Articles de revues : « HIGM1 »

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Vavassori, Valentina, Elisabetta Mercuri, Genni Marcovecchio, Maria Carmina Castiello, Daniele Canarutto, Claudia Asperti, Aurelien Jacob et al. « Towards Clinical Translation of Hematopoietic Cell Gene Editing for Treating Hyper-IgM Type 1 ». Blood 138, Supplement 1 (5 novembre 2021) : 3978. http://dx.doi.org/10.1182/blood-2021-148572.

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Abstract Hyper-IgM Type 1 (HIGM1) is caused by mutations of CD40L, whose absence in CD4 T cells impairs signaling for B cell activation and Ig class-switching. Since unregulated CD40L expression leads to lymphoproliferations/lymphomas in the mouse model of the disease, gene correction must preserve the physiological regulation of the gene. Gene editing of either autologous T cells or hematopoietic stem cells (HSC) held promise for treating HIGM1. We developed a "one size fits all" editing strategy to insert a 5'-truncated corrective CD40L cDNA in the first intron of the native human gene, effectively making expression conditional to targeted insertion in the intended locus. By exploiting a protocol that preserves T stem memory cells (TSCM), we reproducibly obtained ~40% of editing efficiency in healthy donor and patients derived T cells, restoring regulated, although partial, CD40L surface expression. The reconstituted level of expression, however, was sufficient to fully restore helper function to B cells. In order to select, track and potentially deplete edited T cells, we coupled the corrective cDNA with a clinically compatible selector gene and confirmed that enriched T cells preserved their engraftment capacity in NSG mice. Unexpectedly, the presence of an IRES-linked downstream coding frame counteracted the shorter half-life of transcript from the edited locus, allowing replenishment of intracellular stores and surface translocation of physiological amounts of CD40L upon activation. We also tailored the CD40L editing strategy to human HSC, reaching up to 15-30% editing in HSC long term engrafting NSG mice, depending on the HSC source. We then modelled the therapeutic potential of both T cell and HSC gene therapy by infusing increasing proportions of WT murine cells, as surrogates of edited cells, in HIGM1 mice. Administration of functional T cells at clinically relevant doses in HIGM1 mice, preconditioned or not with different lymphodepleting regimens, achieved long term stable T cell engraftment and partial rescue of antigen specific IgG response and germinal center formation in splenic follicles after vaccination with a thymus dependent antigen. Remarkably, infusion of T cells from mice pre-exposed to the antigen, mimicking treatment of chronically infected patients, was effective even in absence of conditioning and protected the mice from a disease relevant infection induced by the opportunistic pathogen Pneumocystis murina. Transplantation of functional T cells admixed with an equal number of HIGM1 T cells resulted in lower vaccination response, indicating competition between WT and HIGM1 cells and implying that increasing the fraction of corrected cells in the graft by selection would improve immune reconstitution. Concerning HSC gene therapy, transplanting 25% WT cells along with HIGM1 ones in HIGM1 mice - mirroring the editing efficiencies achieved in human HSC - rescued antigen specific IgG response and established protection from pathogen comparably to T cell therapy. These findings suggest that autologous edited T cells can provide immediate and substantial benefits to HIGM1 patients and position T cell as competitive strategy to HSC gene therapy, because of more straightforward translation, lower safety challenges and potentially comparable clinical benefits. We thus embarked in assessing GMP compliant reagents and protocols for T cell activation, culture and editing and developed a scalable manufacturing process. Optimization of clinical grade culture conditions allowed further increasing editing efficiency, total cellular yield and maintenance of TSCM thus paving the way to the design of a clinical trial. Disclosures Naldini: Genenta Science: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Other: Founder.

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Callard, R. E., S. H. Smith, J. Herbert, G. Morgan, M. Padayachee, S. Lederman, L. Chess, R. A. Kroczek, W. C. Fanslow et R. J. Armitage. « CD40 ligand (CD40L) expression and B cell function in agammaglobulinemia with normal or elevated levels of IgM (HIM). Comparison of X-linked, autosomal recessive, and non-X-linked forms of the disease, and obligate carriers. » Journal of Immunology 153, n^o 7 (1 octobre 1994) : 3295–306. http://dx.doi.org/10.4049/jimmunol.153.7.3295.

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Abstract Hyper-IgM syndrome is a rare immunodeficiency characterized by low or absent IgG, IgA, and IgE with normal or elevated levels of IgM. It can occur as an acquired or familial disorder with either X-linked or autosomal modes of inheritance. The X-linked form (HIGM1) is a result of mutations in the CD40 ligand (CD40L) gene, but the defect in non-X-linked forms of the disease (HIM) has not been determined. We show here that CD40L expression on activated T cells from non-X-linked patients can be detected by CD40Fc, 5c8 Mab, and anti-TRAP, whereas activated T cells from HIGM1 patients either had no detectable CD40L (Type I), or stained with anti-TRAP but not CD40Fc or 5c8 (Type II). Activated T cells from obligate carriers varied from low to normal expression of CD40L. B cells from HIGM1 and non-X-linked HIM patients proliferated in response to CD40L. Costimulation of B cells from HIGM1, from sporadic HIM, or from non-X-linked HIM patients with CD40L plus IL-2 resulted in some IgM production, but no significant IgG or IgA. Costimulation with CD40L plus IL-10 resulted in significant IgG and/or IgA secretion by B cells from some HIGM1 patients, but consistently failed to stimulate IgG or IgA secretion by B cells from non-X-linked patients. In addition, costimulation with CD40L and IL-4 failed to induce IgE secretion by B cells from one non-X-linked HIM patient, and induced a weak response in another. These results suggest that patients with non-X-linked forms of HIM may have an intrinsic B cell defect preventing heavy chain switching, which is not related to expression of CD40L.

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Shimoda, Michiko, Yoko Takada, Emanual Maverakis, Brunhilde Felding et Yoshikazu Takada. « CD40L acts as an allosteric activator of integrins for signal transduction independent of inside-out signaling ». Journal of Immunology 206, n^o 1_Supplement (1 mai 2021) : 24.04. http://dx.doi.org/10.4049/jimmunol.206.supp.24.04.

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Abstract CD40L plays a major role in immune response and is a target for inflammatory disease therapy. Besides CD40, CD40L binds to several integrins but their role in signaling is unclear. We showed that integrins αvβ3 and α5β1 bind to the CD40L trimeric interface through classical ligand binding site of integrins (site 1). Several CD40L mutants from HIGM1 (hyper-IgM syndrome type 1) patients were clustered in trimeric interface and defective in integrin binding, and in NF-κB and B cell activation, but still bound CD40 and acted as antagonists of CD40L signaling. Thus, integrins play a critical role in CD40L signaling. Previous studies showed that CX3CL1 and sPLA2-IIA can activate integrins by binding to a recently identified allosteric site (site 2) of integrins. Using cell-free assays, we found that soluble (s)-CD40L activated soluble integrins, α4β1, αvβ3 and α5β1, and induced their binding to known specific ligands independent of inside-out signaling. Also, sCD40L activated cell-surface integrins in CHO cells lacking CD40. Finally, sCD40L bound to a cyclic peptide derived from site 2. These findings indicate that CD40L acts as an allosteric activator of integrins by binding to site 2. Docking simulation predicted that the integrin site 2-binding site of CD40L is located outside of CD40L trimer. Importantly, four HIGM1 mutations are clustered in the predicted site 2-binding site of CD40L. The K143T and G144E mutants were the most defective in integrin activation, indicating that integrin binding occurs around these residues of the predicted site 2-binding site. We propose that allosteric integrin activation by CD40L plays a role in CD40L signaling and that defective integrin site 2-binding may be causal for defective CD40L signaling in HIGM1.

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Life, P., J. F. Gauchat, V. Schnuriger, S. Estoppey, G. Mazzei, A. Durandy, A. Fischer et J. Y. Bonnefoy. « T cell clones from an X-linked hyper-immunoglobulin (IgM) patient induce IgE synthesis in vitro despite expression of nonfunctional CD40 ligand. » Journal of Experimental Medicine 180, n^o 5 (1 novembre 1994) : 1775–84. http://dx.doi.org/10.1084/jem.180.5.1775.

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The induction of immunoglobulin E (IgE) switching in B cells requires at least two signals. The first is given by either of the soluble lymphokines interleukin 4 (IL-4) or IL-13, whereas the second is contact dependent. It has been widely reported that a second signal can be provided by the CD40 ligand (CD40L) expressed on the surface of T cells, mast cells, and basophils. A defect in the CD40L has been shown recently to be responsible for the lack of IgE, IgA, and IgG, characteristic of the childhood X-linked immunodeficiency, hyper IgM syndrome (HIGM1). IgE can however be detected in the serum of some HIGM1 patients. In this study, we isolated T cell clones and lines using phytohemagglutinin (PHA) and allergen, respectively, from the peripheral blood of one such patient who expressed a truncated form of CD40L, and investigated their ability to induce IgE switching in highly purified, normal tonsillar B cells in vitro. Unexpectedly, 4 of 12 PHA clones tested induced contact-dependent IgE synthesis in the presence of exogenous IL-4. These clones were also shown to strongly upregulated IL-4-induced germline epsilon RNA and formed dense aggregates with B cells. Of the four helper clones, three were CD8+, of which two were characteristic of the T helper cell 2 (Th2) subtype. Two allergen-specific HIGM1 T cell lines, both of the Th0 subtype, could also drive IgE synthesis when prestimulated using specific allergen. All clones and lines were negative for surface expression of CD40L, and the mutated form of CD40L was confirmed for a representative clone by RNase protection assay and sequencing. The IgE helper activity could not be attributed to membrane tumor necrosis factor alpha (TNF-alpha) although it was strongly expressed on activated clones, and the addition of neutralizing anti-TNF-alpha antibody did not abrogate IgE synthesis. These results therefore suggest the involvement of T cell surface molecules other than CD40L in the induction of IgE synthesis, and that these molecules may also be implicated in other aspects of T-B cell interactions.

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Padayachee, M., R. J. Levinsky, C. Kinnon, A. Finn, C. McKeown, C. Feighery, L. D. Notarangelo, R. W. Hendriks, A. P. Read et S. Malcolm. « Mapping of the X linked form of hyper IgM syndrome (HIGM1) ». Journal of Medical Genetics 30, n^o 3 (1 mars 1993) : 202–5. http://dx.doi.org/10.1136/jmg.30.3.202.

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Kroczek, Richard A., Daniel Graf, Duilio Brugnoni, Silvia Giliani, Ulf Korthauer, Alberto Ugazio, Gabriele Senger, Hans W. Mages, Anna Villa et Luigi D. Notarangelo. « Defective Expression of CD40 Ligand on T Cells Causes "X-Linked Immunodeficiency with Hyper-IgM (HIGM1)" ». Immunological Reviews 138, n^o 1 (avril 1994) : 39–59. http://dx.doi.org/10.1111/j.1600-065x.1994.tb00846.x.

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Padayachee, M., C. Feighery, A. Finn, C. McKeown, R. J. Levinsky, C. Kinnon et S. Malcolm. « Mapping of the x-linked form of hyper-IgM syndrome (HIGM1) to Xq26 by close linkage to HPRT ». Genomics 14, n^o 2 (octobre 1992) : 551–53. http://dx.doi.org/10.1016/s0888-7543(05)80270-8.

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Fontana, Stefania, Daniele Moratto, Surinder Mangal, Maria De Francesco, William Vermi, Simona Ferrari, Fabio Facchetti et al. « Functional defects of dendritic cells in patients with CD40 deficiency ». Blood 102, n^o 12 (1 décembre 2003) : 4099–106. http://dx.doi.org/10.1182/blood-2003-04-1244.

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Abstract We have recently identified 2 patients with a rare autosomal recessive form of hyper IgM disease, known as HIGM3, caused by mutations in the CD40 gene. These patients had opportunistic infections observed on X-linked hyper IgM syndrome (HIGM), suggesting that the CD40-CD40 ligand interaction is important for promoting T-cell-mediated immunity. To evaluate whether innate immunity signals may substitute CD154 for inducing the maturation of dendritic cells (DCs), we analyzed monocyte-derived DCs in these patients. Monocyte-derived DCs of HIGM3 subjects on ex vivo stimulation with tumor necrosis factor-α (TNF-α) or lipopolysaccharide (LPS) combined with interferon-γ (IFN-γ) normally express all the markers of mature DCs, such as CD83 and DC-LAMP. However, cell surface levels of HLA-DR in mature DCs are reduced, as is costimulatory activity of these cells for allogeneic naive T cells. In addition, CD40-deficient DCs secrete lower amounts of interleukin-12 (IL-12) but larger quantities of IL-10 than control subjects. Finally, analysis of circulating plasmacytoid DCs demonstrates a normal percentage of this subset in CD40-deficient cells, but IFN-α secretion in response to herpes simplex virus 1 (HSV-1) infection is severely reduced in patients. These observations suggest that the severe impairment of DC maturation may contribute to the defect of T-cell-mediated immunity observed in HIGM3 patients. (Blood. 2003;102:

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Hollenbaugh, D., L. H. Wu, H. D. Ochs, S. Nonoyama, L. S. Grosmaire, J. A. Ledbetter, R. J. Noelle, H. Hill et A. Aruffo. « The random inactivation of the X chromosome carrying the defective gene responsible for X-linked hyper IgM syndrome (X-HIM) in female carriers of HIGM1. » Journal of Clinical Investigation 94, n^o 2 (1 août 1994) : 616–22. http://dx.doi.org/10.1172/jci117377.

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Hoang, Ngoc H., Vera Strogolova, Jaramys J. Mosley, Rosemary A. Stuart et Jonathan Hosler. « Hypoxia-inducible gene domain 1 proteins in yeast mitochondria protect against proton leak through complex IV ». Journal of Biological Chemistry 294, n^o 46 (7 octobre 2019) : 17669–77. http://dx.doi.org/10.1074/jbc.ra119.010317.

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Hypoxia-inducible gene domain 1 (HIGD1) proteins are small integral membrane proteins, conserved from bacteria to humans, that associate with oxidative phosphorylation supercomplexes. Using yeast as a model organism, we have shown previously that its two HIGD1 proteins, Rcf1 and Rcf2, are required for the generation and maintenance of a normal membrane potential (ΔΨ) across the inner mitochondrial membrane (IMM). We postulated that the lower ΔΨ observed in the absence of the HIGD1 proteins may be due to decreased proton pumping by complex IV (CIV) or enhanced leak of protons across the IMM. Here we measured the ΔΨ generated by complex III (CIII) to discriminate between these possibilities. First, we found that the decreased ΔΨ observed in the absence of the HIGD1 proteins cannot be due to decreased proton pumping by CIV because CIII, operating alone, also exhibited a decreased ΔΨ when HIGD1 proteins were absent. Because CIII can neither lower its pumping stoichiometry nor transfer protons completely across the IMM, this result indicates that HIGD1 protein ablation enhances proton leak across the IMM. Second, we demonstrate that this proton leak occurs through CIV because ΔΨ generation by CIII is restored when CIV is removed from the cell. Third, the proton leak appeared to take place through an inactive population of CIV that accumulates when HIGD1 proteins are absent. We conclude that HIGD1 proteins in yeast prevent CIV inactivation, likely by preventing the loss of lipids bound within the Cox3 protein of CIV.

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Wilson, Rebecca L., Weston Troja, Emily K. Sumser, Alec Maupin, Kristin Lampe et Helen N. Jones. « Insulin-like growth factor 1 signaling in the placenta requires endothelial nitric oxide synthase to support trophoblast function and normal fetal growth ». American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 320, n^o 5 (1 mai 2021) : R653—R662. http://dx.doi.org/10.1152/ajpregu.00250.2020.

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Currently, there is no effective treatment for placental dysfunction in utero. In a ligated mouse model of fetal growth restriction (FGR), nanoparticle-mediated human insulin-like 1 growth factor ( hIGF1) gene delivery (NP-Plac1-hIGF1) increased hIGF1 expression and maintained fetal growth. However, whether it can restore fetal growth remains to be determined. Using the endothelial nitric oxide synthase knockout (eNOS−/−) mouse model, a genetic model of FGR, we found that despite inducing expression of hIGF1 in the placentas treated with NP-Plac1-hIGF1 ( P = 0.0425), FGR did not resolve. This was associated with no change to the number of fetal capillaries in the placental labyrinth; an outcome which was increased with NP-Plac1-hIGF1 treatment in the ligated mouse model, despite increased expression of angiopoietin 1 ( P = 0.05), and suggested IGF1 signaling in the placenta requires eNOS to modulate placenta angiogenesis. To further assess this hypothesis, BeWo choriocarcinoma cell line and human placental explant cultures were treated with NP-Plac1-hIGF1, oxidative stress was induced with hydrogen peroxide (H2O2), and NOS activity was inhibited using the inhibitor NG-monomethyl-l-arginine (l-NMMA). In both BeWo cells and explants, the protective effect of NP-Plac1-hIGF1 treatment against H2O2-induced cell death/lactate dehydrogenase release was prevented by eNOS inhibition ( P = 0.003 and P < 0.0001, respectively). This was associated with an increase in mRNA expression of oxidative stress markers hypoxia inducing factor 1α ( HIF1α; P < 0.0001) and ADAM10 ( P = 0.0002) in the NP-Plac1-hIGF1 + H2O2 + l-NMMA-treated BeWo cells. These findings show for the first time the requirement of eNOS/NOS in IGF1 signaling in placenta cells that may have implications for placental angiogenesis and fetal growth.

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Di Leo, Vincenzo, Patrick J. Gleeson, Fabio Sallustio, Carine Bounaix, Jennifer Da Silva, Gesualdo Loreto, Sanae Ben Mkaddem et Renato C. Monteiro. « Rifaximin as a Potential Treatment for IgA Nephropathy in a Humanized Mice Model ». Journal of Personalized Medicine 11, n^o 4 (16 avril 2021) : 309. http://dx.doi.org/10.3390/jpm11040309.

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IgA Nephropathy (IgAN) is the most common glomerulonephritis worldwide, characterized by the mesangial deposition of abnormally glycosylated IgA1 (Gd-IgA). The production of Gd-IgA occurs in mucose-associated lymphoid tissue (MALT). The microbiota plays a role in MALT modulation. Rifaximin (NORMIX®), a non-absorbable oral antibiotic, induces positive modulation of the gut microbiota, favoring the growth of bacteria beneficial to the host. Here, we evaluate the effect of rifaximin on a humanized mice model of IgAN (α1KI-CD89Tg). Methods: The α1KI-CD89Tg mice were treated by the vehicle (olive oil) or rifaximin (NORMIX®). Serum levels of hIgA, hIgA1–sCD89, and mIgG–hIgA1 immune complexes were determined. Glomerular hIgA1 deposit and CD11b+ cells recruitment were revealed using confocal microscopy. Furthermore, the mRNA of the B-Cell Activating Factor (BAFF), polymeric immunoglobulin receptor (pIgR), and Tumor Necrosing Factor-α (TNF-α) in gut samples were detected by qPCR. Results: Rifaximin treatment decreased the urinary protein-to-creatinine ratio, serum levels of hIgA1–sCD89 and mIgG–hIgA1 complexes, hIgA1 glomerular deposition, and CD11b+ cell infiltration. Moreover, rifaximin treatment decreased significantly BAFF, pIgR, and TNF-α mRNA expression. Conclusions: Rifaximin decreased the IgAN symptoms observed in α1KI-CD89Tg mice, suggesting a possible role for it in the treatment of the disease.

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Català-Moll, Francesc, Anna G. Ferreté-Bonastre, Tianlu Li, Dieter Weichenhan, Pavlo Lutsik, Laura Ciudad, Ángel F. Álvarez-Prado et al. « Activation-induced deaminase is critical for the establishment of DNA methylation patterns prior to the germinal center reaction ». Nucleic Acids Research 49, n^o 9 (5 mai 2021) : 5057–73. http://dx.doi.org/10.1093/nar/gkab322.

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Abstract Activation-induced deaminase (AID) initiates antibody diversification in germinal center B cells by deaminating cytosines, leading to somatic hypermutation and class-switch recombination. Loss-of-function mutations in AID lead to hyper-IgM syndrome type 2 (HIGM2), a rare human primary antibody deficiency. AID-mediated deamination has been proposed as leading to active demethylation of 5-methycytosines in the DNA, although evidence both supports and casts doubt on such a role. In this study, using whole-genome bisulfite sequencing of HIGM2 B cells, we investigated direct AID involvement in active DNA demethylation. HIGM2 naïve and memory B cells both display widespread DNA methylation alterations, of which ∼25% are attributable to active DNA demethylation. For genes that undergo active demethylation that is impaired in HIGM2 individuals, our analysis indicates that AID is not directly involved. We demonstrate that the widespread alterations in the DNA methylation and expression profiles of HIGM2 naïve B cells result from premature overstimulation of the B-cell receptor prior to the germinal center reaction. Our data support a role for AID in B cell central tolerance in preventing the expansion of autoreactive cell clones, affecting the correct establishment of DNA methylation patterns.

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Bakhshpour, Monireh, Aykut Arif Topcu, Nilay Bereli, Huseyin Alkan et Adil Denizli. « Poly(Hydroxyethyl Methacrylate) Immunoaffinity Cryogel Column for the Purification of Human Immunoglobulin M ». Gels 6, n^o 1 (29 janvier 2020) : 4. http://dx.doi.org/10.3390/gels6010004.

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Human immunoglobulin M (hIgM) antibodies are considered as hopeful tools for diseases therapy. Therefore, chromatography approaches are used to purify hIgM with a single step. In this study, we prepared a poly(hydroxyethyl methacrylate) based immunoaffinity p(HEMA-I) cryogel column by using cyanamide to immobilize antihuman immunoglobulin on the p(HEMA) cryogel for purification of hIgM in aqueous solution and artificial human plasma. The characterization of the p(HEMA) cryogel column was performed by using a scanning electron microscope (SEM), micro-computerized tomography (µ-CT), Fourier transform infrared spectroscopy (FTIR), swelling degree and macro-porosity. Further, the optimizations of various parameters were performed such as, pH, ionic strength, temperature and concentration of hIgM in aqueous solutions. In addition, the Langmuir adsorption model was supported by experimental results. Maximum adsorbed amount of hIgM corresponded to 11.1 mg/g at pH 5.75 [morpholino ethanesulfonic acid (MES buffer)]. Our results indicated that the p(HEMA-I) cryogel column can be reused at least 10 times without significant loss in adsorption capacity. As a natural source, artificial human plasma was selected for hIgM adsorption and the purity of hIgM was evaluated using sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE).

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Dong, Qiuting, Jinxia Zhao, Zhongqiang Yao, Xiangyuan Liu et Huiying He. « A Case Report of X-Linked Hyperimmunoglobulin M Syndrome with Lipoma Arborescens of Knees ». Case Reports in Medicine 2016 (2016) : 1–4. http://dx.doi.org/10.1155/2016/5797232.

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The X-linked hyperimmunoglobulin M syndrome (HIGM), caused by mutations in the CD40LG gene, is a kind of primary immunodeficiency disease (PID). Patients with X-linked HIGM are susceptible to infection as well as autoimmune diseases. Lipoma arborescens (LA) is a rare benign tumor, of which the pathogenesis mechanism has not been clearly understood. We report a case of HIGM combined with LA in a 22-year-old male patient. A new deletion mutation of CD40LG gene was detected in this case. The possible relationship between HIGM and LA was also discussed.

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McLean, G. R., K. K. Miller, J. W. Schrader et A. K. Junker. « Biased Immunoglobulin G (IgG) Subclass Production in a Case of Hyper-IgM Syndrome ». Clinical Diagnostic Laboratory Immunology 11, n^o 6 (novembre 2004) : 1192–93. http://dx.doi.org/10.1128/cdli.11.6.1192-1193.2004.

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ABSTRACT Hyper-immunoglobulin M (IgM) syndrome (HIGM) is a rare heterogeneous primary immune deficiency. We describe a patient with HIGM characterized by skewed production of serum IgG subclasses and normal somatic hypermutation. This case may represent a subgroup of HIGM type 4 that is characterized by a biased switching to the V-region proximal constant regions.

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Chemouny, Jonathan M., Patrick J. Gleeson, Lilia Abbad, Gabriella Lauriero, Erwan Boedec, Karine Le Roux, Céline Monot et al. « Modulation of the microbiota by oral antibiotics treats immunoglobulin A nephropathy in humanized mice ». Nephrology Dialysis Transplantation 34, n^o 7 (20 novembre 2018) : 1135–44. http://dx.doi.org/10.1093/ndt/gfy323.

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Abstract Background Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis worldwide. IgA is mainly produced by the gut-associated lymphoid tissue (GALT). Both experimental and clinical data suggest a role of the gut microbiota in this disease. We aimed to determine if an intervention targeting the gut microbiota could impact the development of disease in a humanized mouse model of IgAN, the α1KI-CD89Tg mice. Methods Four- and 12-week old mice were divided into two groups to receive either antibiotics or vehicle control. Faecal bacterial load and proteinuria were quantified both at the beginning and at the end of the experiment, when blood, kidneys and intestinal tissue were collected. Serum mouse immunoglobulin G (mIgG) and human immunoglobulin A1 (hIgA1)-containing complexes were quantified. Renal and intestinal tissue were analysed by optical microscopy after haematoxylin and eosin colouration and immunohistochemistry with anti-hIgA and anti-mouse CD11b antibodies. Results Antibiotic treatment efficiently depleted the faecal microbiota, impaired GALT architecture and impacted mouse IgA production. However, while hIgA1 and mIgG serum levels were unchanged, the antibiotic treatment markedly prevented hIgA1 mesangial deposition, glomerular inflammation and the development of proteinuria. This was associated with a significant decrease in circulating hIgA1–mIgG complexes. Notably, final faecal bacterial load strongly correlated with critical clinical and pathophysiological features of IgAN such as proteinuria and hIgA1–mIgG complexes. In addition, treatment with broad-spectrum antibiotics reverted established disease. Conclusions These data support an essential role of the gut microbiota in the generation of mucosa-derived nephrotoxic IgA1 and in IgAN development, opening new avenues for therapeutic approaches in this disease.

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Keenan, Thomas D., Suresh Radhakrishnan, Michael Bell, Michael Barry et Larry R. Pease. « Retargeting IgM Antibodies with Different Specificities to a Common Cell Type Reveals Shared Mechanisms Regulating Cellular Activation (91.12) ». Journal of Immunology 182, n^o 1_Supplement (1 avril 2009) : 91.12. http://dx.doi.org/10.4049/jimmunol.182.supp.91.12.

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Abstract IgM antibodies, as multivalent ligands, have the capacity to activate cells differentially by cross-linking targeted cell surface signaling molecules. For example, hIgM12 (B7DC Xab) activates dendritic cells (DCs), leading to potent immunomodulation, while hIgM22 binds glial cells and causes remyelination in mouse models of multiple sclerosis. Both antibodies activate common signaling intermediates in their respective cellular targets suggesting a common mechanism of action. Elucidation of these shared mechanisms became possible by targeting both antibodies to a common cell type. Our previous studies demonstrate that B7-DC expression is required to activate downstream signaling in DCs by hIgM12. We utilized a phage display system to identify 7mer peptides bound by each IgM and expressed each peptide attached to a surrogate cell surface carrier on retrovirally tranduced bone marrow-derived DCs from B7-DC -/- mice. Transduced cells were treated with hIgM12, hIgM22 or anti-carrier IgM, and subsequent activity was compared against B7-DC +/+ DCs or B7-DC-reconstituted B7-DC -/- DCs. DC activation by each IgM was specific to expression of their conjugate peptide construct. Activation by hIgM22 was indistinguishable from activation by hIgM12, while anti-carrier IgM caused no activation. This indicates that while their target specificity differs, once bound these IgMs activate cells via common mechanisms.

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DERRIDA, JACQUES. « Le toucherTouch/to touch him1 ». Paragraph 16, n^o 2 (juillet 1993) : 122–57. http://dx.doi.org/10.3366/para.1993.0004.

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Corey, Daniel, et Irving L. Weissman. « Super Cross-Presentation of Tumor Antigens to Elicit Anti-Lymphoma Immunity By Synthetic Design of an Anti-Phosphatidylserine Bridge Protein ». Blood 128, n^o 22 (2 décembre 2016) : 1844. http://dx.doi.org/10.1182/blood.v128.22.1844.1844.

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Abstract Cell loss by apoptosis is a common feature in tumors. Dying tumor cells induce immune tolerance within the tumor microenvironment largely through highly conserved homeostatic clearance programs that restore tissue immune homeostasis and contribute to the formation of an immunosuppressive niche. The translocation of phosphatidylserine (PS) on cellular membranes, during the initial phases of apoptosis, functions as a recognition and removal signal that limits the immunogenicity of cell death. We examined whether altering clearance of dying cancer cells to elicit inflammatory turnover potentiates immune responses against lymphoma cells. To remove inhibitory signals in the homeostatic clearance pathway we utilized a molecular bridge scaffold to engineer a modified phosphatidylserine bridge protein (FA58C2-hIgG1 or C2-hIgG1) that works as a bridge between apoptotic cells expressing aminophospholipids and phagocytes bearing Fc receptors. In vitro administration of C2-hIgG1 to murine bone marrow derived macrophages promotes engulfment of apoptotic murine lymphoma cells (38C13 cell line) and ablates the secretion of the anti-inflammatory cytokine interleukin-10 (IL-10) and suppression of pro-inflammatory cytokines tumor necrosis factor (TNF-α) and IL-12p40 to the presence of apoptotic cells. Similarly, uptake of C2-hIgG1 treated lymphoma cells triggers upregulation of the costimulatory markers CD80, CD86, and MHC class II on macrophages and promotes secretion of Th1-recruiting lymphocyte chemokines CXCL9, CXCL10, and CCL5. Accordingly, in vivo administration of C2-hIgG1 partially restores immune responses to dead lymphoma cells in antigen cross presentation assays and promotes recruitment and retention of tumor antigen specific CD8+ T cells, dendritic cells, and natural killer cells into tumors. These effects combine to elicit anti-lymphoma immunity, improve responses to immune checkpoint inhibitors, and enhance the effectiveness of adoptive T cell transfers using engineered T Cell Receptors (TCRs) but not CD19-directed chimeric antigen receptor engineered (CAR-T) T cells. Disclosures No relevant conflicts of interest to declare.

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Takeda, Tadayuki, Keiko Ogino, Etsuko Matsui, Min Kwan Cho, Hiroyuki Kumagai, Tsuyoshi Miyake, Ken-ichi Arai et Hisao Masai. « A Fission Yeast Gene,him1+/dfp1+, Encoding a Regulatory Subunit for Hsk1 Kinase, Plays Essential Roles in S-Phase Initiation as Well as in S-Phase Checkpoint Control and Recovery from DNA Damage ». Molecular and Cellular Biology 19, n^o 8 (1 août 1999) : 5535–47. http://dx.doi.org/10.1128/mcb.19.8.5535.

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ABSTRACT Saccharomyces cerevisiae CDC7 encodes a serine/threonine kinase required for G1/S transition, and its related kinases are present in fission yeast as well as in higher eukaryotes, including humans. Kinase activity of Cdc7 protein depends on the regulatory subunit, Dbf4, which also interacts with replication origins. We have identified him1+ from two-hybrid screening with Hsk1, a fission yeast homologue of Cdc7 kinase, and showed that it encodes a regulatory subunit of Hsk1. Him1, identical to Dfp1, previously identified as an associated molecule of Hsk1, binds to Hsk1 and stimulates its kinase activity, which phosphorylates both catalytic and regulatory subunits as well as recombinant MCM2 protein in vitro. him1+ is essential for DNA replication in fission yeast cells, and its transcription is cell cycle regulated, increasing at middle M to late G1. The protein level is low at START in G1, increases at the G1/S boundary, and is maintained at a high level throughout S phase. Him1 protein is hyperphosphorylated at G1/S through S during the cell cycle as well as in response to early S-phase arrest induced by nucleotide deprivation. Deletion of one of the motifs conserved in regulatory subunits for Cdc7-related kinases as well as alanine substitution of three serine and threonine residues present in the same motif resulted in a defect in checkpoint regulation normally induced by hydroxyurea treatment. The alanine mutant also showed growth retardation after UV irradiation and the addition of methylmethane sulfonate. In keeping with this result, a database search indicates that him1+ is identical to rad35+ . Our results reveal a novel function of the Cdc7/Dbf4-related kinase complex in S-phase checkpoint control as well as in growth recovery from DNA damage in addition to its predicted essential function in S-phase initiation.

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Braster, Rens, Marijn Bögels, Hreinn Benonisson, Manfred Wuhrer, Rosina Plomp, Arthur E. H. Bentlage, Rianne Korthouwer et al. « Afucosylated IgG Targets FcγRIV for Enhanced Tumor Therapy in Mice ». Cancers 13, n^o 10 (14 mai 2021) : 2372. http://dx.doi.org/10.3390/cancers13102372.

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Promising strategies for maximizing IgG effector functions rely on the introduction of natural and non-immunogenic modifications. The Fc domain of IgG antibodies contains an N-linked oligosaccharide at position 297. Human IgG antibodies lacking the core fucose in this glycan have enhanced binding to human (FcγR) IIIa/b, resulting in enhanced antibody dependent cell cytotoxicity and phagocytosis through these receptors. However, it is not yet clear if glycan-enhancing modifications of human IgG translate into more effective treatment in mouse models. We generated humanized hIgG1-TA99 antibodies with and without core-fucose. C57Bl/6 mice that were injected intraperitoneally with B16F10-gp75 mouse melanoma developed significantly less metastasis outgrowth after treatment with afucosylated hIgG1-TA99 compared to mice treated with wildtype hhIgG1-TA99. Afucosylated human IgG1 showed stronger interaction with the murine FcγRIV, the mouse orthologue of human FcγRIIIa, indicating that this glycan change is functionally conserved between the species. In agreement with this, no significant differences were observed in tumor outgrowth in FcγRIV-/- mice treated with human hIgG1-TA99 with or without the core fucose. These results confirm the potential of using afucosylated therapeutic IgG to increase their efficacy. Moreover, we show that afucosylated human IgG1 antibodies act across species, supporting that mouse models can be suitable to test afucosylated antibodies.

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Subauste, Carlos S., Matthew Wessendarp, Ricardo U. Sorensen et Lily E. Leiva. « CD40-CD40 Ligand Interaction Is Central to Cell-Mediated Immunity Against Toxoplasma gondii : Patients with Hyper IgM Syndrome Have a Defective Type 1 Immune Response That Can Be Restored by Soluble CD40 Ligand Trimer ». Journal of Immunology 162, n^o 11 (1 juin 1999) : 6690–700. http://dx.doi.org/10.4049/jimmunol.162.11.6690.

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Abstract Cell-mediated immunity that results in IL-12/IFN-γ production is essential to control infections by intracellular organisms. Studies in animal models revealed contrasting results in regard to the importance of CD40-CD40 ligand (CD40L) signaling for induction of a type 1 cytokine response against these pathogens. We demonstrate that CD40-CD40L interaction in humans is critical for generation of the IL-12/IFN-γ immune response against Toxoplasma gondii. Infection of monocytes with T. gondii resulted in up-regulation of CD40. CD40-CD40L signaling was required for optimal T cell production of IFN-γ in response to T. gondii. Moreover, patients with hyper IgM (HIGM) syndrome exhibited a defect in IFN-γ secretion in response to the parasite and evidence compatible with impaired in vivo T cell priming after T. gondii infection. Not only was IL-12 production in response to T. gondii dependent on CD40-CD40L signaling, but also, patients with HIGM syndrome exhibited deficient in vitro secretion of this cytokine in response to the parasite. Finally, in vitro incubation with agonistic soluble CD40L trimer enhanced T. gondii-triggered production of IFN-γ and, through induction of IL-12 secretion, corrected the defect in IFN-γ production observed in HIGM patients. Our results are likely to explain the susceptibility of patients with HIGM syndrome to infections by opportunistic pathogens.

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Baeker, T. R., et T. L. Rothstein. « Proliferation of human malignant lymphocytes induced by anti-IgM independent of B cell growth factor. » Journal of Immunology 134, n^o 5 (1 mai 1985) : 3532–38. http://dx.doi.org/10.4049/jimmunol.134.5.3532.

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Abstract Human malignant B lymphocytes were identified that proliferate in response to small doses of anti-immunoglobulin. Proliferation was induced by monoclonal mouse anti-HIgM, polyclonal goat anti-HIgM, and F(ab')2 fragments thereof, in vitro, and was not accompanied by immunoglobulin secretion. Proliferation was found to be unaffected by T cell depletion and was not enhanced by supplementation with B cell growth factor. Culture fluids from unstimulated malignant lymphocytes as well as from malignant lymphocytes stimulated with anti-HIgM contained no measurable B cell growth factor activity. Thus, proliferation of these malignant lymphocytes was not dependent on the presence of T lymphocytes and was independent of the presence of B cell growth factor. These results imply that B cell stimulatory factors may not be required for proliferation of all human B lymphocytes. Moreover, these results imply that treatment with anti-immunoglobulin reagents may be inappropriate for some B lymphocyte malignancies.

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Sullivan, Kathleen E. « IMMUNOHISTOLOGIC ANALYSIS OF INEFFECTIVE CD40-CD40 LIGAND INTERACTION IN LYMPHOID TISSUES FROM PATIENTS WITH X-LINKED IMMUNODEFICIENCY WITH HYPER-IgM ». Pediatrics 98, n^o 2 (1 août 1996) : 350. http://dx.doi.org/10.1542/peds.98.2.350.

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The functional development of B cell follicles and follicular dendritic cells require CD40-CD40 ligand interactions. Both of these abnormalities probably contribute to the immunodeficiency in HIGMX-1.

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WEISS, S., F. ZENG et V. BONAGURA. « 841 Hyper-IgM syndrome (HIgMs) : A B-cell defect ». Journal of Allergy and Clinical Immunology 97, n^o 1 (janvier 1996) : 393. http://dx.doi.org/10.1016/s0091-6749(96)81059-1.

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Chang, Chih-Ching, Janet R. Gilsdorf, Victor J. DiRita et Carl F. Marrs. « Identification and Genetic Characterization ofHaemophilus influenzae Genetic Island 1 ». Infection and Immunity 68, n^o 5 (1 mai 2000) : 2630–37. http://dx.doi.org/10.1128/iai.68.5.2630-2637.2000.

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ABSTRACT The type b capsule of pathogenic Haemophilus influenzaeis a critical factor for H. influenzae survival in the blood and the establishment of invasive infections. Other pathogenic factors associated with type b strains may also play a role in invasion and sustained bacteremia, leading to the seeding of deep tissues. The gene encoding haemocin is the only noncapsular gene found to be specific to type b strains until now. Here we report the discovery of an approximately 16-kb genetic locus, HiGI1, that is present primarily in type b strains. Pulsed-field gel electrophoresis and Southern hybridization were used to map this new locus between secG(HI0445) and fruA (HI0446), which are contiguous in Rd, a nonpathogenic derivative of a serotype d strain. It is inserted at the 3′ end of tRNA4 Leu and has regions whose G+C content differs from the average genomic G+C content of H. influenzae. An integrase gene, which encodes a CP4-57 like integrase, is located downstream of tRNA4 Leu. Hybridization probes based on the sequences within the HiGI1 locus have been used to screen 61 H. influenzae strains (2 type a, 22 type b, 2 type c, 1 type d, 3 type e, 7 type f, and 21 nontypeableH. influenzae [NTHi]) from our collection. This HiGI1 locus exists in all 22 type b strains and two NTHi strains and is likely to have been acquired by an ancestral type b strain.

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Chen, Xinhai, Miaomiao Shi, Xin Tong, Hwan Keun Kim, Lai-Xi Wang, Olaf Schneewind et Dominique Missiakas. « Glycosylation-dependent opsonophagocytic activity of staphylococcal protein A antibodies ». Proceedings of the National Academy of Sciences 117, n^o 37 (27 août 2020) : 22992–3000. http://dx.doi.org/10.1073/pnas.2003621117.

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Antibodies may bind to bacterial pathogens or their toxins to control infections, and their effector activity is mediated through the recruitment of complement component C1q or the engagement with Fcγ receptors (FcγRs). For bacterial pathogens that rely on a single toxin to cause disease, immunity correlates with toxin neutralization. Most other bacterial pathogens, including Staphylococcus aureus, secrete numerous toxins and evolved multiple mechanisms to escape opsonization and complement killing. Several vaccine candidates targeting defined surface antigens of S. aureus have failed to meet clinical endpoints. It is unclear that such failures can be solely attributed to the poor selection of antibody targets. Thus far, studies to delineate antibody-mediated uptake and killing of Gram-positive pathogens remain extremely limited. Here, we exploit 3F6-hIgG1, a human monoclonal antibody that binds and neutralizes the abundant surface-exposed Staphylococcal protein A (SpA). We find that galactosylation of 3F6-hIgG1 that favors C1q recruitment is indispensable for opsonophagocytic killing of staphylococci and for protection against bloodstream infection in animals. However, the simple removal of fucosyl residues, which results in reduced C1q binding and increased engagement with FcγR, maintains the opsonophagocytic killing and protective attributes of the antibody. We confirm these results by engineering 3F6-hIgG1 variants with biased binding toward C1q or FcγRs. While the therapeutic benefit of monoclonal antibodies against infectious disease agents may be debatable, the functional characterization of such antibodies represents a powerful tool for the development of correlates of protection that may guide future vaccine trials.

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Tipton, Thomas R. W., Ali Roghanian, Robert J. Oldham, Matthew J. Carter, Kerry L. Cox, C. Ian Mockridge, Ruth R. French et al. « Antigenic modulation limits the effector cell mechanisms employed by type I anti-CD20 monoclonal antibodies ». Blood 125, n^o 12 (19 mars 2015) : 1901–9. http://dx.doi.org/10.1182/blood-2014-07-588376.

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Key Points Antigenic modulation significantly impacts natural killer cell and macrophage ability to mediate Fc γ receptor-dependent killing. hIgG1 mAbs are unable to elicit natural killer–mediated ADCC in the mouse, supporting ADCP as the dominant effector mechanism.

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Wang, Q. Daniel. « X-Ray Observations of the Hot Intergalactic Medium ». Symposium - International Astronomical Union 188 (1998) : 193–96. http://dx.doi.org/10.1017/s0074180900114743.

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A definite prediction from recent N-body/hydro simulations of the structure formation of the universe is the presence of a diffuse hot intergalactic medium (HIGM; e.g., Ostriker & Cen 1996). The filamentary structure of the today's universe, as seen in various galaxies surveys, is thought to be a result of the gravitational collapse of materials from a more-or-less uniform and isotropic early universe. During the collapse, shock-heating can naturally raise gas temperature to a range of 105 – 107 K. Feedbacks from stars may also be an important heating source and may chemically enrich the HIGM. The understanding of the heating and chemical enrichment of the IGM is critical for studying the structure and evolution of clusters of galaxies, which are nearly virialized systems (e.g., Kaiser 1991; David, Jones, & Forman 1996). Most importantly, the HIGM may explain much of the missing baryon content required by the Big Bang nucleosynthesis theories (e.g., Copi, Schramm, & Turner 1995); the total visible mass in galaxies and in the hot intracluster medium together is known to account for ≲ 10% of the baryon content (e.g., Persic & Salucci 1992).

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Chen, Xiangjun, Xiaolin Sun, Wei Yang, Bing Yang, Xiaozhen Zhao, Shuting Chen, Lili He et al. « An autoimmune disease variant of IgG1 modulates B cell activation and differentiation ». Science 362, n^o 6415 (4 octobre 2018) : 700–705. http://dx.doi.org/10.1126/science.aap9310.

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The maintenance of autoreactive B cells in a quiescent state is crucial for preventing autoimmunity. Here we identify a variant of human immunoglobulin G1 (IgG1) with a Gly396→Arg substitution (hIgG1-G396R), which positively correlates with systemic lupus erythematosus. In induced lupus models, murine homolog Gly390→Arg (G390R) knockin mice generate excessive numbers of plasma cells, leading to a burst of broad-spectrum autoantibodies. This enhanced production of antibodies is also observed in hapten-immunized G390R mice, as well as in influenza-vaccinated human G396R homozygous carriers. This variant potentiates the phosphorylation of the IgG1 immunoglobulin tail tyrosine (ITT) motif. This, in turn, alters the availability of phospho-ITT to trigger longer adaptor protein Grb2 dwell times in immunological synapses, leading to hyper–Grb2–Bruton’s tyrosine kinase (Btk) signaling upon antigen binding. Thus, the hIgG1-G396R variant is important for both lupus pathogenesis and antibody responses after vaccination.

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Razanajaona, D., C. van Kooten, S. Lebecque, J. M. Bridon, S. Ho, S. Smith, R. Callard, J. Banchereau et F. Brière. « Somatic mutations in human Ig variable genes correlate with a partially functional CD40-ligand in the X-linked hyper-IgM syndrome. » Journal of Immunology 157, n^o 4 (15 août 1996) : 1492–98. http://dx.doi.org/10.4049/jimmunol.157.4.1492.

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Abstract X-linked hyper-IgM (HIGM-1) syndrome is a rare disorder resulting from mutations in the CD40-ligand (CD40L) gene. This defect is associated with normal or elevated serum levels of IgM, and with low to undetectable levels of serum IgG, IgA, and IgE. We analyzed the somatic mutation status in Ig V genes from three unrelated HIGM-1 patients by reverse-transcription PCR and sequence analysis. Two patients (B.S. and P.S.) expressed unmutated VH6 genes. In contrast, one patient (A.T.) was found to express mutated VH6 genes. Whether the presence of somatic mutations in this patient was related to a functional CD40L was assessed by deriving T cell clones from his peripheral blood cells. Upon activation, these T cell clones expressed weakly and transiently surface CD40L, and were able to induce limited isotype switch of normal native B cells, indicating residual CD40L function. Altogether, our results 1) confirm the central role played by CD40L in the generation of somatic mutation (patients B.S. and P.S.), 2) provide an unusual illustration of the relative dissociation between somatic mutation and isotype switching (patient A.T.), and 3) demonstrate a further complexity of the X-linked HIGM syndrome that may occur despite a partially functional CD40L.

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Toropainen, Maija, Leena Saarinen, Gestur Vidarsson et Helena Käyhty. « Protection by Meningococcal Outer Membrane Protein PorA-Specific Antibodies and a Serogroup B Capsular Polysaccharide-Specific Antibody in Complement-Sufficient and C6-Deficient Infant Rats ». Infection and Immunity 74, n^o 5 (mai 2006) : 2803–8. http://dx.doi.org/10.1128/iai.74.5.2803-2808.2006.

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ABSTRACT The relative contributions of antibody-induced complement-mediated bacterial lysis and antibody/complement-mediated phagocytosis to host immunity against meningococcal infections are currently unclear. Further, the in vivo effector functions of antibodies may vary depending on their specificity and Fc heavy-chain isotype. In this study, a mouse immunoglobulin G2a (mIgG2a) monoclonal antibody (MN12H2) to meningococcal outer membrane protein PorA (P1.16), its human IgG subclass derivatives (hIgG1 to hIgG4), and an mIgG2a monoclonal antibody (Nmb735) to serogroup B capsular polysaccharide (B-PS) were evaluated for passive protection against meningococcal serogroup B strain 44/76-SL (B:15:P1.7,16) in an infant rat infection model. Complement component C6-deficient (PVG/c−) rats were used to assess the importance of complement-mediated bacterial lysis for protection. The PorA-specific parental mIgG2a and the hIgG1 to hIgG3 derivatives all induced efficient bactericidal activity in vitro in the presence of human or infant rat complement and augmented bacterial clearance in complement-sufficient HsdBrlHan:WIST rats, while the hIgG4 was unable to do so. In C6-deficient PVG/c− rats, lacking complement-mediated bacterial lysis, the augmentation of bacterial clearance by PorA-specific mIgG2a and hIgG1 antibodies was impaired compared to that in the syngeneic complement-sufficient PVG/c+ rat strain. This was in contrast to the case for B-PS-specific mIgG2a, which conferred similar protective activity in both rat strains. These data suggest that while anti-B-PS antibody can provide protection in the infant rats without membrane attack complex formation, the protection afforded by anti-PorA antibody is more dependent on the activation of the whole complement pathway and subsequent bacterial lysis.

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Iurian, Sorin Ioan, Laszlo Marodi et Capucine Picard. « Peculiar hyper-IgM syndrome. Case report / Sindrom hiper-IgM atipic. Prezentare de caz ». Revista Romana de Medicina de Laborator 23, n^o 3 (1 août 2015) : 341–45. http://dx.doi.org/10.1515/rrlm-2015-0027.

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AbstractWe report a male infant diagnosed at the age of 10 months with hyper-IgM syndrome (HIGM) in context of severe infections caused by Streptococcus pneumoniae, Staphylococcus aureus and Candida albicans. In patient’s outcome, in spite of immunoglobulin therapy, he continues presenting bilateral suppurative otitis media due to both Candida and penicillin-resistant pneumococcus and forearm abscess caused by Staphylococcus aureus. The infant developed bilateral cataracts, chronic hepatitis and comminuted fracture secondary to bone demineralization. The patient didn’t develop opportunistic infections as compare to CD40 Ligand deficiency patients. In contrast with the majority of HIGM cases, the infant necessity for immunoglobulin substitution was very limited. As a particularity of immunological phenotype, the patient IgM value progressively increased at a high level.

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Gallo, Vera, Emilia Cirillo, Rosaria Prencipe, Alessio Lepore, Luigi Del Vecchio, Giulia Scalia, Vincenzo Martinelli et al. « Clinical, Immunological, and Functional Characterization of Six Patients with Very High IgM Levels ». Journal of Clinical Medicine 9, n^o 3 (17 mars 2020) : 818. http://dx.doi.org/10.3390/jcm9030818.

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Very high IgM levels represent the hallmark of hyper IgM (HIGM) syndromes, a group of primary immunodeficiencies (PIDs) characterized by susceptibility to infections and malignancies. Other PIDs not fulfilling the diagnostic criteria for HIGM syndromes can also be characterized by high IgM levels and susceptibility to malignancies. The aim of this study is to characterize clinical phenotype, immune impairment, and pathogenic mechanism in six patients with very high IgM levels in whom classical HIGM syndromes were ruled out. The immunological analysis included extended B-cell immunophenotyping, evaluation of class switch recombination and somatic hypermutation, and next generation sequencing (NGS). Recurrent or severe infections and chronic lung changes at the diagnosis were reported in five out of six and two out of six patients, respectively. Five out of six patients showed signs of lymphoproliferation and four patients developed malignancies. Four patients showed impaired B-cell homeostasis. Class switch recombination was functional in vivo in all patients. NGS revealed, in one case, a pathogenic mutation in PIK3R1. In a second case, the ITPKB gene, implicated in B- and T-cell development, survival, and activity was identified as a potential candidate gene. Independent of the genetic basis, very high IgM levels represent a risk factor for the development of recurrent infections leading to chronic lung changes, lymphoproliferation, and high risk of malignancies.

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Hartley, Andrew M., Brigitte Meunier, Nikos Pinotsis et Amandine Maréchal. « Rcf2 revealed in cryo-EM structures of hypoxic isoforms of mature mitochondrial III-IV supercomplexes ». Proceedings of the National Academy of Sciences 117, n^o 17 (14 avril 2020) : 9329–37. http://dx.doi.org/10.1073/pnas.1920612117.

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The organization of the mitochondrial electron transport chain proteins into supercomplexes (SCs) is now undisputed; however, their assembly process, or the role of differential expression isoforms, remain to be determined. In Saccharomyces cerevisiae, cytochrome c oxidase (CIV) forms SCs of varying stoichiometry with cytochrome bc1 (CIII). Recent studies have revealed, in normoxic growth conditions, an interface made exclusively by Cox5A, the only yeast respiratory protein that exists as one of two isoforms depending on oxygen levels. Here we present the cryo-EM structures of the III2-IV1 and III2-IV2 SCs containing the hypoxic isoform Cox5B solved at 3.4 and 2.8 Å, respectively. We show that the change of isoform does not affect SC formation or activity, and that SC stoichiometry is dictated by the level of CIII/CIV biosynthesis. Comparison of the CIV5B- and CIV5A-containing SC structures highlighted few differences, found mainly in the region of Cox5. Additional density was revealed in all SCs, independent of the CIV isoform, in a pocket formed by Cox1, Cox3, Cox12, and Cox13, away from the CIII–CIV interface. In the CIV5B-containing hypoxic SCs, this could be confidently assigned to the hypoxia-induced gene 1 (Hig1) type 2 protein Rcf2. With conserved residues in mammalian Hig1 proteins and Cox3/Cox12/Cox13 orthologs, we propose that Hig1 type 2 proteins are stoichiometric subunits of CIV, at least when within a III-IV SC.

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Lee, Wen-I., Troy R. Torgerson, Michael J. Schumacher, Leman Yel, Qili Zhu et Hans D. Ochs. « Molecular analysis of a large cohort of patients with the hyper immunoglobulin M (IgM) syndrome ». Blood 105, n^o 5 (1 mars 2005) : 1881–90. http://dx.doi.org/10.1182/blood-2003-12-4420.

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AbstractThe hyper immunoglobulin M (IgM) syndrome (HIGM), characterized by recurrent infections, low serum IgG and IgA, normal or elevated IgM, and defective class switch recombination and somatic hypermutation, is a heterogenous disorder with at least 5 distinct molecular defects, including mutations of the genes coding for the CD40 ligand (CD40L) and IKK-gamma (NEMO) genes, both X-linked; and mutations of CD40, activation-induced cytidine deaminase (AICDA), and uracil-DNA glycosylase (UNG), associated with autosomal recessive HIGM syndromes. To investigate the molecular basis of HIGM, we determined the prevalence of mutations affecting these 5 genes in a cohort of 140 patients (130 males and 10 females). Those patients without a molecular diagnosis were subsequently evaluated for mutations of the following genes: inducible CO-stimulator molecule (ICOS), ICOS ligand (ICOSL), and if male, Bruton tyrosine kinase (Btk) and SLAM-associated protein (SAP/SH2D1A). We found mutations of CD40L in 98 males; AICDA in 4 patients (3 males, 1 female); UNG in one adult male; and Btk in 3 boys. Of the remaining 25 males, one infant with hypohidrotic ectodermal dysplasia had a mutation of NEMO. None of the remaining 33 patients (24 males/9 females) had mutations affecting CD40, ICOS, ICOSL, or SH2D1, and are best classified as common variable immune deficiency (CVID), although other genes, including some not yet identified, may be responsible.

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Jiang, Ning, Wei Chen, Prithiviraj Jothikumar, Jaina M. Patel, Rangaiah Shashidharamurthy, Periasamy Selvaraj et Cheng Zhu. « Effects of anchor structure and glycosylation of Fcγ receptor III on ligand binding affinity ». Molecular Biology of the Cell 27, n^o 22 (7 novembre 2016) : 3449–58. http://dx.doi.org/10.1091/mbc.e16-06-0470.

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Isoforms of the Fcγ receptor III (FcγRIII or CD16) are cell surface receptors for the Fc portion of IgG and important regulators of humoral immune responses. Different ligand binding kinetics of FcγRIII isoforms are obtained in three dimensions by surface plasmon resonance and in two dimensions by a micropipette adhesion frequency assay. We show that the anchor structure of CD16 isoforms isolated from the cell membrane affects their binding affinities in a ligand-specific manner. Changing the receptor anchor structure from full to partial to none decreases the ligand binding affinity for human IgG1 (hIgG1) but increases it for murine IgG2a (mIgG2a). Removing N-glycosylation from the CD16 protein core by tunicamycin also increases the ligand binding affinity. Molecular dynamics simulations indicate that deglycosylation at Asn-163 of CD16 removes the steric hindrance for the CD16-hIgG1 Fc binding and thus increases the binding affinity. These results highlight an unexpected sensitivity of ligand binding to the receptor anchor structure and glycosylation and suggest their respective roles in controlling allosterically the conformation of the ligand binding pocket of CD16.

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Maslova, N. N., et A. Ye Iusov. « ANALYSIS OF THE RELATIONSHIP DIAGNOSED MILD COGNITIVE IMPAIRMENT IN ELDERLY AND SENILE PATIENTS WITH CERTAIN FEATURES OF MEDICAL HISTORY AND DEPRESSION ». Bulletin of Siberian Medicine 12, n^o 5 (28 octobre 2013) : 46–50. http://dx.doi.org/10.20538/1682-0363-2013-5-46-50.

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Are defined frequency of mild cognitive impairment (MCI) at patients of advanced and senile age with chronic ischemia of a brain (HIGM) in comparison with frequency of existence of a depression, an education level and the place of residence and their interrelation. 100 patients with HIGM 2 age групп: 1 – advanced age (from 60 to 74 years – 48 people), 2 – senile age (from 75 to 89 years – 52 persons) are surveyed. In research didn't join: patients with Alzheimer's disease and other forms of a dementias. Diagnostics of UKN it was carried out by means of a short scale of an assessment of the mental status (MMSE). For an assessment of existence of a depression – Bek's scale. For objective justification of conclusions from results of the carried-out research the statistical analysis of primary information was used.

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Hubbard, Nicholas, David Hagin, Karen Sommer, Yumei Song, Iram Khan, Courtnee Clough, Hans D. Ochs, David J. Rawlings, Andrew M. Scharenberg et Troy R. Torgerson. « Targeted gene editing restores regulated CD40L function in X-linked hyper-IgM syndrome ». Blood 127, n^o 21 (26 mai 2016) : 2513–22. http://dx.doi.org/10.1182/blood-2015-11-683235.

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Key PointsThe CD40LG locus can be specifically targeted and repaired in primary human T cells by insertion of a spliced CD40LG complementary DNA. Gene editing restores regulated CD40L expression in X-HIGM T cells, reconstituting B-cell immunoglobulin class switching.

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Hubbard, Nicholas Wesley, David Hagin, Karen Sommer, Yumei Song, Iram Khan, Courtnee Clough, Hans D. Ochs, David J. Rawlings, Andrew Scharenberg et Troy R. Torgerson. « Targeted Gene Editing Restores Regulated CD40L Expression and Function in X-HIGM T cells. » Journal of Immunology 196, n^o 1_Supplement (1 mai 2016) : 214.28. http://dx.doi.org/10.4049/jimmunol.196.supp.214.28.

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Abstract Loss of CD40L expression or function results in X-Linked Hyper-IgM Syndrome (X-HIGM), characterized by recurrent infections due to impaired immunoglobulin class-switching and somatic hypermutation. Previous attempts using retroviral gene transfer to correct murine CD40L expression restored immune function; however, treated mice developed lymphoproliferative disease, likely due to viral-promoter dependent constitutive CD40L expression. These observations highlight the importance of preserving endogenous gene regulation in order to safely correct this disorder. Here we report efficient, on-target, homology directed repair (HDR) editing of the CD40LG locus in primary human T cells using a combination of a TALEN-induced double-strand break and a donor template delivered by recombinant Adeno-Associated Virus (rAAV). HDR mediated insertion of a coding sequence (GFP or CD40L) upstream of the translation start site within Exon 1 allowed transgene expression to be regulated by endogenous CD40LG promoter/enhancer elements. Additionally, inclusion of the CD40LG 3′-untranslated region (3′-UTR) in the transgene preserved post-transcriptional regulation. Expression kinetics of the transgene paralleled that of endogenous CD40L in unedited T cells, both at rest and in response to T cell stimulation. The use of this method to edit X-HIGM patient T cells restored normal expression of CD40L and CD40-muIg binding, and rescued IgG class switching of naïve B-cells in vitro. These results demonstrate the feasibility of engineered nuclease-directed gene repair to restore endogenously regulated CD40L, and the potential for its use in T cell therapy for X-HIGM syndrome.

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Ramesh, Narayanaswamy, Tomohiro Morio, Ramsay Fuleihan, Margitta Worm, Anthony Horner, Erdyni Tsitsikov, Emanuela Castigli et Raif S. Geha. « CD40—CD40 ligand (CD40L) interactions and X-linked hyperIgM syndrome (HIGMX-1) ». Clinical Immunology and Immunopathology 76, n^o 3 (septembre 1995) : S208—S213. http://dx.doi.org/10.1016/s0090-1229(95)90252-x.

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Wilson, Jacqueline Z. « Adolescent resistance narratives in a satirical schoolyard : the case ofSummer Heights High1 ». Journal of Australian Studies 33, n^o 3 (septembre 2009) : 305–16. http://dx.doi.org/10.1080/14443050903079698.

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Gosselin, E. J., K. Wardwell, D. R. Gosselin, N. Alter, J. L. Fisher et P. M. Guyre. « Enhanced antigen presentation using human Fc gamma receptor (monocyte/macrophage)-specific immunogens. » Journal of Immunology 149, n^o 11 (1 décembre 1992) : 3477–81. http://dx.doi.org/10.4049/jimmunol.149.11.3477.

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Abstract A major new challenge for vaccine development is to target APC such as monocytes and macrophages for efficient Ag processing and presentation. It has been shown that Fc gamma R-mediated uptake of Ag-antibody complexes can enhance Ag presentation by myeloid cells at least 100-fold, and directing Ag to Fc gamma R in mice brings about a substantial increase in the effectiveness of immunization while eliminating the requirement for adjuvant. It has not been determined which of the three subclasses of human Fc gamma R on myeloid cells (Fc gamma RI, Fc gamma RII, or Fc gamma RIII) function to enhance Ag presentation. We have targeted our Ag (TT) to each of the three subclasses of human Fc gamma R on monocytes using Fc gamma R subclass-specific mAb-TT conjugates, and have measured TT presentation by monitoring T cell proliferation in response to TT. In addition, we have examined enhanced Ag presentation mediated by a human IgG1 (HIgG1) anti-TT mAb. All anti-Fc gamma R-TT conjugates enhanced Ag presentation. HIgG1 anti-TT, in monomeric form, enhanced Ag presentation through Fc gamma RI only. Anti-Fc gamma RI-Ag conjugates appear to be optimal for application as vaccines. They are monocyte/macrophage-specific, are very efficiently processed and presented, and enhance Ag presentation despite occupation of Fc gamma RI with HIgG.

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Longo, Nancy S., Patricia L. Lugar, Sule Yavuz, Wen Zhang, Peter H. L. Krijger, Daniel E. Russ, Dereje D. Jima, Sandeep S. Dave, Amrie C. Grammer et Peter E. Lipsky. « Analysis of somatic hypermutation in X-linked hyper-IgM syndrome shows specific deficiencies in mutational targeting ». Blood 113, n^o 16 (16 avril 2009) : 3706–15. http://dx.doi.org/10.1182/blood-2008-10-183632.

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Abstract Subjects with X-linked hyper-IgM syndrome (X-HIgM) have a markedly reduced frequency of CD27+ memory B cells, and their Ig genes have a low level of somatic hypermutation (SHM). To analyze the nature of SHM in X-HIgM, we sequenced 209 nonproductive and 926 productive Ig heavy chain genes. In nonproductive rearrangements that were not subjected to selection, as well as productive rearrangements, most of the mutations were within targeted RGYW, WRCY, WA, or TW motifs (R = purine, Y = pyrimidine, and W = A or T). However, there was significantly decreased targeting of the hypermutable G in RGYW motifs. Moreover, the ratio of transitions to transversions was markedly increased compared with normal. Microarray analysis documented that specific genes involved in SHM, including activation-induced cytidine deaminase (AICDA) and uracil-DNA glycosylase (UNG2), were up-regulated in normal germinal center (GC) B cells, but not induced by CD40 ligation. Similar results were obtained from light chain rearrangements. These results indicate that in the absence of CD40-CD154 interactions, there is a marked reduction in SHM and, specifically, mutations of AICDA-targeted G residues in RGYW motifs along with a decrease in transversions normally related to UNG2 activity.

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Gray, D., P. Dullforce et S. Jainandunsing. « Memory B cell development but not germinal center formation is impaired by in vivo blockade of CD40-CD40 ligand interaction. » Journal of Experimental Medicine 180, n^o 1 (1 juillet 1994) : 141–55. http://dx.doi.org/10.1084/jem.180.1.141.

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To study the role of the CD40-CD40 ligand interaction in the development of memory B cells and its level of action during primary antibody responses in vivo, mice were injected with a soluble CD40 fusion protein (sCD40-gamma 1), so as to block the interaction. The effects of the treatment on the primary antibody response were reminiscent of hyper-immunoglobulin M (IgM) syndrome (HIMG1): antigen-specific IgG responses were grossly inhibited whereas the IgM response was augmented severalfold. The latter observation suggests that there is a T-dependent, CD40 ligand-independent pathway of B cell activation that leads to IgM responses and that a significant component of the IgM in HIMG1 patients is derived from T-dependent responses. The secondary response was not readily blocked by sCD40-gamma 1 treatment, indicating a relative independence of CD40 ligation of antigen-experienced B cells. The most striking finding from these studies is that the development of memory B cell populations (measured by adoptive transfer) is grossly impaired by administration of sCD40-gamma 1 during the early induction phase of the response. It is surprising that although the generation memory is diminished, there is no quantitative difference in the development of germinal centers. Whereas entry of B cells into the memory cell pathway is dependent on CD40 ligation, the clonal expansion of the potential memory precursors in germinal centers seems not to require a CD40 signal.

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Gigolashvili, Tamara, Bettina Berger, Hans-Peter Mock, Caroline Müller, Bernd Weisshaar et Ulf-Ingo Flügge. « The transcription factor HIG1/MYB51 regulates indolic glucosinolate biosynthesis in Arabidopsis thaliana ». Plant Journal 50, n^o 5 (25 avril 2007) : 886–901. http://dx.doi.org/10.1111/j.1365-313x.2007.03099.x.

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Hayashi, Hiroki, Hironori Nakagami, Makiko Takeichi, Munehisa Shimamura, Nobutaka Koibuchi, Eiji Oiki, Naoyuki Sato et al. « HIG1, a novel regulator of mitochondrial γ‐secretase, maintains normal mitochondrial function ». FASEB Journal 26, n^o 6 (21 février 2012) : 2306–17. http://dx.doi.org/10.1096/fj.11-196063.

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Stonans, I., S. Zielen, U. Junker, R. Bialek, F. Zepp, E. Stonane et L. Jäger. « Defects of interleukins and their receptors in hypogammaglobulinemia with hyper-IgM (HIGM) ». Cytokine 6, n^o 5 (septembre 1994) : 570. http://dx.doi.org/10.1016/1043-4666(94)90268-2.

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Alekseeva, E. A., T. A. Evstyukhina, V. T. Peshekhonov et V. G. Korolev. « INTERACTION OF THE HIM1 GENE PRODUCT WITH HELICASES Srs2 (RadH) AND Mph1 YEAST SACCHAROMYCES CEREVISIAE ». Tsitologiya 60, n^o 7 (2018) : 555–57. http://dx.doi.org/10.31116/tsitol.2018.07.13.

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