2 in Various Body Fluids." Clinical and Vaccine Immunology 17, no. 3 (January 20, 2010): 393–401. http://dx.doi.org/10.1128/cvi.00475-09.
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ABSTRACT Although secretory IgA is the most abundantly produced Ig isotype, the mechanisms underlying the differential distribution of IgA subclasses in various body fluids remain unclear. To explore these mechanisms, we examined the distribution of IgA subclasses, the influence of the nature and sites of encounters with antigens, and the correlation between IgA subclass distribution and homing potentials of circulating IgA plasmablasts. IgA1 predominated in serum, tears, nasal wash fluid, and saliva; the levels of IgA1 and IgA2 were comparable in vaginal wash fluid; and IgA2 predominated in intestinal lavage fluids. Seventy-one percent of circulating IgA plasmablasts secreted IgA1. The intestinal homing receptor (HR), α4β7, was expressed more frequently on IgA2 than on IgA1 plasmablasts, with no differences in the expression of other HRs. IgA subclass distribution among circulating antigen-specific antibody-secreting cells (ASC) was dependent on the nature of the antigen: following vaccination with Salmonella enterica serovar Typhi, unconjugated pneumococcal polysaccharide, or Haemophilus influenzae polysaccharide-diphtheria toxoid conjugate, the proportions of specific IgA1 ASC were 74%, 47%, 56%, and 80%, respectively. HR expression depended on the route of administration: expression of HRs was different after oral than after parenteral vaccination, while no difference was seen between HR expression of antigen-specific IgA1 and IgA2 ASC induced via the same route. The key factors determining IgA subclass distribution in a given secretion are the nature of the antigens encountered at a particular site and the site-specific homing instructions given to lymphocytes at that site. These two factors are reflected as differences in the homing profiles of the total populations of circulating IgA1 and IgA2 plasmablasts.
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Heilmann, C., T. Barington, and T. Sigsgaard. "Subclass of individual IgA-secreting human lymphocytes. Investigation of in vivo pneumococcal polysaccharide-induced and in vitro mitogen-induced blood B cells by monolayer plaque-forming cell assays." Journal of Immunology 140, no. 5 (March 1, 1988): 1496–99. http://dx.doi.org/10.4049/jimmunol.140.5.1496.
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Abstract The subclass of individual human IgA B cells was investigated by means of monolayer plaque-forming cell assays permitting analysis of all IgA-secreting cells as well as of cells secreting IgA anti-pneumococcal polysaccharide antibody. Center cells were examined by indirect immunofluorescence staining with mouse mAb against either of the two IgA subclasses as primary antibodies and FITC-conjugated rabbit anti-mouse Ig as the second antibody. Blood lymphocytes spontaneously secreting IgA (mean 399/10(6) mononuclear cells) produced mainly IgA1 (73%). A similar distribution of subclasses was recorded among IgA-secreting blood cells in PWM- and EBV-stimulated cultures. In contrast, a predominance of IgA2 (54%) was found among IgA-secreting cells (2531/10(6)) isolated from the blood 7 days after in vivo stimulation with pneumococcal polysaccharides, and a similar proportion (51%) of IgA2 producing cells was found among IgA anti-pneumococcal polysaccharide-secreting cells. It was thus confirmed that IgA1 is the predominant subclass of blood IgA-secreting cells in general. However, the high percentage of IgA2-secreting cells found after vaccination with pneumococcal polysaccharides suggests that these Ag have an unusually high ability to activate IgA2 B cells, or that the B cells stimulated originate from lymphatic tissues with a high frequency of IgA2 committed cells.
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Heck, L. W., P. G. Alarcon, R. M. Kulhavy, K. Morihara, M. W. Russell, and J. F. Mestecky. "Degradation of IgA proteins by Pseudomonas aeruginosa elastase." Journal of Immunology 144, no. 6 (March 15, 1990): 2253–57. http://dx.doi.org/10.4049/jimmunol.144.6.2253.
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Abstract Human colostral IgA and myeloma proteins of both IgA1 and IgA2 subclasses were susceptible to cleavage by Pseudomonas aeruginosa elastase. Detailed analysis of the cleavage products of IgA myeloma proteins revealed complete degradation of Fab with no evidence of intact Fab fragments as intermediate cleavage products. In contrast, both IgA1 and IgA2 proteins were resistant to cleavage by alkaline protease from P. aeruginosa. The susceptibility of human IgA proteins to elastase suggests a mechanism by which P. aeruginosa might evade the potentially protective function of IgA by producing this enzyme.
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Mazengera, R. L., and M. A. Kerr. "The specificity of the IgA receptor purified from human neutrophils." Biochemical Journal 272, no. 1 (November 15, 1990): 159–65. http://dx.doi.org/10.1042/bj2720159.
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A receptor for IgA was purified from human polymorphonuclear neutrophils (PMN) by affinity chromatography on human serum IgA-Sepharose. The receptor appeared on SDS/polyacrylamide gels as a diffuse band with an apparent molecular mass of 50-70 kDa, whether reduced or non-reduced. During purification, the protein showed remarkable stability to proteolytic digestion by endogenous PMN proteinases. Purified radioiodinated receptor re-bound to IgA-Sepharose, but not to IgG-Sepharose or BSA-Sepharose. The binding of the receptor to IgA-Sepharose was inhibited in a dose-dependent manner by human serum IgA1 or IgA2 or secretory IgA1 or IgA2, but not by IgG or IgM. Binding of receptor to IgA-Sepharose was also inhibited by the Fc fragment of IgA, but not by the Fab fragment. An IgA fragment produced by digestion with pepsin which lacks the CH3 domain also inhibited binding, but to a more limited extent than did the whole IgA molecule.
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Engström, P. E., G. Norhagen, A. Bottaro, A. O. Carbonara, G. Lefranc, M. Steinitz, P. O. Söder, C. I. Smith, and L. Hammarström. "Subclass distribution of antigen-specific IgA antibodies in normal donors and individuals with homozygous C alpha 1 or C alpha 2 gene deletions." Journal of Immunology 145, no. 1 (July 1, 1990): 109–16. http://dx.doi.org/10.4049/jimmunol.145.1.109.
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Abstract To analyze the subclass restriction of Ag-specific IgA, sera and saliva from healthy blood donors and from IgA class or subclass deficient individuals were studied. The latter included donors with or without C alpha 1 or C alpha 2 gene deletions. Monoclonal human IgA1 and a genetically engineered IgA2 antibody, normal human serum and colostrum IgA were used as standards to estimate serum and saliva levels of Ag-specific antibodies. In normal individuals, there was a strong IgA1 preference of naturally acquired antibodies in serum against both polysaccharide Ag (PPS 6A, PPS 23, pneumococcal C-polysaccharide, and LPS from Escherichia coli) and protein Ag (Staphylococcus aureus alpha-toxin and HSV). Specific IgA2 in serum against the tested Ag were frequently not measurable. In contrast, most of the individuals with homozygous C alpha 1 gene deletions displayed substantial amounts of specific IgA2 against protein as well as polysaccharide Ag. The median levels of specific IgA in serum against protein Ag were approximately one-third as compared to normal individuals and one-fifth, or less, against polysaccharide Ag. Normal serum levels of IgA against the tested Ag, restricted to the IgA1 subclass, were noted in two individuals with IgA2 deficiency, one of whom carried a homozygous C alpha 2 gene deletion. Median values of specific IgA, against the tested Ag S. aureus alpha-toxin, HSV, and pneumococcal C-poly-saccharide, from normal healthy donors were approximately four to eight times higher in serum as compared to saliva. Individuals with homozygous C alpha 1 gene deletions displayed increased levels of the various specific IgA2 antibodies in saliva. In conclusion, the individuals with homozygous C alpha 1 gene deletions displayed decreased median levels of specific IgA antibodies in serum despite normal levels of total IgA. Normal levels of both specific IgA and total IgA in saliva were found.
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Jackson, S., R. I. Montgomery, J. Mestecky, and C. Czerkinsky. "Normal human sera contain antibodies directed at Fab of IgA." Journal of Immunology 138, no. 7 (April 1, 1987): 2244–48. http://dx.doi.org/10.4049/jimmunol.138.7.2244.
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Abstract Serum samples from 26 normal volunteers were evaluated by isotype-specific ELISA for the presence of IgG and IgM antibodies directed at IgA. Although there were wide variations in antibody levels, anti-IgA antibodies of both isotypes were found in all individuals tested. The anti-IgA activity was detected against a variety of polymeric and monomeric IgA1 and IgA2 myeloma proteins containing both kappa and lambda light chains. By using Fab and Fc fragments generated by incubation of an IgA1 myeloma protein with IgA1 protease, it was shown that the anti-IgA activity was specific for the Fab portion of the IgA molecule. It was also demonstrated that the serum of two individuals contained both IgG and IgM activity directed at autologous affinity-purified IgA. IgM antibody levels against both whole IgA and Fab of IgA were significantly higher than IgG antibody levels. Cells producing anti-IgA antibodies of both isotypes were detected in lipopolysaccharide-stimulated human spleen.
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Conley, M. E., M. A. Chan, and N. H. Sigal. "In vitro regulation of IgA subclass production. III. Selective transformation of IgA1 producing cells by Epstein-Barr virus." Journal of Immunology 138, no. 5 (March 1, 1987): 1403–7. http://dx.doi.org/10.4049/jimmunol.138.5.1403.
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Abstract In past experiments, using limited dilution analysis, we have demonstrated that a high percentage of immunoglobulin-secreting clones derived from Epstein-Barr virus- (EBV) stimulated lymphocytes secrete IgA. To further characterize the IgA produced by these clones, the IgA subclass of supernatants from clones stimulated 4 to 6 wk previously with EBV was determined by radioimmunoassay. All of 17 IgA-producing clones secreted IgA1; none secreted IgA2. Because we have shown that surface IgM+ (sIgM+) B cells are an enriched source of IgA2 plasma cell precursors, panning techniques were used to purify sIgM+ B cells from tonsils. Of 103 clones derived from these sIgM+ B cells, 102 secreted IgA1 and only one secreted IgA2. The relative absence of IgA2-producing clones could not be attributed to an absence of EBV receptors on IgA2 cells. A mean of 84 +/- 4% of freshly isolated IgA2 B cells and 78 +/- 6% of IgA1 B cells could be stained with a monoclonal antibody binding the EBV receptor; and there was no failure of EBV to infect IgA2 plasma cells precursors. Of IgA2 plasma cells derived from peripheral blood lymphocytes stimulated 7 days previously with EBV, 54 +/- 7% were positive for the EBV nuclear antigen, compared with 54 +/- 18% of IgA1 plasma cells from the same cultures. Seven days after EBV stimulation, a mean of 25% of the total IgA plasma cells were positive for cytoplasmic IgA2, whereas by 21 days after stimulation only 7% were positive for IgA2. This shift in the proportions of IgA1 and IgA2 plasma cells could be attributed to a failure of the IgA2 plasma cell number to increase after 10 days in culture. There was no evidence for selective suppression of IgA2 production by T cells or selective lysis of IgA2 plasma cells by infectious EBV particles. These results demonstrate that although precursors for both IgA1- and IgA2-producing cells can be stimulated to differentiate in response to EBV, there is preferential transformation of IgA1-producing cells.
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Moura, Ivan C., Miguel N. Centelles, Michelle Arcos-Fajardo, Denise M. Malheiros, James F. Collawn, Max D. Cooper, and Renato C. Monteiro. "Identification of the Transferrin Receptor as a Novel Immunoglobulin (Ig)a1 Receptor and Its Enhanced Expression on Mesangial Cells in Iga Nephropathy." Journal of Experimental Medicine 194, no. 4 (August 13, 2001): 417–26. http://dx.doi.org/10.1084/jem.194.4.417.
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The biological functions of immunoglobulin (Ig)A antibodies depend primarily on their interaction with cell surface receptors. Four IgA receptors are presently characterized. The FcαRI (CD89) expressed by myeloid cells selectively binds IgA1 and IgA2 antibodies, whereas the poly-IgR, Fcα/μR, and asialoglycoprotein receptors bind other ligands in addition to IgA. IgA binding by mesangial cells, epithelial cells, and proliferating lymphocytes is also well documented, but the nature of the IgA receptors on these cells remains elusive. A monoclonal antibody (A24) is described here that specifically blocks IgA binding to epithelial and B lymphocyte cell lines. Both the A24 antibody and IgA1 myelomas bind a cell surface protein that is identified as the transferrin receptor (CD71). The transferrin receptor selectively binds IgA1 antibodies, monomeric better than polymeric forms, and the IgA1 binding is inhibitable by transferrin. Transferrin receptor expression is upregulated on cultured mesangial cells as well as on glomerular mesangial cells in patients with IgA nephropathy. The characterization of transferrin receptor as a novel IgA1 receptor on renal mesangial cells suggests its potential involvement in the pathogenesis of IgA nephropathy.
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Romero, Sandra, Erick Saúl Sánchez-Salguero, Jiram José Torres-Ruiz, Carlos Núñez-Álvarez, Leopoldo Santos-Argumedo, Rommel Chacón-Salinas, Diana Gómez-Martín, and José Luis Maravillas-Montero. "Salivary IgA as biomarker of disease activity in Systemic Lupus Erythematosus." Journal of Immunology 202, no. 1_Supplement (May 1, 2019): 179.7. http://dx.doi.org/10.4049/jimmunol.202.supp.179.7.
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Abstract Immunoglobulin A (IgA) is the main antibody isotype present in the body fluids such as tears, intestinal mucous, colostrum and saliva. There are two subtypes of IgA in humans: IgA1 mainly present in blood and IgA2, the preferentially expressed mucosal antibody. In clinical practice, immunoglobulins are typically measured in venous or capillary blood; however, alternative samples including saliva are now being considered given its non-invasive and easy collection nature. Since IgA deficiency could be frequently detected in patients with autoimmune diseases, we decided to evaluate the levels of both IgA subtypes in serum and saliva of systemic lupus erythematosus (SLE) patients. Specific IgA1 and IgA2 levels were measured by a light chain capture-based ELISA in a cohort of 32 patients with SLE that were compared with antibody levels of healthy volunteers. Surprisingly, our results indicated that in saliva of SLE patients, both IgA subtypes were significantly elevated; however, serum IgA1 levels were decreased when compared with control subjects. Interestingly, we also found that salivary IgA levels, most specifically IgA1, positively correlate with the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) values as well with the amount of serum anti-nucleosomes and anti-dsDNA IgG autoantibodies. Strikingly, we also were able to detect the presence of salivary anti-nucleosome IgA antibodies in SLE patients, a feature that was not previously reported elsewhere. According to our results, IgA characterization in saliva could be used as a pre-diagnostic or follow-up clinical tool in SLE with easier, faster and safer to manipulate than blood samples.
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Morton, H. C., J. D. Atkin, R. J. Owens, and J. M. Woof. "Purification and characterization of chimeric human IgA1 and IgA2 expressed in COS and Chinese hamster ovary cells." Journal of Immunology 151, no. 9 (November 1, 1993): 4743–52. http://dx.doi.org/10.4049/jimmunol.151.9.4743.
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Abstract Ag-specific chimeric human IgA molecules, of the two human subclasses, IgA1 and IgA2, have been expressed in two mammalian cell systems. Analysis of the secreted IgA molecules, purified in milligram quantities from stable Chinese hamster ovary transfectants by Ag affinity chromatography, has allowed a direct comparison of the biologic properties of the two subclasses. HPLC gel filtration analysis revealed that in both subclasses, the IgA molecules associate predominantly into dimers. The monomer units are presumed to interact noncovalently, inasmuch as no dimers are evident when the antibodies are subjected to SDS-PAGE. The recombinant antibodies are glycosylated, inasmuch as a lectin blotting procedure revealed that the H chains of both subclasses are recognized by Con A. When subjected to digestion by preparations of IgA1-specific proteases secreted by two pathogenic streptococcal strains, Streptococcus sanguis and Streptococcus oralis, the recombinant IgA molecules behave just as their natural equivalents. Thus, only the chimeric IgA1 molecule is cleaved, with the IgA2 remaining intact. In terms of interaction with natural effector molecules, both recombinant IgA isotypes were shown to interact with Fc alpha receptors on calcitriol-stimulated HL-60 cells with similar affinity, but neither antibody was found to interact with human C1q. The expression system described readily permits manipulation of the human IgA genes, which should lead to a fuller molecular understanding of how this important antibody mediates its function.
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Dechant, Michael, Thomas Beyer, Stefan Lohse, Tanja Schneider-Merck, Wencke Weisner, Sven Berger, Matthias Peipp, Jan G. J. van de Winkel, and Thomas Valerius. "Recombinant Chimeric IgA1 and IgA2 Antibodies for Tumor Immunotherapy." Blood 110, no. 11 (November 16, 2007): 4892. http://dx.doi.org/10.1182/blood.v110.11.4892.4892.
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Abstract The therapeutic potential of human IgA antibodies has hardly been explored, although IgA is the most abundantly produced antibody isotype in humans. Here, we describe the generation and functional characterization of human/mouse chimeric IgA antibodies against the epidermal growth factor receptor (EGF-R), which is a validated target antigen for tumor immunotherapy. Human IgG1, IgA1 and IgA2 variants of the C225 antibody were produced in CHO-K1 transfectomas using serum-free, non-adherent culture conditions. Productivity rates of selected IgA producing clones were approximately 5 pg/cell/day. A two-step purification procedure consisting of thiophilic agarose columns followed by gel electrophoresis on Superdex 200 yielded highly purified monomeric IgA antibodies, which were stable at 4° C. Silver staining and Western blots with human kappa-light- and human α-heavy chain antibodies confirmed the purity and correct assemby of IgA1 and IgA2 antibodies. Co-transfection of a His-tagged joining (J) chain significantly increased the amount of dimeric IgA antibodies, which were detected by anti-His antibodies. IgG1 and monomeric IgA antibodies demonstrated similar binding to EGF-R expressing A431 tumor cells (EC50 approx. 10 μg/ml) and to EGF-R transfectants. Furthermore, IgA1 and IgA2, but not IgG1 demonstrated binding to FcαRI (CD89)- transfected cells. All three isotypes were similarly effective in recruiting F(ab’)- mediated killing mechanisms such as blockade of EGF binding, inhibiting EGF-R phosphorylation, and mediating growth inhibition of EGF-R expressing cells. All three isotypes did not activate complement- mediated killing. Human IgG1 effectively triggered MNC- mediated ADCC, but activated PMN only weakly. Importantly, both human IgA isotypes were significantly more effective than IgG1 in recruiting neutrophils for ADCC (EC50 approx. 0.25 μg/ml), and triggered ADCC at effector to target cell ratios as low as 5:1. Since neutrophils constitute the most abundant effector cell population in human blood, IgA antibodies triggered higher levels of tumor cell killing in whole blood assays than human IgG1 antibodies - particularly when blood from G-CSF- primed donors was compared to healthy donor blood. Together, these data suggest that recombinant human IgA antibodies can be produced in reasonable amounts, and that they may constitute promising reagents for immunotherapy.
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Fernaays, Matthew M., Alan J. Lesse, Xueya Cai, and Timothy F. Murphy. "Characterization of igaB, a Second Immunoglobulin A1 Protease Gene in Nontypeable Haemophilus influenzae." Infection and Immunity 74, no. 10 (October 2006): 5860–70. http://dx.doi.org/10.1128/iai.00796-06.
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ABSTRACT Nontypeable Haemophilus influenzae is an important respiratory pathogen, causing otitis media in children and lower respiratory tract infection in adults with chronic obstructive pulmonary disease (COPD). Immunoglobulin A1 (IgA1) protease is a well-described protein and potential virulence factor in this organism as well as other respiratory pathogens. IgA1 proteases cleave human IgA1, are involved in invasion, and display immunomodulatory effects. We have identified a second IgA1 protease gene, igaB, in H. influenzae that is present in addition to the previously described IgA1 protease gene, iga. Reverse transcriptase PCR and IgA1 protease assays indicated that the gene is transcribed, expressed, and enzymatically active in H. influenzae. The product of this gene is a type 2 IgA1 protease with homology to the iga gene of Neisseria species. Mutants that were deficient in iga, igaB, and both genes were constructed in H. influenzae strain 11P6H, a strain isolated from a patient with COPD who was experiencing an exacerbation. Analysis of these mutants indicated that igaB is the primary mediator of IgA1 protease activity in this strain. IgA1 protease activity assays on 20 clinical isolates indicated that the igaB gene is associated with increased levels of IgA1 protease activity. Approximately one-third of 297 strains of H. influenzae of diverse clinical and geographic origin contained igaB. Significant differences in the prevalence of igaB were observed among isolates from different sites of isolation (sputum > middle ear > nasopharynx). These data support the hypothesis that the newly discovered igaB gene is a potential virulence factor in nontypeable H. influenzae.
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Sokolova, M. V., J. Rech, M. Hagen, G. Schett, and U. Steffen (née Harre). "POS0460 ASSOCIATION OF ANTI-CITRULLINATED PROTEIN ANTIBODIES OF IgA SUBCLASSES WITH SUSTAINED REMISSION AND FLARE IN RHEUMATOID ARTHRITIS." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 461. http://dx.doi.org/10.1136/annrheumdis-2021-eular.2004.
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Background:Understanding key mechanisms of flare development and sustained remission is one of the acute goals in modern rheumatology. Anti-citrullinated protein antibodies (ACPA) are the most abundant and specific autoantibodies in rheumatoid arthritis (RA) patients. However, the impact of ACPA of IgA isotype is poorly defined. IgA ACPA were previously shown to have a higher percentage of IgA2 in comparison to total IgA; and a correlation between IgA2% ACPA with the DAS28 score was observed in a previous study [1]. Of note, IgA1 and IgA2 were shown to exhibit different effector functions, with IgA2 being pro-inflammatory, which might be the background for its role in RA [1].Objectives:We aimed to investigate, whether IgA ACPA could be used as a predictive factor for flare development in RA; and to look further into the changes in IgA ACPA levels in patients remaining in stable remission versus patients developing flare.Methods:We analysed serum of 111 patients from a multicentre randomized controlled trial ‘RETRO’. The study observational period was 12 months. Patients in the trial had to be in stable remission (DAS28-ESR<2.6) for a minimum of 6 months and were randomized into 3 different treatment arms: continuation of treatment, tapering by 50% or a gradual tapering until discontinuation [2]. IgA ACPA concentrations were measured with an enzyme-linked immunosorbent assay on CCP2-pre-coated plates.Results:60% of patients had IgG-ACPA. IgA ACPA levels were higher among the IgG-ACPA-positive patients (median 4.7 versus 2.24 µg/ml, p<0.0001). Baseline IgA1 and 2 ACPA levels were not different between patients who had a flare later on in the study period and those remaining in remission, showing no predictive value for flare development. However, the percentage of IgA2 in ACPA was correlating with the first registered DAS28 after flare (r=0.36, p=0.046). After the 12 months study period, IgA2 ACPA as well as IgA2% ACPA decreased significantly in patients who remained in stable remission by 17.5% (median, p<0.0001) and 13.6% (p=0.0006), respectively. By contrast, there was no significant change in IgA2 ACPA levels over time in patients who developed a flare. IgA1 ACPA levels remained stable over time. Disease management strategies did not seem to influence IgA ACPA levels in a specific way, as baseline levels were similar between patients on biological and conventional DMARDs and changes in levels after 12 months did not depend on the assignment to either of the study arms.Conclusion:Neither IgA1 nor IgA2 ACPA levels were predictive of flare development or associated with treatment strategies (though rituximab, JAK-inhibitors and abatacept were not amongst treatment options). However, in patients remaining in sustained remission after 1 year a decrease in IgA2 and IgA2% ACPA was observed and IgA2% ACPA was associated with DAS28 score registered after flare. This could be an indication towards ACPA of IgA2 isotype contributing to the severity of flare, alongside other factors, and its reduction being associated with a prolonged state of remission.References:[1]Steffen U, Koeleman CA, Sokolova MV, et al. IgA subclasses have different effector functions associated with distinct glycosylation profiles. Nat Commun 11, 120 (2020).[2]Haschka J, Englbrecht M, Hueber AJ, et al. Relapse rates in patients with rheumatoid arthritis in stable remission tapering or stopping antirheumatic therapy: interim results from the prospective randomised controlled RETRO study. Ann Rheum Dis. 75:45-51 (2016).Disclosure of Interests:None declared
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Sokolova, M. V., F. Hartmann, D. Sieghart, G. Steiner, A. Kleyer, G. Schett, and U. Steffen (Née Harre). "POS0517 IgA ACPA ARE ASSOCIATED WITH PROGRESSION TO RHEUMATOID ARTHRITIS IN INDIVIDUALS AT-RISK AND DECLINE IN LEVELS AROUND THE DISEASE ONSET." Annals of the Rheumatic Diseases 81, Suppl 1 (May 23, 2022): 515.2–516. http://dx.doi.org/10.1136/annrheumdis-2022-eular.1049.
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BackgroundAnti-citrullinated protein antibodies (ACPA) can precede the diagnosis of rheumatoid arthritis (RA) up to a decade. However, while some ACPA-positive individuals rapidly develop the disease, a considerable proportion are not progressing to RA, and the events triggering the disease outbreak are still poorly understood. While a lot is known about ACPA of IgG class, the role of IgA ACPA is still not defined.ObjectivesWe aimed to look into IgA ACPA isotypes in individuals at-risk for RA and their role in RA development.MethodsIgA1 and IgA2 ACPA were measured cross-sectionally in 30 seropositive (IgG ACPA-positive) RA patients, 29 seronegative RA patients, 63 individuals at-risk for RA (positive for IgG ACPA and/or anti-modified citrullinated vimentin antibodies and with joint complaints) and 32 healthy controls. In addition, IgA ACPA levels were compared in 24 RA at-risk individuals who developed RA during a follow-up of 14 months and in 21 individuals who did not. Furthermore, longitudinal measurements of IgA1 and IgA2 ACPA levels 1-28 months prior to, at and 1-18 months after the onset of RA were performed in 14 at-risk individuals and in 9 individuals from a confirmation retrospective cohort of RA patients from the Medical University of Vienna. Cut-offs were set based on the comparison of IgA ACPA levels in RA patients versus healthy controls. Rather than prioritizing specificity, as is done for diagnostic tests, we aimed to define reliably detectable amounts of IgA ACPA, with both sensitivity and specificity not under 70% – 3 µg/ml for total IgA ACPA; 2.46 µg/ml for IgA1 and 0.6 µg/ml for IgA2 ACPA.ResultsSerum levels of both IgA ACPA subclasses were elevated in individuals at-risk, with no significant difference to patients with established IgG ACPA-positive RA. Interestingly, 41.4% of IgG ACPA-negative patients had detectable amounts of IgA ACPA. IgA1 ACPA, but not IgA2 ACPA levels were higher in individuals at-risk who developed RA in the next 14 months than in those who did not (4.54 vs. 2.05 µg/mL, p=0.03); and the percentage of those developing RA was higher in IgA1 ACPA-positive at-risk individuals (64.3% versus 35.3%). Interestingly, during the transition to RA, in the majority of IgA ACPA-positive individuals a decline in IgA1 ACPA levels at the time of RA diagnosis (-26%; p=0.085), as well as in the first months after the RA diagnosis (-38%; p=0.0002) was observed. This observation was confirmed in an independent cohort. IgA2 ACPA declined only after the diagnosis (33%; 10-64%; p=0.0237), and no significant change was observed for IgG ACPA.ConclusionBoth IgA ACPA subclasses were elevated in individuals at-risk for RA. Positivity for IgA1 ACPA was associated with the progression to RA in the next 14 months. IgA1 ACPA levels declined in the months preceding the diagnosis of RA and in the months after the diagnosis, which might reflect pathophysiological events happening at the time of the disease outbreak.AcknowledgementsWe thank Holger Bank from Orgentec Deiagnostika, Mainz for the supply of CCP-coated plates.Disclosure of InterestsMaria V Sokolova: None declared, Fabian Hartmann: None declared, Daniela Sieghart: None declared, Günter Steiner: None declared, Arnd Kleyer Speakers bureau: Novartis, Lilly, Consultant of: Lilly, Gilead, Novartis,Abbvie, Georg Schett Speakers bureau: AbbVie, BMS, Celgene, Janssen, Eli Lilly, Ulrike Steffen (née Harre): None declared.
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Li, Guanhong, Xiaoyan Wang, Zhe Yang, Qing Zhao, Yubing Wen, Xuemei Li, and Ruitong Gao. "Serum Levels of Joining Chain-Containing IgA1 Are Not Elevated in Patients with IgA Nephropathy." Disease Markers 2019 (July 2, 2019): 1–11. http://dx.doi.org/10.1155/2019/9802839.
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Background. It has been suggested that mesangial IgA deposits are dimeric or polymeric in IgA nephropathy (IgAN). However, evidence concerning the molecular form of serum IgA in IgAN is controversial. And there is no direct evidence that the serum levels of joining chain- (J chain-) containing IgA (J-IgA) are elevated in IgAN. In this study, we aimed to measure serum J-IgA and glomerular J chain deposition with anti-J chain monoclonal antibody in IgAN. Methods. BALB/c mice were immunized with human J chain-GST recombinant peptide to obtain anti-J chain monoclonal antibody. The levels of serum total IgA and J-IgA were measured by sandwich enzyme-linked immunosorbent assay in 115 patients with IgAN and 117 healthy volunteers. J chain deposition in kidney specimens was analyzed by immunohistochemistry staining. Results. Serum levels of total IgA1 were elevated in IgAN patients compared to healthy subjects. However, serum levels of IgA, J-IgA, and J chain-containing IgA1 (J-IgA1), the J-IgA to total IgA ratio, and the J-IgA1 to total IgA1 ratio were not significantly different between IgAN patients and healthy subjects. Western blot analysis and gel filtration analysis using purified IgA1 also showed that the proportion of J chain-containing polymeric IgA1 was lower in IgAN patients compared to healthy subjects. No correlation was found between serum J-IgA or J-IgA1 and clinical features in IgAN. Immunohistochemistry analysis showed that glomerular J chain was positive in 12 IgAN patients (57.1%). The values of the J-IgA to IgA ratio and J-IgA1 to IgA ratio were significantly higher in IgAN patients with glomerular J chain deposition than those without. However, the serum levels of J-IgA and J-IgA1 and the J-IgA1 to IgA1 ratio were not significantly higher in two subgroups. Conclusions. Although serum levels of total IgA1 were elevated in IgAN, the serum levels of J-IgA1 were not elevated. And serum J-IgA, serum J-IgA1, and J chain deposition were not correlated with disease severity in IgAN.
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Irabu, Hitoshi, Masaki Shimizu, Shuya Kaneko, Natsumi Inoue, Mao Mizuta, Kazuhide Ohta, and Akihiro Yachie. "Clinical Significance of Serum Galactose-Deficient IgA1 Level in Children with IgA Nephropathy." Journal of Immunology Research 2020 (May 21, 2020): 1–10. http://dx.doi.org/10.1155/2020/4284379.
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This study was aimed at investigating the clinical significance of serum galactose-deficient IgA1 (Gd-IgA1) levels measured by a novel lectin-independent enzyme-linked immunosorbent assay (ELISA) using an anti-Gd-IgA1 monoclonal antibody (KM55) as a disease-specific biomarker for IgA nephropathy (IgAN) in children. Thirty-three children with IgAN, 40 with non-IgA glomerular diseases, and 38 age-matched healthy controls (HCs) were enrolled. Serum Gd-IgA1 levels were quantified by ELISA using KM55. Results were statistically compared with clinical features and pathological findings of IgAN. Serum Gd-IgA1 levels were significantly elevated in children with IgAN compared with children with non-IgA glomerular diseases and HCs. Serum Gd-IgA1 levels in children with IgAN were positively correlated with serum total IgA levels. However, the serum Gd-IgA1/total IgA ratio (Gd-IgA1/IgA) was also significantly elevated in children with IgAN. Serum Gd-IgA1 levels in children with IgAN increased in an age-dependent manner. The cutoff value of serum Gd-IgA1 levels for differentiating IgAN from non-IgA glomerular diseases was 3236 in children<12 years and 5284 in children≥12 years, respectively. In contrast, serum Gd-IgA1/IgA was age-independent. The cutoff value of serum Gd-IgA1/IgA for differentiating IgAN from non-IgA glomerular diseases was 0.2401. Serum Gd-IgA1 levels were negatively correlated with eGFR and positively correlated with mesangial IgA deposition. In contrast, serum Gd-IgA1/IgA levels were not correlated with any clinical parameters of IgAN. In conclusion, serum Gd-IgA1 levels were significantly elevated in children with IgAN. However, those levels were age-dependent; therefore, serum Gd-IgA1 levels classified by age and/or serum Gd-IgA1/IgA might have diagnostic values in children with IgAN.
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Rifai, Abdalla, Kim Fadden, Sherie L. Morrison, and Koteswara R. Chintalacharuvu. "The N-Glycans Determine the Differential Blood Clearance and Hepatic Uptake of Human Immunoglobulin (Ig)a1 and Iga2 Isotypes." Journal of Experimental Medicine 191, no. 12 (June 19, 2000): 2171–82. http://dx.doi.org/10.1084/jem.191.12.2171.
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Human immunoglobulin (Ig)A exists in blood as two isotypes, IgA1 and IgA2, with IgA2 present as three allotypes: IgA2m(1), IgA2m(2), and IgA2m(n). We now demonstrate that recombinant, chimeric IgA1 and IgA2 differ in their pharmacokinetic properties. The major pathway for the clearance of all IgA2 allotypes is the liver. Liver-mediated uptake is through the asialoglycoprotein receptor (ASGR), since clearance can be blocked by injection of excess galactose-Ficoll ligand and suppressed in ASGR-deficient mice. In contrast, only a small percentage of IgA1 is cleared through this pathway. The clearance of IgA1 lacking the hinge region with its associated O-linked carbohydrate was more rapid than that of wild-type IgA1. IgA1 and IgA2 that are not rapidly eliminated by the ASGR are both removed through an undefined ASGR-independent pathway with half-lives of 14 and 10 h, respectively. The rapid clearance of IgA2 but not IgA1 through the liver may in part explain why the serum levels of IgA1 are greater than those of IgA2. In addition, dysfunction of the ASGR or altered N-linked glycosylation, but not O-glycans, that affects recognition by this receptor may account for the elevated serum IgA seen in liver disease and IgA nephropathy.
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Noailly, Blandine, Melyssa Yaugel-Novoa, Justine Werquin, Fabienne Jospin, Daniel Drocourt, Thomas Bourlet, Nicolas Rochereau, and Stéphane Paul. "Antiviral Activities of HIV-1-Specific Human Broadly Neutralizing Antibodies Are Isotype-Dependent." Vaccines 10, no. 6 (June 6, 2022): 903. http://dx.doi.org/10.3390/vaccines10060903.
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Broadly neutralizing antibodies (bNAbs) offer promising opportunities for preventing HIV-1 infection. The protection mechanisms of bNAbs involve the Fc domain, as well as their Fab counterpart. Here, different bNAb isotypes including IgG1, IgA1, IgA2, and IgA122 (IgA2 with the hinge of IgA1) were generated and then produced in CHO cells. Their ability to neutralize pseudovirus and primary HIV-1 isolates were measured, as well as their potential ADCC-like activity using a newly developed assay. In our work, gp41-specific IgA seems to be more efficient than IgG1 in inducing ADCC-like activity, but not in its virus neutralization effect. We show that either gp120-specific IgA or IgG1 isotypes are both efficient in neutralizing different viral strains. In contrast, gp120-specific IgG1 was a better ADCC-like inducer than IgA isotypes. These results provide new insights into the neutralization and ADCC-like activity of different bNAbs that might be taken into consideration when searching for new treatments or antibody-based vaccines.
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Jones, C. L., C. S. Hosking, P. Kincaid-Smith, H. R. Powell, S. C. Richardson, F. H. Sennhauser, and D. M. Roberton. "Antibodies to polyclonal IgA, IgA1, and IgA2 and isotype-specific immune complexes in IgA nephropathy." Journal of Clinical Immunology 9, no. 4 (July 1989): 306–12. http://dx.doi.org/10.1007/bf00918662.
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Arnold, Marie-Luise, Ulrike Steffen, Michael Wiesener, Christian Bach, Bernd M. Spriewald, and Monika Lindemann. "Correlation of Anti-HLA IgA Alloantibodies and Fc Receptor Motives with Kidney Allograft Survival." Immuno 2, no. 2 (April 29, 2022): 372–86. http://dx.doi.org/10.3390/immuno2020023.
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Immunoglobulin A (IgA) is the most abundant antibody isotype in humans and anti-HLA IgA was found in sera of transplant recipients. Focusing on patients awaiting kidney re-transplantation, we tested the impact of anti-HLA-class I/II IgA antibodies on graft survival. We analyzed 276 patients with and 238 without allograft failure. Eight motives of the Fcα receptor (FCAR) and Fcγ receptor were analyzed in patients with allograft failure. The distribution of anti-HLA IgA1/A2 and IgG antibodies differed significantly (p < 0.0001) between both patient groups, and IgA1 plus IgA2 antibodies were more abundant in patients with allograft failure. Allograft survival was significantly impaired if anti-HLA-class I plus II IgA was present, in the first 105 months (9 years) of follow-up (median of 43 vs. >105 months, p = 0.007). Patients with anti-HLA IgA and IgG vs. anti-HLA IgG only had a significantly shorter allograft survival within that follow-up period (88 vs. >105 months, p = 0.008). Moreover, allograft survival was shorter (p = 0.02) in carriers of GG vs. AA + AG genotypes of FCAR rs16986050. Thus, the presence of anti-HLA IgA plus IgG vs. IgG only was associated with shorter kidney allograft survival and FCAR motives may impact on graft survival.
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Dechant, Michael, Gestur Vidarsson, Bernhard Stockmeyer, Roland Repp, Martin J. Glennie, Martin Gramatzki, Jan G. J. van de Winkel, and Thomas Valerius. "Chimeric IgA antibodies against HLA class II effectively trigger lymphoma cell killing." Blood 100, no. 13 (December 15, 2002): 4574–80. http://dx.doi.org/10.1182/blood-2002-03-0687.
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Antibodies against human leukocyte antigen (HLA) class II, such as 1D10 or Lym-1, are currently being evaluated for the treatment of B-cell lymphomas. Previous studies have demonstrated that, in addition to IgG Fc receptors, the human myeloid IgA receptor (FcαRI, CD89) also effectively triggered tumor cell killing. Therefore, we used the variable light and heavy chain sequences from another murine anti–HLA class II hybridoma, F3.3, to generate a panel of chimeric human/mouse antibodies, including human immunoglobulin A1 (IgA1), IgA2, IgG1, IgG2, IgG3, and IgG4. Antibody production was accomplished by stable transfection of baby hamster kidney cells, and binding activity and specificity were confirmed by enzyme-linked immunosorbent assay (ELISA) and Western blotting. All constructs demonstrated similar binding to HLA class II. Functional studies revealed that chimeric IgG1, IgA1, and IgA2 triggered similar levels of tumor cell lysis. Analyses of effector populations, however, demonstrated that killing by chimeric IgG1 constructs was triggered mainly by human mononuclear cells and complement, while IgA1 and IgA2 mediated effective lysis by polymorphonuclear neutrophils. Importantly, IgG1 and both IgA isotypes were equally effective at killing freshly isolated human chronic lymphocytic leukemia cells. Chimeric IgA antibodies against HLA class II may constitute attractive reagents for lymphoma therapy.
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Sofue, Tadashi, Hideyo Oguchi, Masahiko Yazawa, Makoto Tsujita, Kenta Futamura, Morikuni Nishihira, Mariko Toyoda, Toshiki Kano, and Hitoshi Suzuki. "Serological and histopathological assessment of galactose-deficient immunoglobulin A1 deposition in kidney allografts: A multicenter prospective observational study." PLOS ONE 18, no. 2 (February 16, 2023): e0281945. http://dx.doi.org/10.1371/journal.pone.0281945.
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Background Recurrent immunoglobulin A (IgA) nephropathy is an important risk factor for kidney allograft loss. However, there is no classification system for IgA deposition in kidney allografts based on serological and histopathological evaluation of galactose-deficient IgA1 (Gd-IgA1). This study aimed to establish a classification system for IgA deposition in kidney allografts based on serological and histological evaluation of Gd-IgA1. Methods This multicenter prospective study included 106 adult kidney transplant recipients in whom an allograft biopsy was performed. Serum and urinary Gd-IgA1 levels were investigated in 46 transplant recipients who were IgA-positive and classified into four subgroups according to the presence or absence of mesangial Gd-IgA1 (KM55 antibody) deposits and C3. Results Minor histological changes without an acute lesion were observed in recipients with IgA deposition. Fourteen (30%) of the 46 IgA-positive recipients were KM55-positive and 18 (39%) were C3-positive. The C3 positivity rate was higher in the KM55-positive group. Serum and urinary Gd-IgA1 levels were significantly higher in KM55-positive/C3-positive recipients than in the other three groups with IgA deposition. Disappearance of IgA deposits was confirmed in 10 of 15 IgA-positive recipients in whom a further allograft biopsy was performed. The serum Gd-IgA1 level at the time of enrollment was significantly higher in recipients in whom IgA deposition continued than in those in whom it disappeared (p = 0.02). Conclusions The population with IgA deposition after kidney transplantation is serologically and pathologically heterogeneous. Serological and histological assessment of Gd-IgA1 is useful for identifying cases that should be carefully observed.
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Puligedda, Rama Devudu, Vladimir Vigdorovich, Diana Kouiavskaia, Chandana Devi Kattala, Jiang-yang Zhao, Fetweh H. Al-Saleem, Konstantin Chumakov, D. Noah Sather, and Scott K. Dessain. "Human IgA Monoclonal Antibodies That Neutralize Poliovirus, Produced by Hybridomas and Recombinant Expression." Antibodies 9, no. 1 (February 28, 2020): 5. http://dx.doi.org/10.3390/antib9010005.
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Poliovirus (PV)-specific intestinal IgAs are important for cessation of PV shedding in the gastrointestinal tract following an acute infection with wild type or vaccine-derived PV strains. We sought to produce IgA monoclonal antibodies (mAbs) with PV neutralizing activity. We first performed de novo IgA discovery from primary human B cells using a hybridoma method that allows assessment of mAb binding and expression on the hybridoma surface: On-Cell mAb Screening (OCMS™). Six IgA1 mAbs were cloned by this method; three potently neutralized type 3 Sabin and wt PV strains. The hybridoma mAbs were heterogeneous, expressed in monomeric, dimeric, and aberrant forms. We also used recombinant methods to convert two high-potency anti-PV IgG mAbs into dimeric IgA1 and IgA2 mAbs. Isotype switching did not substantially change their neutralization activities. To purify the recombinant mAbs, Protein L binding was used, and one of the mAbs required a single amino acid substitution in its κ LC in order to enable protein L binding. Lastly, we used OCMS to assess IgA expression on the surface of hybridomas and transiently transfected, adherent cells. These studies have generated potent anti-PV IgA mAbs, for use in animal models, as well as additional tools for the discovery and production of human IgA mAbs.
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Hastings, M. Colleen, Sabahat Afshan, John T. Sanders, Oulimata Kane, T. Matthew Eison, Keith K. Lau, Zina Moldoveanu, Bruce A. Julian, Jan Novak, and Robert J. Wyatt. "Serum Galactose-Deficient IgA1 Level Is Not Associated with Proteinuria in Children with IgA Nephropathy." International Journal of Nephrology 2012 (2012): 1–7. http://dx.doi.org/10.1155/2012/315467.
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Introduction. Percentage of galactose-deficient IgA1 (Gd-IgA1) relative to total IgA in serum was recently reported to correlate with proteinuria at time of sampling and during follow-up for pediatric and adult patients with IgA nephropathy. We sought to determine whether this association exists in another cohort of pediatric patients with IgA nephropathy.Methods. Subjects were younger than 18 years at entry. Blood samples were collected on one or more occasions for determination of serum total IgA and Gd-IgA1. Gd-IgA1 was expressed as serum level and percent of total IgA. Urinary protein/creatinine ratio was calculated for random specimens. Spearman’s correlation coefficients assessed the relationship between study variables.Results. The cohort had 29 Caucasians and 11 African-Americans with a male : female ratio of 1.9 : 1. Mean age at diagnosis was 11.7 ± 3.7 years. No statistically significant correlation was identified between serum total IgA, Gd-IgA1, or percent Gd-IgA1 versus urinary protein/creatinine ratio determined contemporaneously with biopsy or between average serum Gd-IgA1 or average percent Gd-IgA1 and time-average urinary protein/creatinine ratio.Conclusion. The magnitude of proteinuria in this cohort of pediatric patients with IgA nephropathy was influenced by factors other than Gd-IgA1 level, consistent with the proposed multi-hit pathogenetic pathways for this renal disease.
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Zhao, Yuhong, Youngki Kim, Milind Junghare, Viral Vakil, Xuesong Su, Faqian Li, and Lihong Bu. "Galactose-Deficient IgA1 Deposits in Clear Cell Renal Cell Carcinoma-Related Henoch–Schönlein Purpura Nephritis." Case Reports in Nephrology 2020 (August 24, 2020): 1–7. http://dx.doi.org/10.1155/2020/8828336.
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Recent studies suggest that galactose-deficient IgA1 (Gd-IgA1) plays a role in the pathogenesis of primary IgA nephropathy (IgAN) and Henoch–Schönlein purpura nephritis (HSPN). Furthermore, immunostaining of KM55, an antibody that identifies Gd-IgA1, may be helpful to differentiate primary IgAN and HSPN from secondary causes of glomerular IgA deposition. We report sequential kidney biopsies of a malignancy-associated HSPN, showing intense glomerular mesangial IgA deposition at the initial kidney biopsy and dramatic decrease in disappearance of glomerular deposits after tumor removal. We demonstrate that the glomerular IgA deposition contains Gd-IgA1, detected by immunostaining of KM55, with similar distribution and intensity to IgA. This suggests that renal Gd-IgA1 deposition may play a role in the pathogenesis of malignancy-associated HSPN.
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Lue, C., A. Tarkowski, and J. Mestecky. "Systemic immunization with pneumococcal polysaccharide vaccine induces a predominant IgA2 response of peripheral blood lymphocytes and increases of both serum and secretory anti-pneumococcal antibodies." Journal of Immunology 140, no. 11 (June 1, 1988): 3793–800. http://dx.doi.org/10.4049/jimmunol.140.11.3793.
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Abstract Ig class-, and IgA and IgG subclass-specific immune responses to a 23 valent pneumococcal polysaccharide vaccine were studied at a single-cell level in the peripheral blood of systemically immunized adults. With a solid phase enzyme-linked immunospot (ELISPOT) assay, PBMC from immunized individuals were assayed for spontaneous Ag-specific antibody (Ab) production before, and on days 7, 14, and 28 after vaccination. On the day of immunization, no spontaneous Ag-specific Ab-secreting cells could be detected. On day 7 after vaccination, a high frequency of cells secreting Ab specific for pneumococcal polysaccharides (PPS) was observed. The IgA class comprised 79% (geometric mean) of the Ag-specific Ab-secreting cells, whereas IgG- and IgM-secreting cells accounted for 12% and 9%, respectively. The majority of Ag-specific IgA-secreting cells produced Ab of the IgA2 isotype. Serum, saliva, and tears collected before and on days 7, 14, and 28 after vaccination were assayed for specific Ab to the vaccine (anti-PPS Ab) by an ELISA. Serum IgA anti-PPS Ab showed the highest increase after vaccination with a 19-fold increase (geometric mean) which peaked on day 14. However, the ratio of Ag-specific polymeric vs monomeric IgA did not change after immunization. Serum IgG and IgM anti-PPS Ab displayed mean increases of 5.5-fold and 5.6-fold, respectively, on day 14. The most pronounced increase of salivary anti-PPS Ab was observed in the IgG class (4.5-fold on day 28) followed by IgM (4-fold on day 28), IgA (2.0-fold on day 14), IgA1 (2.4-fold on day 14) and IgA2 (2.0-fold on day 14). The levels of total IgA, IgG, and IgM in saliva did not change significantly throughout the course of immunization. IgG and IgM anti-PPS Ab levels in tears increased less than in saliva, whereas IgA behaved similarly as in saliva. There were no significant differences in the Ag-specific increase rates between the IgA, IgG, and IgM isotypes in tears.
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Dann, Sara M., Pablo C. Okhuysen, Bassam M. Salameh, Herbert L. DuPont, and Cynthia L. Chappell. "Fecal Antibodies to Cryptosporidium parvum in Healthy Volunteers." Infection and Immunity 68, no. 9 (September 1, 2000): 5068–74. http://dx.doi.org/10.1128/iai.68.9.5068-5074.2000.
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ABSTRACT This study examined the intestinal antibody response in 26 healthy volunteers challenged with Cryptosporidium parvum oocysts. Fecal extracts were assayed for total secretory immunoglobulin A (IgA) and C. parvum-specific IgA reactivity. Specific IgA reactivity was standardized to IgA concentration and expressed as a reactivity index (RI). Anti-C. parvum fecal IgA (fIgA) increased significantly in 17 of 26 (65.4%) following oocyst ingestion. Of those with detectable responses, 59, 76.5, and 94.1% were positive by days 7, 14, and 30, respectively. Volunteers receiving high challenge doses (>1,000 and 300 to 500 oocysts) had higher RIs (RI = 5.57 [P = 0.027] and RI = 1.68 [P = 0.039], respectively) than those ingesting low doses (30 to 100 oocysts; RI = 0.146). Subjects shedding oocysts and experiencing a diarrheal illness had the highest fIgA reactivity. When evaluated separately, oocyst excretion was associated with an increased fIgA response compared to nonshedders (RI = 1.679 versus 0.024, respectively; P = 0.003). However, in subjects experiencing diarrhea with or without oocyst shedding, a trend toward a higher RI (P = 0.065) was seen. Extracts positive for fecal IgA were further examined for IgA subclass. The majority of stools contained both IgA1 and IgA2, and the relative proportions did not change following challenge. Also, no C. parvum-specific IgM or IgG was detected in fecal extracts. Thus, fecal IgA to C. parvum antigens was highly associated with infection in subjects who had no evidence of previous exposure and may provide a useful tool in detecting recent infections.
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Monteiro, R. C., H. Kubagawa, and M. D. Cooper. "Cellular distribution, regulation, and biochemical nature of an Fc alpha receptor in humans." Journal of Experimental Medicine 171, no. 3 (March 1, 1990): 597–613. http://dx.doi.org/10.1084/jem.171.3.597.
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In these studies, we characterize an Fc receptor (FcR) for IgA that is present on human granulocytes, monocyte/macrophages, and their corresponding cell lines. Receptor expression appears to be constitutive but can be selectively upregulated on monocyte cell lines by stimulation with a phorbol ester and polymeric IgA. Both the induction requirements and ligand specificity of the IgA receptor differ from the IgG receptors, Fc gamma R I, II, and III, that are also expressed on monocytes and granulocytes. IgA binding to the cell surface receptor is mediated via the Fc alpha region. The Fc alpha R is a heterogenously charged, approximately 60-kD molecule with an isoelectric point of 4.5-5.6 that binds monomeric or polymeric IgA1 and IgA2 molecules. This transmembrane glycoprotein appears to be composed of 32- and 36-kD protein cores with multiple N-linked carbohydrate moieties. We conclude that this Fc alpha R represents a novel member of the FcR family that may have a distinctive role in host defense.
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Brown, W. R., I. Kacskovics, B. A. Amendt, N. B. Blackmore, M. Rothschild, R. Shinde, and J. E. Butler. "The hinge deletion allelic variant of porcine IgA results from a mutation at the splice acceptor site in the first C alpha intron." Journal of Immunology 154, no. 8 (April 15, 1995): 3836–42. http://dx.doi.org/10.4049/jimmunol.154.8.3836.
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Abstract Recently published genomic and cDNA sequences for porcine IgA suggested that the splice acceptor site in the C alpha 1-C alpha 2 intron was an AA rather than an AG dinucleotide. This possibility was tested in an in vitro HeLa cell splicing system using an RNA substrate corresponding to the genomic DNA with the putative AA splice site. Data indicated that splicing occurred at a cryptic AG site 12 nucleotides into the C alpha 2 domain rather than at the AA site. The possibility that swine B cells could use either site was tested by preparing the cDNAs from 13 different samples representing nine animals and amplifying the segment from the first C alpha 1 nucleotide to nucleotide 532 in C alpha 2 (genomic DNA numbering system). Analysis on a 6% polyacrylamide sequencing gel revealed two polynucleotide products in most samples that differed by the expected 12 nucleotides, suggesting that swine could use both splice sites. Sequence analysis confirmed that the shorter form was spliced at the downstream site and the larger form at the apparent upstream AA site. However, when the genomic DNA from an animal expressing only the longer polynucleotide was cloned and sequenced, the upstream splice acceptor site was AG not AA. Thus the data suggested that porcine IgA occurred in two allelic forms, designated IgAa and IgAb, which differ by an apparent G to A mutation in the last nucleotide of intron 1 resulting in a short-hinged (two amino acids, IgAb) variant, in which the downstream cryptic splice site is used, as well as a "normal-hinged" (six amino acids, IgAa) variant. Evidence that IgAa and IgAb are allelic was confirmed by genotypic analyses of progeny from matings of IgAa/IgAb heterozygotes. Evidence that both transcripts are functional was confirmed by showing that serum IgA levels were similar in animals homozygous for each variant.
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Klasen, Ina S., Joop H. C. Göertz, Gertrude A. S. van de Wiel, Corry M. R. Weemaes, Jos W. M. van der Meer, and Joost P. H. Drenth. "Hyper-Immunoglobulin A in the Hyperimmunoglobulinemia D Syndrome." Clinical Diagnostic Laboratory Immunology 8, no. 1 (January 1, 2001): 58–61. http://dx.doi.org/10.1128/cdli.8.1.58-61.2001.
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ABSTRACT The hyperimmunoglobulinemia D syndrome (HIDS) is an autosomal recessive disorder characterized by recurrent febrile attacks with abdominal, articular, and skin manifestations. Apart from elevated immunoglobulin D (IgD) levels (>100 IU/ml), there are high IgA levels in the majority of cases. Mutations in the gene encoding mevalonate kinase constitute the molecular defect in HIDS. The cause of elevated IgA concentrations in HIDS patients remains to be elucidated. We studied the hyper-IgA response in serum of a group of HIDS patients. Elevated IgA concentrations result from increased IgA1 concentrations. IgA and IgA1 concentrations correlated significantly with IgD concentrations, and levels of IgA polymers were significantly higher than the levels in healthy donors. These results indicate a continuous, presumably systemic, stimulation of IgA in HIDS patients.
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Chintalacharuvu, K. R., and S. L. Morrison. "Residues critical for H-L disulfide bond formation in human IgA1 and IgA2." Journal of Immunology 157, no. 8 (October 15, 1996): 3443–49. http://dx.doi.org/10.4049/jimmunol.157.8.3443.
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Abstract There are two subclasses of human IgA, IgA1 and IgA2. IgA2 exists as two known allotypes, IgA2 m(1) and IgA2 m(2) with a recently reported novel IgA2 (IgA2(n)) possibly representing a third allotype. The variants of human IgA differ in their H and L chain disulfide-bonding pattern; in IgA1, IgA2(n), and IgA2 m(2), a disulfide bond connects a cysteine residue in CH1 of the H chain with the L chains while human IgA2 m(1) has been reported to lack a covalent bond between the H and L chains. Here we have used site-directed mutagenesis to demonstrate that Cys133 is essential for the formation of the H-L disulfide bond in IgA1. However, IgA2 m(2) and the IgA2(n) but not IgA2 m(1) form an H-L disulfide in the absence of Cys133. IgA2 m(1) differs from IgA2 m(2) and the IgA2(n) at two positions in CH1; IgA2 m(1) has Pro212 and Pro221 whereas IgA2 m(2) and the IgA2(n) have Ser212 and Arg221. Our studies demonstrate that it is the presence of Pro221 in IgA2 m(1) that interferes with the H-L disulfide in the absence of Cys133. Contrary to what has been previously reported, protein purified from culture supernatants of IgA2 m(1) show some HL, H2L2, and H4L4J, suggesting that IgA2 m(1) can exist either as a form lacking H-L disulfide bonds or as a form with H-L disulfides.
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WAGA, SHINOBU, KAZUHIKO SUGIMOTO, HIROSHI TANAKA, TATSUO ITO, TOHRU NAKAHATA, TAKASHI TATEYAMA, YOSHIKI KAKIZAKI, and MASARU YOKOYAMA. "IgA Interaction with Carboxy-Terminal 43-kD Fragment of Fibronectin in IgA Nephropathy." Journal of the American Society of Nephrology 10, no. 2 (February 1999): 256–63. http://dx.doi.org/10.1681/asn.v102256.
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Abstract. IgA deposition in the glomerular mesangial matrix is a prerequisite for the diagnosis of IgA nephropathy, and circulating IgA-containing complex has been implicated in this process. Since fibronectin is known to be involved in the assembly of extracellular matrix, this study was conducted to investigate whether fibronectin and its fragments are present in sera of patients and are capable of binding IgA1. Sera from patients with IgA nephropathy were purified by heparin-affinity chromatography, and column eluate were analyzed for the presence of fibronectin using Western blot and a set of anti-fibronectin monoclonal antibodies. Native fibronectin was digested with cathepsin D to obtain fragments similar to those of serum fibronectin. The capacity of fibronectin to bind IgA was examined with a mixture of purified IgA1 and cathepsin D-digested fibronectin fragments. A 43-kD carboxy-terminal fragment of fibronectin was detected in samples derived from sera of patients with IgA nephropathy but not in healthy control subjects. A similar-sized fragment was generated by cathepsin D digestion of the native molecule and was shown to bind to IgA1 in vitro. Since the carboxy-terminal domain is known to be critical in assembling exogenous fibronectin into the extracellular matrix, the affinity to IgA1 to a fragment found in patients may have pathogenic potential to mediate extracellular IgA deposition in IgA nephropathy.
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Islam, K. B., B. Baskin, L. Nilsson, L. Hammarström, P. Sideras, and C. I. Smith. "Molecular analysis of IgA deficiency. Evidence for impaired switching to IgA." Journal of Immunology 152, no. 3 (February 1, 1994): 1442–52. http://dx.doi.org/10.4049/jimmunol.152.3.1442.
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Abstract The most common form of primary immunodeficiency is IgA deficiency (IgAD). However, the molecular basis of this disease remains elusive. Therefore, to address this issue we made a systematic analysis of the molecular events leading to IgA production. B lymphocytes that produce IgA have undergone somatic rearrangement that joins the switch (S) mu to S alpha region with deletion of the intervening sequences. Examination of the resulting S mu/S alpha junctions in unstimulated PBMC from IgAD patients by nested primer PCR revealed a significant decrease in the number of the S mu/S alpha fragments. To obtain the antisense primers to generate the S mu/S alpha fragments, we sequenced the human S alpha 1 and the downstream region extending to the C alpha 1 locus. Similar to previously reported switch sequences, we also found the S alpha 1 to be predominantly composed of pentameric repeats GAGCT and GGGCT. The decrease in the number of S mu/S alpha fragments is consistent with a profound decrease in the C alpha membrane mRNA expression in unstimulated PBMC, as well as in the C alpha mRNA levels and IgA production in PWM-stimulated PBMC. Sequence analysis of the switch junctions from IgA-producing cell lines, control donors, and an IgAD patient showed direct joining in 8 of 9 cases examined. TGF-beta 1, previously shown to be the switch factor for human and mouse IgA, was also examined. No difference in the TGF-beta 1 mRNA levels in unstimulated PBMC between the control subjects and the IgAD patients were detected. Our findings indicate that the failure to switch to IgA-producing B lymphocytes, or an impaired survival of such cells, may be an important molecular mechanism in IgAD.
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Knoppova, Barbora, Colin Reily, R. Glenn King, Bruce A. Julian, Jan Novak, and Todd J. Green. "Pathogenesis of IgA Nephropathy: Current Understanding and Implications for Development of Disease-Specific Treatment." Journal of Clinical Medicine 10, no. 19 (September 29, 2021): 4501. http://dx.doi.org/10.3390/jcm10194501.
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IgA nephropathy, initially described in 1968 as a kidney disease with glomerular “intercapillary deposits of IgA-IgG”, has no disease-specific treatment and is a common cause of kidney failure. Clinical observations and laboratory analyses suggest that IgA nephropathy is an autoimmune disease wherein the kidneys are damaged as innocent bystanders due to deposition of IgA1-IgG immune complexes from the circulation. A multi-hit hypothesis for the pathogenesis of IgA nephropathy describes four sequential steps in disease development. Specifically, patients with IgA nephropathy have elevated circulating levels of IgA1 with some O-glycans deficient in galactose (galactose-deficient IgA1) and these IgA1 glycoforms are recognized as autoantigens by unique IgG autoantibodies, resulting in formation of circulating immune complexes, some of which deposit in glomeruli and activate mesangial cells to induce kidney injury. This proposed mechanism is supported by observations that (i) glomerular immunodeposits in patients with IgA nephropathy are enriched for galactose-deficient IgA1 glycoforms and the corresponding IgG autoantibodies; (ii) circulatory levels of galactose-deficient IgA1 and IgG autoantibodies predict disease progression; and (iii) pathogenic potential of galactose-deficient IgA1 and IgG autoantibodies was demonstrated in vivo. Thus, a better understanding of the structure–function of these immunoglobulins as autoantibodies and autoantigens will enable development of disease-specific treatments.
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Wehbi, Batoul, Christelle Oblet, François Boyer, Arnaud Huard, Anne Druilhe, François Paraf, Etienne Cogné, et al. "Mesangial Deposition Can Strongly Involve Innate-Like IgA Molecules Lacking Affinity Maturation." Journal of the American Society of Nephrology 30, no. 7 (June 21, 2019): 1238–49. http://dx.doi.org/10.1681/asn.2018111089.
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BackgroundIgA nephropathy (IgAN) often follows infections and features IgA mesangial deposition. Polymeric IgA deposits in the mesangium seem to have varied pathogenic potential, but understanding their pathogenicity remains a challenge. Most mesangial IgA1 in human IgAN has a hypogalactosylated hinge region, but it is unclear whether this is required for IgA deposition. Another important question is the role of adaptive IgA responses and high-affinity mature IgA antibodies and whether low-affinity IgA produced by innate-like B cells might also yield mesangial deposits.MethodsTo explore the effects of specific qualitative variations in IgA and whether altered affinity maturation can influence IgA mesangial deposition and activate complement, we used several transgenic human IgA1-producing models with IgA deposition, including one lacking the DNA-editing enzyme activation-induced cytidine deaminase (AID), which is required in affinity maturation. Also, to explore the potential role of the IgA receptor CD89 in glomerular inflammation, we used a model that expresses CD89 in a pattern observed in humans.ResultsWe found that human IgA induced glomerular damage independent of CD89. When comparing mice able to produce high-affinity IgA antibodies with mice lacking AID-enabled Ig affinity maturation, we found that IgA deposition and complement activation significantly increased and led to IgAN pathogenesis, although without significant proteinuria or hematuria. We also observed that hinge hypoglycosylation was not mandatory for IgA deposition.ConclusionsIn a mouse model of IgAN, compared with high-affinity IgA, low-affinity innate-like IgA, formed in the absence of normal antigen-driven maturation, was more readily involved in IgA glomerular deposition with pathogenic effects.
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Berthelot, Laureline, Christina Papista, Thiago T. Maciel, Martine Biarnes-Pelicot, Emilie Tissandie, Pamela H. M. Wang, Houda Tamouza, et al. "Transglutaminase is essential for IgA nephropathy development acting through IgA receptors." Journal of Experimental Medicine 209, no. 4 (March 26, 2012): 793–806. http://dx.doi.org/10.1084/jem.20112005.
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IgA nephropathy (IgAN) is a common cause of renal failure worldwide. Treatment is limited because of a complex pathogenesis, including unknown factors favoring IgA1 deposition in the glomerular mesangium. IgA receptor abnormalities are implicated, including circulating IgA–soluble CD89 (sCD89) complexes and overexpression of the mesangial IgA1 receptor, TfR1 (transferrin receptor 1). Herein, we show that although mice expressing both human IgA1 and CD89 displayed circulating and mesangial deposits of IgA1–sCD89 complexes resulting in kidney inflammation, hematuria, and proteinuria, mice expressing IgA1 only displayed endocapillary IgA1 deposition but neither mesangial injury nor kidney dysfunction. sCD89 injection into IgA1-expressing mouse recipients induced mesangial IgA1 deposits. sCD89 was also detected in patient and mouse mesangium. IgA1 deposition involved a direct binding of sCD89 to mesangial TfR1 resulting in TfR1 up-regulation. sCD89–TfR1 interaction induced mesangial surface expression of TGase2 (transglutaminase 2), which in turn up-regulated TfR1 expression. In the absence of TGase2, IgA1–sCD89 deposits were dramatically impaired. These data reveal a cooperation between IgA1, sCD89, TfR1, and TGase2 on mesangial cells needed for disease development. They demonstrate that TGase2 is responsible for a pathogenic amplification loop facilitating IgA1–sCD89 deposition and mesangial cell activation, thus identifying TGase2 as a target for therapeutic intervention in this disease.
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van den Wall Bake, A. W. L. "Increased percentage of IgA and IgA1 plasma cells in IgA nephropathy." American Journal of Kidney Diseases 26, no. 1 (July 1995): 266. http://dx.doi.org/10.1016/0272-6386(95)90183-3.
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Wang, Yan-Na, Xu-Jie Zhou, Pei Chen, Gui-Zhen Yu, Xue Zhang, Ping Hou, Li-Jun Liu, Su-Fang Shi, Ji-Cheng Lv, and Hong Zhang. "Interaction between GALNT12 and C1GALT1 Associates with Galactose-Deficient IgA1 and IgA Nephropathy." Journal of the American Society of Nephrology 32, no. 3 (February 16, 2021): 545–52. http://dx.doi.org/10.1681/asn.2020060823.
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BackgroundGalactose-deficient IgA1 plays a key role in the pathogenesis of IgA nephropathy, the most common primary GN worldwide. Although serum levels of galactose-deficient IgA1 have a strong genetic component, the genetic link between this molecule and IgA nephropathy has not yet been clearly established.MethodsTo identify novel loci associated with galactose-deficient IgA1, we performed a quantitative genome-wide association study for serum galactose-deficient IgA1 levels, on the basis of two different genome-wide association study panels conducted in 1127 patients with IgA nephropathy. To test genetic associations with susceptibility to IgA nephropathy, we also enrolled 2352 patients with biopsy-diagnosed IgA nephropathy and 2632 healthy controls. Peripheral blood samples from 59 patients and 27 healthy controls were also collected for gene expression analysis.ResultsWe discovered two loci, in C1GALT1 and GALNT12, that achieved genome-wide significance, explaining about 3.7% and 3.4% of variance in serum galactose-deficient IgA1 levels, respectively. We confirmed the previously reported association of C1GALT1 with serum galactose-deficient IgA1 levels, but with a different lead single-nucleotide polymorphism (rs10238682; β=0.26, P=1.20×10−9); the locus we identified at GALNT12 (rs7856182; β=0.73, P=2.38×10−9) was novel. Of more interest, we found that GALNT12 exhibits genetic interactions with C1GALT1 in both galactose-deficient IgA1 levels (P=1.40×10−2) and disease risk (P=6.55×10−3). GALNT12 mRNA expression in patients with IgA nephropathy was significantly lower compared with healthy controls.ConclusionsOur data identify GALNT12 as a novel gene associated with galactose-deficient IgA1 and suggest novel genetic interactions. These findings support a key role of genetically conferred dysregulation of galactose-deficient IgA1 in the development of IgA nephropathy.
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Tanaka, Mototsugu, George Seki, Tomonosuke Someya, Michio Nagata, and Toshiro Fujita. "Aberrantly Glycosylated IgA1 as a Factor in the Pathogenesis of IgA Nephropathy." Clinical and Developmental Immunology 2011 (2011): 1–7. http://dx.doi.org/10.1155/2011/470803.
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Predominant or codominant immunoglobulin (Ig) A deposition in the glomerular mesangium characterizes IgA nephropathy (IgAN). Accumulated glomerular IgA is limited to the IgA1 subclass and usually galactose-deficient. This underglycosylated IgA may play an important role in the pathogenesis of IgAN. Recently, antibodies against galactose-deficient IgA1 were found to be well associated with the development of IgAN. Several therapeutic strategies based on corticosteroids or other immunosuppressive agents have been shown to at least partially suppress the progression of IgAN. On the other hand, several case reports of kidney transplantation or acquired IgA deficiency uncovered a remarkable ability of human kidney to remove mesangial IgA deposition, resulting in the long-term stabilization of kidney function. Continuous exposure to circulating immune complexes containing aberrantly glycosylated IgA1 and sequential immune response seems to be essential in the disease progression of IgAN. Removal of mesangial IgA deposition may be a challenging, but fundamental approach in the treatment of IgAN.
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Fujiyama, Y., K. Kobayashi, S. Senda, Y. Benno, T. Bamba, and S. Hosoda. "A novel IgA protease from Clostridium sp. capable of cleaving IgA1 and IgA2 A2m(1) but not IgA2 A2m(2) allotype paraproteins." Journal of Immunology 134, no. 1 (January 1, 1985): 573–76. http://dx.doi.org/10.4049/jimmunol.134.1.573.
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Abstract Three bacterial strains of Bifidobacterium and Clostridium sp. from patients with inflammatory bowel disease (I.B.D.) and Streptococcus pneumoniae from a patient with pneumonia were identified to produce extracellular proteases cleaving IgA into Fab and Fc fragments. Although the proteases from the Bifidobacterium and the Streptococcus pneumoniae showed the characteristics of typical IgA1 proteases, cleaving the IgA of only the IgA1 subclass, the protease from Clostridium sp. revealed a dual substrate specificity, in that it cleaved both IgA1 and IgA2 of the A2m(1) allotype. The latter protease, however, did not show any activity with respect to the IgA2 of the A2m(2) allotype. Fc fragments isolated from the IgA1 and the IgA2 A2m(1) by digestion with the Clostridium sp. protease were identified to have an identical amino terminal residue of valine. The site of cleavage in both the alpha 1 and the alpha 2 of A2m(1) by the protease was assumed to be an identical peptide bond at Pro(221)-Val(222), which is a common one present just before the hinge of both the alpha 1 and the alpha 2 of the A2m(1) but not of the alpha 2 of the A2m(2). The protease was sensitive to ethylene-diamino tetraacetic acid, a chelating agent, similar to other already reported IgA1 proteases.
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Marro, Julien, Andrew J. Chetwynd, Samuel Edwards, Rachael D. Wright, and Louise Oni. "Increased Urinary IgA in Paediatric IgA Vasculitis Nephritis." International Journal of Molecular Sciences 23, no. 23 (November 22, 2022): 14548. http://dx.doi.org/10.3390/ijms232314548.
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IgA vasculitis (IgAV) is the most common form of paediatric vasculitis, with up to 50% of patients experiencing kidney inflammation. Much remains unknown about IgAV, but it is believed to arise due to galactose-deficient IgA1 promoting an auto-inflammatory response. This study assesses whether urinary IgA can be detected in children with IgAV to allow further evaluation of IgA1 and whether it has any relationship with nephritis. Urinary and serum IgA concentrations were measured using commercially available ELISA kits. Patients were grouped into IgAV nephritis (IgAVN) or IgAV without nephritis (IgAVwoN). Fifty-nine children were included: IgAVN n = 12, IgAVwoN n = 35, and healthy controls (HC) n = 12, with a mean age of 8.2 ± 4.1 years. Urinary IgA concentrations were statistically significantly higher in patients with IgAV (107.1 ± 136.3 μg/mmol) compared to HC (50.6 ± 26.3 μg/mmol; p = 0.027) and IgAVN (229.8 ± 226.3 μg/mmol) compared to both IgAVwoN (65.0 ± 37.8 μg/mmol; p = 0.002) and HC (p < 0.001). Urinary IgA concentrations were able to distinguish between renal status (AUC 0.838, 95%CI [0.704–0.973], p < 0.001) and did not correlate with proteinuria (r = 0.124; p = 0.407). Urinary IgA concentrations are increased in children with IgAVN, and it has the potential to act as a non-invasive biofluid to further evaluate nephritis in this disease.
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Silvain, C., C. Patry, P. Launay, A. Lehuen, and R. C. Monteiro. "Altered expression of monocyte IgA Fc receptors is associated with defective endocytosis in patients with alcoholic cirrhosis. Potential role for IFN-gamma." Journal of Immunology 155, no. 3 (August 1, 1995): 1606–18. http://dx.doi.org/10.4049/jimmunol.155.3.1606.
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Abstract Expression, saturation, and endocytosis of IgA Fc receptors (Fc alpha R) were analyzed in blood phagocytic cells of patients with alcoholic liver cirrhosis (ALC). Surface Fc alpha R expression was decreased in monocytes but not in neutrophils, as evaluated by IgA binding and anti-Fc alpha R mAb. The Fc alpha R of ALC patients were saturated by IgA1 and IgA2. ALC Fc alpha R had a higher M(r) (60 to 90 kDa) than those of controls (55 to 75 kDa) with a similar 32-kDa protein core after N-glycanase treatment, suggesting the expression of Fc alpha R molecules with altered carbohydrate moieties. Treatment of U937 cells with IFN-gamma induced a decrease of surface Fc alpha R expression in a dose-dependent manner, with a similar M(r) as observed for ALC patient Fc alpha R (60 to 90 kDa). Fc alpha R endocytosis was induced by anti-Fc alpha R or IgA. Neutrophils internalized Fc alpha R molecules faster than did monocytes. Endocytosed Fc alpha R co-localized with cathepsin D, suggesting an endolysosomal compartment pathway. In ALC monocytes, Fc alpha R endocytosis was defective, with nearly 50 to 60% of receptors detected on the cell surface even after 90 min at 37 degrees C. Similarly, delayed Fc alpha R endocytosis was observed on IFN-gamma-treated U937 cells as compared with PMA-activated cells. Defective internalization of surface-bound IgA with reflux of IgA to cell surface was also observed on ALC monocytes, but not on normal cells preincubated with patients' plasma, ruling out direct effects of IgA. The inverse correlation between monocyte Fc alpha R levels and serum IgA levels associated with defective endocytosis suggest that altered Fc alpha R expression might contribute to receptor saturation and generation of increased plasma levels of IgA and IgA-immune complexes in ALC patients.
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Zhang, Q., S. Choo, J. Everard, R. Jennings, and A. Finn. "Mucosal Immune Responses to Meningococcal Group C Conjugate and Group A and C Polysaccharide Vaccines in Adolescents." Infection and Immunity 68, no. 5 (May 1, 2000): 2692–97. http://dx.doi.org/10.1128/iai.68.5.2692-2697.2000.
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ABSTRACT Previous studies in children have shown that Haemophilus influenzae type b (Hib) polysaccharide conjugate vaccines can reduce nasopharyngeal carriage of H. influenzae and provide herd immunity and suggest that this effect is mediated through mucosal antibodies. As this phenomenon may operate in other invasive bacterial infections which are propagated by nasopharyngeal carriage, mucosal antibody responses to meningococcal C conjugate and A/C polysaccharide vaccines were investigated. A total of 106 school children aged 11 to 17 years were randomized to receive a single dose of either conjugate or polysaccharide vaccine in an observer-blind study. Before and at 1, 6, and 12 months after immunization, samples of unstimulated saliva were collected and assayed by enzyme-linked immunosorbent assay for group C polysaccharide-specific immunoglobulin A (IgA), IgA1, IgA2 and secretory component, IgG antibodies, and total IgG and IgA. A subset of serum samples were also assayed for specific IgA and IgG antibodies. The concentrations of specific IgA and IgG in saliva were expressed both as nanograms per milliliter and as nanograms per microgram of total IgA or IgG. One month after immunization, significant increases in antibody titers (both IgA and IgG) were observed in saliva in both groups. There were significant subsequent falls in antibody titers by 6 months. Anti-meningococcal C-specific secretory component and IgA antibody titers were closely correlated (r = 0.85,P < 0.001), but there was no significant correlation between salivary and serum IgA titers, suggesting that IgA antibodies are locally produced. Significant correlation was found between salivary and serum IgG titers (r = 0.52,P < 0.01), suggesting that salivary IgG may be serum derived. Compared with polysaccharide vaccine, the conjugate vaccine induced significantly higher salivary IgG responses (P< 0.05), although there were no significant differences between salivary IgA responses to the two vaccines. The conjugate vaccine induced greater salivary IgG responses than a polysaccharide vaccine. Both vaccines induced significant salivary IgA antibodies. Further studies are needed to establish the functional significance of these mucosal responses.
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Fayette, Jérôme, Bertrand Dubois, Stéphane Vandenabeele, Jean-Michel Bridon, Béatrice Vanbervliet, Isabelle Durand, Jacques Banchereau, Christophe Caux, and Francine Brière. "Human Dendritic Cells Skew Isotype Switching of CD40-activated Naive B Cells towards IgA1 and IgA2." Journal of Experimental Medicine 185, no. 11 (June 2, 1997): 1909–18. http://dx.doi.org/10.1084/jem.185.11.1909.
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Within T cell–rich areas of secondary lymphoid organs, interdigitating dendritic cells recruit antigen-specific T cells that then induce B cells to secrete Igs. This study investigates the possible role(s) of dendritic cells in the regulation of human B cell responses. In the absence of exogenous cytokines, in vitro generated dendritic cells (referred to as Dendritic Langerhans cells, D-Lc) induced surface IgA expression on ∼10% of CD40-activated naive sIgD+ B cells. In the presence of IL-10 and TGF-β, a combination of cytokines previously identified for its capacity to induce IgA switch, D-Lc strongly potentiated the induction of sIgA on CD40-activated naive B cells from 5% to 40–50%. D-Lc alone did not induce the secretion of IgA by CD40-activated naive B cells, which required further addition of IL-10. Furthermore, D-Lc skewed towards the IgA isotype at the expense of IgG, the Ig production of CD40-activated naive B cells cultured in the presence of IL-10 and TGF-β. Importantly, under these culture conditions, both IgA1 and IgA2 were detected. In the presence of IL-10, secretion of IgA2 by CD40-activated naive B cells could be detected only in response to D-Lc and was further enhanced by TGF-β. Collectively, these results suggest that in addition to activating T cells in the extrafollicular areas of secondary lymphoid organs, human D-Lc also directly modulate T cell–dependent B cell growth and differentiation, by inducing the IgA isotype switch.
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Bu, Lihong, Bo Ye, Anne M. Kouri, and Youngki Kim. "Diagnostic Utility of Galactose-Deficient Immunoglobulin A1 Immunostaining in the Differentiation of Lupus Nephritis and Immunoglobulin A Nephropathy." Glomerular Diseases 1, no. 1 (2021): 34–39. http://dx.doi.org/10.1159/000511056.
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<b><i>Background:</i></b> Renal biopsy plays an important role in the establishment of the diagnosis and the management of patients with lupus nephritis. Immunoglobulin A (IgA) nephropathy rarely has been reported in kidney biopsy of lupus patients. Lupus nephritis and IgA nephropathy can be readily diagnosed on renal biopsy when the classic patterns are present. However, atypical patterns can become a diagnostic challenge. Galactose-deficient IgA1 (Gd-IgA1) is a key element in the pathogenesis of primary IgA nephropathy. Glomerular Gd-IgA1 deposits, detected by immunofluorescent staining of KM-55 (a Gd-IgA1-specific monoclonal antibody), are consistently identified in the mesangium of IgA nephropathy but are significantly less or absent in lupus nephritis accompanied by significant IgA deposition. <b><i>Case Presentation:</i></b> Here we report the case of an 11-year-old girl who was recently diagnosed with systemic lupus erythematosus (SLE) and was found to have hematuria and proteinuria. Renal biopsy showed focal mesangial hypercellularity with IgA dominant, “full house” like pattern of mesangial deposition. The biopsy findings present a diagnostic dilemma with the differential diagnosis of IgA nephropathy versus lupus nephritis with atypical immunofluorescence, and IgA nephropathy is favored, in the absence of strong straining of C1q or C3, extraglomerular deposits, tissue antinuclear antibodies, and endothelial tubuloreticular inclusions. However, no detectable glomerular KM-55 staining was seen in the kidney biopsy. <b><i>Conclusions:</i></b> We demonstrate the unique diagnostic utility of immunostaining for KM-55 in a challenging kidney biopsy of an SLE patient with features suggestive of IgA nephropathy. The absence of KM-55 staining excludes IgA nephropathy, supporting a diagnosis of lupus nephritis with atypical immunofluorescence in this patient with SLE.
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Fasching, Claudine E., Tracy Grossman, Blaise Corthésy, Andrew G. Plaut, Jeffrey N. Weiser, and Edward N. Janoff. "Impact of the Molecular Form of Immunoglobulin A on Functional Activity in Defense against Streptococcus pneumoniae." Infection and Immunity 75, no. 4 (January 29, 2007): 1801–10. http://dx.doi.org/10.1128/iai.01758-06.
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ABSTRACT Antibodies of the immunoglobulin A (IgA) class react with capsular polysaccharides of Streptococcus pneumoniae and support complement-dependent opsonophagocytosis (OPC) of the organism by phagocytes. We characterized the biologic impact of the molecular forms of human monoclonal capsule-specific IgA (monomeric IgA [mIgA], polymeric IgA [pIgA], and secretory IgA [SIgA]) on OPC and susceptibility to cleavage by IgA1 protease. The efficiency of SIgA in support of OPC of S. pneumoniae was comparable to that of pIgA, and both forms exceeded that of mIgA by a fivefold margin. This structure-function relationship was associated with three factors. First, the avidities, or functional affinities, of both pIgA and SIgA for pneumococcal capsules exceeded those of mIgA. Second, both pIgA and SIgA required less complement to achieve similar levels of bacterial OPC than did mIgA, indicating that secretory component does not hinder the effect of complement. Third, both pIgA and SIgA mediated agglutination of the organism, whereas mIgA did not. All three forms of capsule-specific IgA showed comparable susceptibilities to cleavage and functional inhibition by bacterial IgA1 protease, demonstrating that secretory component does not prevent the proteolytic degradation of IgA1 by IgA1 protease. IgA1 cleavage results in formation of identical Fab fragments for each of the molecular forms, thereby abolishing the contribution of multivalence of pIgA and SIgA. In summary, the polymeric forms of IgA (both pIgA and SIgA) provide a substantial advantage in binding, agglutination, and OPC of the organism.
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Zhang, Minfang, Wenyan Zhou, Shaojun Liu, Liyin Zhang, Zhaohui Ni, and Chuanming Hao. "KM55 Monoclonal Antibody Staining in IgA-Dominant Infection-Related Glomerulonephritis." Nephron 145, no. 3 (2021): 225–37. http://dx.doi.org/10.1159/000513269.
Full textAbstract:
<b><i>Introduction:</i></b> IgA-dominant infection-related glomerulonephritis (IgA-IRGN) is a unique form of IRGN, which needs to be distinguished from IgA nephropathy (IgAN), due to overlapping clinical and pathological features. The key factor in the pathogenesis of IgAN is galactose-deficient IgA1 (Gd-IgA1). However, the mechanism of glomerular IgA deposition in patients with IgA-IRGN is unclear. Therefore, we evaluated whether Gd-IgA1 could be a useful biomarker to distinguish between these 2 diseases. <b><i>Methods:</i></b> A case-control study was conducted to analyze the clinical and pathological characteristics of 12 patients with IgA-IRGN. The intensity and distribution of glomerular Gd-IgA1 (KM55) staining in renal biopsies were assessed. The control group consisted of 15 patients diagnosed with IgAN and an additional 17 patients with glomerulopathy involving IgA deposition. <b><i>Results:</i></b> The main clinical manifestations of patients with IgA-IRGN were nephrotic-range proteinuria, hematuria, acute renal injury, and hypocomplementemia. Active lesions were the leading pathological feature, while focal segmental sclerosis was rare. Half of the patients exhibited hump-shaped subepithelial deposits. Glomerular KM55 staining was negative in 7 patients, trace in 4 patients, and 2+ in 1 patient. The median intensity of KM55 staining in IgA-IRGN patients was 0 (range 0∼2+), which was significantly lower than that of primary IgAN patients (median 2+, range 1+∼3+). The receiver operating characteristic analysis demonstrated that the optimal cutoff level to identify these 2 diseases was 0.5+. <b><i>Conclusions:</i></b> Glomerular KM55 staining intensity might be helpful to distinguish IgA-IRGN from primary IgAN. Weak or negative staining may favor IgA-IRGN. In addition, integrated analysis including clinical data, pathological findings, and prognostic information would further improve the differential diagnosis.