Journal articles: 'LIPOPOLYSACCHARIDE RESPONSIVE BEIGE-LIKE ANCHOR PROTEIN'

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Berger, J., H. Frudden, A. Van Hersh, C. Vethody, and K. Schikler. "AN ATYPICAL PRESENTATION OF LIPOPOLYSACCHARIDE-RESPONSIVE BEIGE-LIKE ANCHOR PROTEIN DEFICIENCY." Annals of Allergy, Asthma & Immunology 129, no. 5 (November 2022): S122—S123. http://dx.doi.org/10.1016/j.anai.2022.08.855.

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Tang, Wen-Juan, Wen-Hui Hu, Ying Huang, Bing-Bing Wu, Xiao-Min Peng, Xiao-Wen Zhai, Xiao-Wen Qian, et al. "Potential protein–phenotype correlation in three lipopolysaccharide-responsive beige-like anchor protein-deficient patients." World Journal of Clinical Cases 9, no. 21 (July 26, 2021): 5873–88. http://dx.doi.org/10.12998/wjcc.v9.i21.5873.

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Mehta, Rushita, John F. Thompson, Kelly Fradin, and Jasmeen S. Dara. "Consanguineous Siblings with a Novel Mutation in Lipopolysaccharide-Responsive Beige-like Anchor protein (LRBA)." Journal of Allergy and Clinical Immunology 139, no. 2 (February 2017): AB16. http://dx.doi.org/10.1016/j.jaci.2016.12.009.

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Kutluǧ, Şeyhan, Kaan Boztuǧ, and Alişan Yıldıran. "Development of multiple gallstones in a child with lipopolysaccharide-responsive beige-like anchor protein mutation." Central European Journal of Immunology 44, no. 3 (2019): 332–35. http://dx.doi.org/10.5114/ceji.2019.89613.

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Maggiore, Rosario, Alice Grossi, Francesca Fioredda, Elena Palmisani, Paola Terranova, Enrico Cappelli, Tiziana Lanza, et al. "Unusual Late-onset Enteropathy in a Patient With Lipopolysaccharide-responsive Beige-like Anchor Protein Deficiency." Journal of Pediatric Hematology/Oncology 42, no. 8 (December 23, 2019): e768-e771. http://dx.doi.org/10.1097/mph.0000000000001708.

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Martinez-Jaramillo, Catalina, and Claudia M. Trujillo-Vargas. "Dissecting the localization of lipopolysaccharide-responsive and beige-like anchor protein (LRBA) in the endomembrane system." Allergologia et Immunopathologia 48, no. 1 (January 2020): 8–17. http://dx.doi.org/10.1016/j.aller.2019.07.011.

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Yadav, Arti, Rakesh Kumar, Amit Rawat, and Radha Venkatesan. "Neonatal diabetes with a rare LRBA mutation." BMJ Case Reports 15, no. 11 (November 2022): e250243. http://dx.doi.org/10.1136/bcr-2022-250243.

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Neonatal diabetes mellitus (NDM) is characterised by onset of persistent hyperglycaemia within the first 6 months of life. NDM is frequently caused by a mutation in a single gene affecting pancreatic beta cell function. We report an infant, born to a non-consanguineous couple, who presented with osmotic symptoms and diabetic ketoacidosis. The genetic analysis showed a mutation in LRBA (lipopolysaccharide-responsive and beige-like anchor protein) gene. We highlight the importance of considering genetic analysis in every infant with NDM, to understand the nature of genetic mutation, associated comorbidities, response to glibenclamide and future prognosis.

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Pérez-Pérez, Daniela, Leopoldo Santos-Argumedo, Juan Carlos Rodríguez-Alba, and Gabriela López-Herrera. "Role of Protein Kinase A Activation in the Immune System with an Emphasis on Lipopolysaccharide-Responsive and Beige-like Anchor Protein in B Cells." International Journal of Molecular Sciences 24, no. 4 (February 4, 2023): 3098. http://dx.doi.org/10.3390/ijms24043098.

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Cyclic AMP-dependent protein kinase A (PKA) is a ubiquitous enzymatic complex that is involved in a broad spectrum of intracellular receptor signaling. The activity of PKA depends on A-kinase anchoring proteins (AKAPs) that attach to PKAs close to their substrates to control signaling. Although the relevance of PKA-AKAP signaling in the immune system is evident in T cells, its relevance in B and other immune cells remains relatively unclear. In the last decade, lipopolysaccharide-responsive and beige-like anchor protein (LRBA) has emerged as an AKAP that is ubiquitously expressed in B and T cells, specifically after activation. A deficiency of LRBA leads to immune dysregulation and immunodeficiency. The cellular mechanisms regulated by LRBA have not yet been investigated. Therefore, this review summarizes the functions of PKA in immunity and provides the most recent information regarding LRBA deficiency to deepen our understanding of immune regulation and immunological diseases.

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Pandya, D. B. "POS1469 POLYAUTOIMMUNITY AS THE PRESENTING FEATURE OF LIPOPOLYSACCHARIDE RESPONSIVE BEIGE-LIKE ANCHOR PROTEIN DEFICIENCY IN A YOUNG INDIAN BOY." Annals of the Rheumatic Diseases 81, Suppl 1 (May 23, 2022): 1080.2–1080. http://dx.doi.org/10.1136/annrheumdis-2022-eular.2453.

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BackgroundLPS-responsive beige-like anchor protein(LRBA) deficiency is an autosomal recessive disorder caused by biallelic mutations in the LRBA gene leading to a syndrome of autoimmunity, lymphoproliferation and humoral immune deficiency.LRBA protein plays a major immuno-regulatory role in the expression, function and trafficking of cytotoxic T lymphocyte-associated protein 4 (CTLA4) in Tregs which is an immune effector molecule that acts as an inhibitory checkpoint for the immune response.1,2,3ObjectivesWe report a 7 years old boy with LRBA deficiency who was presented with polyautoimmuity primarily affecting gut, pancreas & joints with recurrent infections.MethodsHe was born to a non-consanguineous Indian parents with uneventful birth, development and vaccination history.He had been unwell from the age of one with multiple episodes of lower respiratory tract infections warranting usage of prolonged antibiotics. 2.5 years of age, he had been diagnosed as Type 1 Diabetes Mellitus and he was commenced on insulin therapy. 3.5 years, he developed chronic diarrhoea.Evaluation revealed sterile blood, urine and stool cultures with normal abdominal imaging(USG & CT scan), elevated TTg-IgA & HTTP/DGP screen and negative HLADQ2-DQ8. He failed gluten-free diet. Gastrointestinal endoscopy showed duodenum and terminal ileum nodularity & biopsy was suggestive of non-celiac autoimmune enteropathy. 4 years, he developed two episodes of stridor, tetany and breathing difficulty which were promptly reversed by IV calcium infusion. He had low serum calcium, low parathyroid hormone with normal vitamin D level, serum phosphorous, magnesium, thyroid profile, anti-thyroid antibodies, renal and liver functions. 5.5 years, he first presented to us with chronic unexplained polyarthritis involving small and large joints in an additive pattern. Family history was significant for a death of the previous male sibling at 7 months of age due to chronic unexplained diarrhoea. Examination revealed facial dysmorphism and failure to thrive with no systmic findings.ResultsInvestigations showed HB 8.1gm%,TLC6700/cumm with normal differential counts and platelet counts 233000/ul. ESR was 39mm/hr and CRP was negative. Direct coomb’s test, RF, ANA were negative. He had a mild elevation in IgG levels with normal B-T cells populations. Genetic evaluation revelaed pathogenic homozygous splice site mutation in intron 11 of LRBA gene. Both the parents are heterozygous carriers. A largest systematic review3 of 212 cases of LRBA deficiency showed autoimmunity(70%), non malignanat lymphoproliferation(54%), enteropathy(41%), endocrinopathy(41%) and lower respiratory tract infections(41%) as the most common clinical manifestations with normal or abnormal immunoglobulin level and B-T cells populations. Arthritis(8%) was amongst the rare manifestations. Hypoparathyroidism was the rarest endocrine manifestations. No data available regarding prevalence of positive celiac disease antibodies. There was no haematological manifestations in our case.ConclusionLRBA deficiency should be strongly considered in a child recurrent infection and polyautoimmunity including arthritis. Abatacept could be used as a steroid sparing agent and as a bridging agent awaiting transplant.References[1]Am J Hum Genet.2012; Deleterious mutations in LRBA are associated with a syndrome of immune deficiency and autoimmunity. Lopez-Herrera G, Tampella G, Hammarström Q, et al.[2]J Allergy Clin Immunol Pract Sep-Oct 2019; Clinical, Immunologic, and Molecular Spectrum of Patients with LPS-Responsive Beige-Like Anchor Protein Deficiency: A Systematic Review Sima Habibi, Majid Zaki-Dizaji, Hosein Rafiemanesh, Bernice Lo, Mahnaz Jamee[3]Clinical and Experimental Immunology, 31st March 2021, Comprehensive comparison between 222 CTLA-4 haploinsufficiency and 212 LRBA deficiency patients: a systematic review, M. Jamee, S. Hosseinzadeh, N. Sharifinejad, M. Zaki-DizajiAcknowledgementsDr Hitesh Bhambhani, Dr Nitin Trivedi, Dr Zalak Shah Upadhyay, Dr Chetan DaveDisclosure of InterestsNone declared

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Martínez Jaramillo, Catalina, and Claudia Milena Trujillo Vargas. "LRBA in the endomembrane system." Colombia Médica 49, no. 3 (September 1, 2018): 236–43. http://dx.doi.org/10.25100/cm.v49i3.3802.

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Bi-allelic mutations in LRBA (from Lipopolysaccharide-responsive and beige-like anchor protein) result in a primary immunodeficiency with clinical features ranging from hypogammaglobulinemia and lymphoproliferative syndrome to inflammatory bowel disease and heterogeneous autoimmune manifestations. LRBA deficiency has been shown to affect vesicular trafficking, autophagy and apoptosis, which may lead to alterations of several molecules and processes that play key roles for immunity. In this review, we will discuss the relationship of LRBA with the endovesicular system in the context of receptor trafficking, autophagy and apoptosis. Since these mechanisms of homeostasis are inherent to all living cells and not only limited to the immune system and also, because they are involved in physiological as well as pathological processes such as embryogenesis or tumoral transformation, we envisage advancing in the identification of potential pharmacological agents to manipulate these processes.

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Kondratenko, I. V., S. S. Vakhlayrskaya, and D. V. Rogozhin. "DEFICIENCY OF LRBA: BIBLIOGRAPHICAL REVIEW AND CASE REPORT." Pediatria. Journal named after G.N. Speransky 100, no. 2 (April 12, 2021): 192–203. http://dx.doi.org/10.24110/0031-403x-2021-100-2-192-203.

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Since the description of the first primary immunodeficiencies (PIDs) in the 50–60s of the last century, they have been the subject of intensive research aimed at elucidating their etiology and finding effective treatments. The development of next-generation sequencing (NGS) methods made it possible to reveal the genetic basis of many new forms of PID, which were previously attributed to various syndromes due to their clinical and immunological characteristics. An example of such a PID is the LRBA (the lipopolysaccharide-responsive and beige-like anchor protein) deficiency, sometimes called LATAIE [LRBA deficiency with autoantibodies, regulatory T (Treg) cell defects, autoimmune infiltration, and enteropathy]. The article provides information on the main role of the LRBA molecule in the functions of immunocompetent cells, describes immunological disorders and clinical manifestations of LRBA deficiency and the principles of treatment of diseases. Two own observations of LRBA deficiency are presented.

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Bonilla, Francisco A. "Personalized therapy for common variable immunodeficiency." Allergy and Asthma Proceedings 41, no. 1 (January 1, 2020): 19–25. http://dx.doi.org/10.2500/aap.2020.41.190012.

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Background: Common variable immunodeficiency (CVID) represents a clinical descriptive diagnosis that was defined in the 1970s. Despite the vast increase in knowledge with regard to immune function and genetics, the pathophysiology of this disorder remains poorly understood in the majority of patients (75%); however, recent advances have led to a much clearer understanding of this heterogeneous group of disorders in the remaining 25%. These advances, along with developments in immune modulatory and reconstitution therapies, now permit sophisticated and specific targeting of therapies for individual patients. Methods: A literature review and author experience. Results: For > 50 years, immune globulin therapy has been applied to patients with CVID. There are several options open to patients, including a diversity of products and modes of administration. Stem cell therapy is increasingly applicable in patients with severe immune dysregulation. In some disorders (e.g., lipopolysaccharide-responsive and beige-like anchor protein, and cytotoxic T lymphocyte antigen 4 deficiencies), knowledge of the genetic basis and molecular pathophysiology permit targeted therapy by using small-molecule immune modulators and biologics. Conclusion: In the near future, it is likely that further advances in understanding the pathophysiology of CVID, together with ongoing development of biologics and small-molecule immune modulators will lead to additional targeted therapies for these patients.

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Rajpurkar, Madhvi, Steven Buck, Jennifer Lafferty, Erin Wakeling, Yaddanapudi Ravindranath, and Süreyya Savaşan. "Acquired Pure Red Cell Aplasia and Acquired Amegakaryocytic Thrombocytopenia Associated With Clonal Expansion of T-Cell Large Granular Lymphocytes in a Patient With Lipopolysaccharide-responsive Beige-like Anchor (LRBA) Protein Deficiency." Journal of Pediatric Hematology/Oncology 41, no. 8 (November 2019): e542-e545. http://dx.doi.org/10.1097/mph.0000000000001292.

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Strakova, Veronika, Lenka Elblova, Matthew B. Johnson, Petra Dusatkova, Barbora Obermannova, Lenka Petruzelkova, Stanislava Kolouskova, et al. "Screening of monogenic autoimmune diabetes among children with type 1 diabetes and multiple autoimmune diseases: is it worth doing?" Journal of Pediatric Endocrinology and Metabolism 32, no. 10 (October 25, 2019): 1147–53. http://dx.doi.org/10.1515/jpem-2019-0261.

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Abstract Background Paediatric type 1 diabetes (T1D) and rare syndromes of monogenic multi-organ autoimmunity share basic features such as full insulin dependency and the presence of circulating beta-cell autoantibodies. However, the aetiopathogenesis, natural course and treatment of these conditions differ; therefore, monogenic multi-organ autoimmunity requires early recognition. We aimed to search for these monogenic conditions among a large cohort of children with T1D. Methods Of 519 children with T1D followed-up in a single centre, 18 had multiple additional autoimmune conditions – either autoimmune thyroid disease (AITD) and coeliac disease (CD) or at least one additional organ-specific autoimmune condition in addition to AITD or CD. These 18 children were tested by direct Sanger sequencing (four patients with a suggestive phenotype of immune dysregulation, polyendocrinopathy, enteropathy, X-linked [IPEX] or signal transducer and activator of transcription 3 [STAT3]- and cytotoxic T-lymphocyte protein 4 [CTLA4]-associated syndromes) or by whole-exome sequencing (WES) focused on autoimmune regulator (AIRE), forkhead box protein 3 (FOXP3), CTLA4, STAT3, signal transducer and activator of transcription 1 (STAT1), lipopolysaccharide-responsive and beige-like anchor protein (LRBA) and interleukin-2 receptor subunit α (IL2RA) genes. In addition, we assessed their T1D genetic risk score (T1D-GRS). Results We identified novel variants in FOXP3, STAT3 and CTLA4 in four cases. All patients had a severe phenotype suggestive of a single gene defect. No variants were identified in the remaining 14 patients. T1D-GRS varied among the entire cohort; four patients had scores below the 25th centile including two genetically confirmed cases. Conclusions A monogenic cause of autoimmune diabetes was confirmed only in four patients. Genetic screening for monogenic autoimmunity in children with a milder phenotype and a combination of AITD and CD is unlikely to identify a monogenic cause. In addition, the T1D-GRS varied among individual T1D patients.

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Liburd, Kyndra, and Christopher Chang. "Lipopolysaccharide Responsive Beige-Like Anchor (LRBA) Protein Deficiency in a 12-year-old Female with Failure To Thrive Liburd, K., Chang, C. Division of Pediatric Immunology and Allergy. Joe DiMaggio Children’s Hospital, Hollywood, FL." Journal of Allergy and Clinical Immunology 145, no. 2 (February 2020): AB123. http://dx.doi.org/10.1016/j.jaci.2019.12.493.

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Schreiner, Felix, Michaela Plamper, Gesche Dueker, Stefan Schoenberger, Laura Gámez-Díaz, Bodo Grimbacher, Alina C. Hilger, Bettina Gohlke, Heiko Reutter, and Joachim Woelfle. "Infancy-Onset T1DM, Short Stature, and Severe Immunodysregulation in Two Siblings With a Homozygous LRBA Mutation." Journal of Clinical Endocrinology & Metabolism 101, no. 3 (March 1, 2016): 898–904. http://dx.doi.org/10.1210/jc.2015-3382.

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Abstract Context: Type 1 diabetes mellitus (T1DM) is caused by autoimmunity against pancreatic β-cells. Although a significant number of T1DM patients have or will develop further autoimmune disorders during their lifetime, coexisting severe immunodysregulation is rare. Objective: Presuming autosomal-recessive inheritance in a complex immunodysregulation disorder including T1DM and short stature in two siblings, we performed whole-exome sequencing. Case Presentation: Two Libyan siblings born to consanguineous parents were presented to our diabetology department at ages 12 and 5 years, respectively. Apart from T1DM diagnosed at age 2 years, patient 1 suffered from chronic restrictive lung disease, mild enteropathy, hypogammaglobulinemia, and GH deficiency. Fluorescence-activated cell sorting analysis revealed B-cell deficiency. In addition, CD4+/CD25+ and CD25high/FoxP3+ cells were diminished, whereas an unusual CD25−/FoxP3+ population was detectable. The younger brother, patient 2, also developed T1DM during infancy. Although his enteropathy was more severe and electrolyte derangements repeatedly led to hospitalization, he did not have significant pulmonary problems. IgG levels and B-lymphocytes were within normal ranges. Results: By whole-exome sequencing we identified a homozygous truncating mutation (c.2445_2447del(C)3ins(C)2, p.P816Lfs*4) in the lipopolysaccharide-responsive beige-like anchor (LRBA) gene in both siblings. The diagnosis of LRBA deficiency was confirmed by a fluorescence-activated cell sorting-based immunoassay showing the absence of LRBA protein in phytohemagglutinin-stimulated peripheral blood mononuclear cells. Conclusion: We identified a novel truncating LRBA mutation in two siblings with T1DM, short stature, and severe immunodysregulation. LRBA mutations have previously been reported to cause multiorgan autoimmunity and immunodysfunction. In light of the variable phenotypes reported so far in LRBA-mutant individuals, LRBA deficiency should be considered in all patients presenting with T1DM and signs of severe immunodysregulation.

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Tuğcu, Gökçen Dilşa, Sanem Eryilmaz Polat, Ayşe Metin, Diclehan Orhan, and Güzin Cinel. "Interstitial Lung Disease in an Adolescent Girl with Lipopolysaccharide-Responsive Beige-Like Anchor Deficiency." Pediatric Allergy, Immunology, and Pulmonology 35, no. 3 (September 1, 2022): 133–38. http://dx.doi.org/10.1089/ped.2022.0088.

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Wang, Jia-Wang, Michelle A. Reiser, Kunyu Li, Bangmei Wang, and Richard F. Lockey. "Lipopolysaccharide-Responsive Beige-like Anchor Is Required for Both Activation and Deactivation of NFkB." Journal of Allergy and Clinical Immunology 135, no. 2 (February 2015): AB152. http://dx.doi.org/10.1016/j.jaci.2014.12.1436.

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Salami, Fereshte, Afshin Shirkani, Mohammad Shahrooei, Gholamreza Azizi, Reza Yazdani, Hassan Abolhassani, and Asghar Aghamohammadi. "Leishmaniasis and Autoimmunity in Patient with LPS-Responsive Beige-Like Anchor Protein (LRBA) Deficiency." Endocrine, Metabolic & Immune Disorders - Drug Targets 20, no. 3 (March 24, 2020): 479–84. http://dx.doi.org/10.2174/1871530319666190807161546.

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Background/Objective: LPS-responsive beige-like anchor protein (LRBA) deficiency is a combined immunodeficiency and immune dysregulation. The authors present a case report of LPSresponsive beige-like anchor protein (LRBA) deficiency with the history of autoimmunity, enteropathy and visceral leishmaniasis. Sirolimus therapy was started for autoimmunity and enteropathy but was discontinued due to recurrent leishmaniasis. Therefore, a common side-effect of many immunosuppressive drugs in patients with LRBA deficiency is increased susceptibility to infections. Methods: Whole exome sequencing was performed to detect the underlying genetic mutation and Leishmania DNA was detected by the PCR technique in this patient. Results: Whole exome sequencing of the patient reported a homozygous frameshift deletion mutation in the LRBA gene (NM_006726: exon29: c.4638delC, p. S1546fs). Leishmania DNA PCR was positive in this case. Conclusion: Parasite infections manifestations report in LRBA deficiency. Leishmania infections in patients with chronic diarrhea and autoimmunity should be considered for immunodeficiency.

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Gámez-Díaz, Laura, Dietrich August, Polina Stepensky, Shoshana Revel-Vilk, Markus G. Seidel, Mitsuiki Noriko, Tomohiro Morio, et al. "The extended phenotype of LPS-responsive beige-like anchor protein (LRBA) deficiency." Journal of Allergy and Clinical Immunology 137, no. 1 (January 2016): 223–30. http://dx.doi.org/10.1016/j.jaci.2015.09.025.

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Shamriz, Oded, Bella Shadur, Adeeb NaserEddin, Irina Zaidman, Natalia Simanovsky, Orly Elpeleg, Eitan Kerem, Joel Reiter, and Polina Stepensky. "Respiratory manifestations in LPS-responsive beige-like anchor (LRBA) protein-deficient patients." European Journal of Pediatrics 177, no. 8 (May 18, 2018): 1163–72. http://dx.doi.org/10.1007/s00431-018-3171-5.

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Mozdarani, Hossein, Fatemeh Kiaee, Saba Fekrvand, Gholamreza Azizi, Reza Yazdani, Majid Zaki-Dizaji, Sahar Mozdarani, et al. "G2-lymphocyte chromosomal radiosensitivity in patients with LPS responsive beige-like anchor protein (LRBA) deficiency." International Journal of Radiation Biology 95, no. 6 (February 13, 2019): 680–90. http://dx.doi.org/10.1080/09553002.2019.1577570.

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Cody, Joseph S., Patrick Brady, Qingmin Wang, and Frank Vasey. "LPS-RESPONSIVE BEIGE-LIKE ANCHOR PROTEIN AND ITS ROLE IN THE PATHOGENESIS OF CROHNʼS DISEASE." American Journal of Gastroenterology 99 (October 2004): S262. http://dx.doi.org/10.14309/00000434-200410001-00804.

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Seidel, Markus G., Katrin Böhm, Figen Dogu, Austen Worth, Adrian Thrasher, Benoit Florkin, Aydan İkincioğulları, et al. "Treatment of severe forms of LPS-responsive beige-like anchor protein deficiency with allogeneic hematopoietic stem cell transplantation." Journal of Allergy and Clinical Immunology 141, no. 2 (February 2018): 770–75. http://dx.doi.org/10.1016/j.jaci.2017.04.023.

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Habibi, Sima, Majid Zaki-Dizaji, Hosein Rafiemanesh, Bernice Lo, Mahnaz Jamee, Laura Gámez-Díaz, Fereshte Salami, et al. "Clinical, Immunologic, and Molecular Spectrum of Patients with LPS-Responsive Beige-Like Anchor Protein Deficiency: A Systematic Review." Journal of Allergy and Clinical Immunology: In Practice 7, no. 7 (September 2019): 2379–86. http://dx.doi.org/10.1016/j.jaip.2019.04.011.

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Khoza, Thembisile, Ian Dubery, and Lizelle Piater. "Identification of Candidate Ergosterol-Responsive Proteins Associated with the Plasma Membrane of Arabidopsis thaliana." International Journal of Molecular Sciences 20, no. 6 (March 14, 2019): 1302. http://dx.doi.org/10.3390/ijms20061302.

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The impact of fungal diseases on crop production negatively reflects on sustainable food production and overall economic health. Ergosterol is the major sterol component in fungal membranes and regarded as a general elicitor or microbe-associated molecular pattern (MAMP) molecule. Although plant responses to ergosterol have been reported, the perception mechanism is still unknown. Here, Arabidopsis thaliana protein fractions were used to identify those differentially regulated following ergosterol treatment; additionally, they were subjected to affinity-based chromatography enrichment strategies to capture and categorize ergosterol-interacting candidate proteins using liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS). Mature plants were treated with 250 nM ergosterol over a 24 h period, and plasma membrane-associated fractions were isolated. In addition, ergosterol was immobilized on two different affinity-based systems to capture interacting proteins/complexes. This resulted in the identification of defense-related proteins such as chitin elicitor receptor kinase (CERK), non-race specific disease resistance/harpin-induced (NDR1/HIN1)-like protein, Ras-related proteins, aquaporins, remorin protein, leucine-rich repeat (LRR)- receptor like kinases (RLKs), G-type lectin S-receptor-like serine/threonine-protein kinase (GsSRK), and glycosylphosphatidylinositol (GPI)-anchored protein. Furthermore, the results elucidated unknown signaling responses to this MAMP, including endocytosis, and other similarities to those previously reported for bacterial flagellin, lipopolysaccharides, and fungal chitin.

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Seidel, Markus G. "Autoimmune and other cytopenias in primary immunodeficiencies: pathomechanisms, novel differential diagnoses, and treatment." Blood 124, no. 15 (October 9, 2014): 2337–44. http://dx.doi.org/10.1182/blood-2014-06-583260.

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Abstract Autoimmunity and immune dysregulation may lead to cytopenia and represent key features of many primary immunodeficiencies (PIDs). Especially when cytopenia is the initial symptom of a PID, the order and depth of diagnostic steps have to be performed in accordance with both an immunologic and a hematologic approach and will help exclude disorders such as systemic lupus erythematosus, common variable immunodeficiency, and autoimmune lymphoproliferative syndromes, hemophagocytic disorders, lymphoproliferative diseases, and novel differential diagnoses such as MonoMac syndrome (GATA2 deficiency), CD27 deficiency, lipopolysaccharide-responsive beige-like anchor (LRBA) deficiency, activated PI3KD syndrome (APDS), X-linked immunodeficiency with magnesium defect (MAGT1 deficiency), and others. Immunosuppressive treatment often needs to be initiated urgently, which impedes further relevant immunologic laboratory analyses aimed at defining the underlying PID. Awareness of potentially involved disease spectra ranging from hematologic to rheumatologic and immunologic disorders is crucial for identifying a certain proportion of PID phenotypes and genotypes among descriptive diagnoses such as autoimmune hemolytic anemia, chronic immune thrombocytopenia, Evans syndrome, severe aplastic anemia/refractory cytopenia, and others. A synopsis of pathomechanisms, novel differential diagnoses, and advances in treatment options for cytopenias in PID is provided to facilitate multidisciplinary management and to bridge different approaches.

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De Bruyne, Marieke, Delfien J. Bogaert, Koen Venken, Lien Van den Bossche, Carolien Bonroy, Lisa Roels, Simon J. Tavernier, et al. "A novel LPS-responsive beige-like anchor protein (LRBA) mutation presents with normal cytotoxic T lymphocyte-associated protein 4 (CTLA-4) and overactive TH17 immunity." Journal of Allergy and Clinical Immunology 142, no. 6 (December 2018): 1968–71. http://dx.doi.org/10.1016/j.jaci.2018.08.026.

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Wang, Kuan-wen, Xiaoming Zhan, William McAlpine, Zhao Zhang, Jin Huk Choi, Hexin Shi, Takuma Misawa, et al. "Enhanced susceptibility to chemically induced colitis caused by excessive endosomal TLR signaling in LRBA-deficient mice." Proceedings of the National Academy of Sciences 116, no. 23 (May 16, 2019): 11380–89. http://dx.doi.org/10.1073/pnas.1901407116.

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LPS-responsive beige-like anchor (LRBA) protein deficiency in humans causes immune dysregulation resulting in autoimmunity, inflammatory bowel disease (IBD), hypogammaglobulinemia, regulatory T (Treg) cell defects, and B cell functional defects, but the cellular and molecular mechanisms responsible are incompletely understood. In an ongoing forward genetic screen forN-ethyl-N-nitrosourea (ENU)-induced mutations that increase susceptibility to dextran sodium sulfate (DSS)-induced colitis in mice, we identified two nonsense mutations inLrba. Although Tregcells have been a main focus in LRBA research to date, we found that dendritic cells (DCs) contribute significantly to DSS-induced intestinal inflammation in LRBA-deficient mice.Lrba−/−DCs exhibited excessive IRF3/7- and PI3K/mTORC1-dependent signaling and type I IFN production in response to the stimulation of the Toll-like receptors (TLRs) 3, TLR7, and TLR9. Substantial reductions in cytokine expression and sensitivity to DSS in LRBA-deficient mice were caused by knockout ofUnc93b1, a chaperone necessary for trafficking of TLR3, TLR7, and TLR9 to endosomes. Our data support a function for LRBA in limiting endosomal TLR signaling and consequent intestinal inflammation.

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Sudan, Raki, Mi Young Park, Neetu Srivastava, Sudha Neelam, Christie Youngs, Jia-Wang Wang, Robert W. Engelman, and William Kerr. "LRBA is essential for allogeneic responses in bone marrow transplantation." Journal of Immunology 196, no. 1_Supplement (May 1, 2016): 140.22. http://dx.doi.org/10.4049/jimmunol.196.supp.140.22.

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Abstract Members of the PH-BEACH-WD40 repeat gene family (PBW) play a role in coordinating receptor signaling and intracellular vesicle trafficking. LPS-Responsive Beige-like Anchor (LRBA) is a PBW protein whose immune function has not been defined. Here we show that LRBA−/− mice are viable with normal and healthful life span, but exhibit compromised rejection of allogeneic, xenogeneic and missing self bone marrow grafts. Further we demonstrate that LRBA−/− Natural Killer (NK) cells exhibit impaired signaling by the key NK activating receptors, NKp46 and NKG2D. However, induction of γ-IFN by co-culture with IL12 and IL18 remains intact, indicating LRBA selectively facilitates signals by receptors for ligands expressed on the surface of NK targets. Surprisingly, LRBA limits immunoregulatory cell numbers in tissues where Graft versus Host Disease (GvHD) is primed or initiated, and consistent with this LRBA−/− mice demonstrate resistance to lethal GvHD. These findings demonstrate that LRBA is redundant for host longevity while being essential for both host and donor-mediated immune responses in allogeneic transplantation and thus represent a unique and novel molecular target in transplant immunology.

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Bohl, Thomas E., and Hideki Aihara. "Current Progress in the Structural and Biochemical Characterization of Proteins Involved in the Assembly of Lipopolysaccharide." International Journal of Microbiology 2018 (November 25, 2018): 1–32. http://dx.doi.org/10.1155/2018/5319146.

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The lipid component of the outer leaflet of the outer membrane of Gram-negative bacteria is primarily composed of the glycolipid lipopolysaccharide (LPS), which serves to form a protective barrier against hydrophobic toxins and many antibiotics. LPS is comprised of three regions: the lipid A membrane anchor, the nonrepeating core oligosaccharide, and the repeating O-antigen polysaccharide. The lipid A portion is also referred to as endotoxin as its overstimulation of the toll-like receptor 4 during systemic infection precipitates potentially fatal septic shock. Because of the importance of LPS for the viability and virulence of human pathogens, understanding how LPS is synthesized and transported to the outer leaflet of the outer membrane is important for developing novel antibiotics to combat resistant Gram-negative strains. The following review describes the current state of our understanding of the proteins responsible for the synthesis and transport of LPS with an emphasis on the contribution of protein structures to our understanding of their functions. Because the lipid A portion of LPS is relatively well conserved, a detailed description of the biosynthetic enzymes in the Raetz pathway of lipid A synthesis is provided. Conversely, less well-conserved biosynthetic enzymes later in LPS synthesis are described primarily to demonstrate conserved principles of LPS synthesis. Finally, the conserved LPS transport systems are described in detail.

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Moreno‐Corona, Nidia Carolina, Orestes Lopez‐Ortega, Jose Mizael Flores Hermenegildo, Laura Berron‐Ruiz, Juan Carlos Rodriguez‐Alba, Leopoldo Santos‐Argumedo, and Gabriela Lopez‐Herrera. "Lipopolysaccharide‐responsive beige‐like anchor acts as a cAMP‐dependent protein kinase anchoring protein in B cells." Scandinavian Journal of Immunology 92, no. 3 (July 14, 2020). http://dx.doi.org/10.1111/sji.12922.

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Hara, Yu, Fumiaki Ando, Daisuke Oikawa, Koichiro Ichimura, Hideki Yanagawa, Yuriko Sakamaki, Azuma Nanamatsu, et al. "LRBA is essential for urinary concentration and body water homeostasis." Proceedings of the National Academy of Sciences 119, no. 30 (July 21, 2022). http://dx.doi.org/10.1073/pnas.2202125119.

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Protein kinase A (PKA) directly phosphorylates aquaporin-2 (AQP2) water channels in renal collecting ducts to reabsorb water from urine for the maintenance of systemic water homeostasis. More than 50 functionally distinct PKA-anchoring proteins (AKAPs) respectively create compartmentalized PKA signaling to determine the substrate specificity of PKA. Identification of an AKAP responsible for AQP2 phosphorylation is an essential step toward elucidating the molecular mechanisms of urinary concentration. PKA activation by several compounds is a novel screening strategy to uncover PKA substrates whose phosphorylation levels were nearly perfectly correlated with that of AQP2. The leading candidate in this assay proved to be an AKAP termed lipopolysaccharide-responsive and beige-like anchor protein (LRBA). We found that LRBA colocalized with AQP2 in vivo, and Lrba knockout mice displayed a polyuric phenotype with severely impaired AQP2 phosphorylation. Most of the PKA substrates other than AQP2 were adequately phosphorylated by PKA in the absence of LRBA, demonstrating that LRBA-anchored PKA preferentially phosphorylated AQP2 in renal collecting ducts. Furthermore, the LRBA–PKA interaction, rather than other AKAP–PKA interactions, was robustly dissociated by PKA activation. AKAP–PKA interaction inhibitors have attracted attention for their ability to directly phosphorylate AQP2. Therefore, the LRBA–PKA interaction is a promising drug target for the development of anti-aquaretics.

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Rasouli, Seyed Erfan, Niusha Sharifinejad, Mazdak Fallahi, Seyedeh Atefeh Hashemi Moghaddam, Mahnaz Jamee, Mahsa Rekabi, Zahra Daneshmand, Seyed Alireza Mahdaviani, and Ali Akbar Velayati. "Joint Involvement in Patients with LPS-Responsive and Beige-Like Anchor Protein (LRBA) Deficiency: A Case Report and Literature Review." Immunology and Genetics Journal, January 18, 2022. http://dx.doi.org/10.18502/igj.v4i1.8396.

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Background: Lipopolysaccharide-responsive beige-like anchor (LRBA) deficiency is an inborn error of immunity characterized by a heterogeneous spectrum of manifestations, including enteropathy, immune dysregulation, and autoimmune disorder. Joint involvement has been less frequently reported, and limited data regarding its clinical presentation in LRBA deficiency has been published. Case presentation and review results: We reported an Iranian girl who was initially presented with recurrent respiratory tract infections and otitis media, later complicated by arthritis, growth failure, and organomegaly. The diagnosis of LRBA deficiency was confirmed by the identification of a novel homozygous missense variant in the LRBA gene (c.7742T>A, p.M2581K). Along with this report, a literature review focused on joint involvement, on 26 patients with LRBA deficiency was performed. Conclusion: Non-infectious manifestations such as joint involvement have a broad spectrum in LRBA deficiency. For the timely diagnosis and appropriate clinical management, LRBA deficiency should always be kept in mind as a differential diagnosis in patients with joint involvement and clinically typical immune dysregulation.

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Fetyan, Saja, Nida Fatima Sakrani, Fawwaz Yassin, Mohammad Fahad Abdallah, Naser Elzein, Gholamreza Azizi, and Gehad ElGhazali. "Lipopolysaccharide Responsive Beige-like Anchor Protein Deficiency in a Patient with Autoimmune Lymphoproliferative Syndrome-like Disease Phenotype: A Case Report and Literature Review." Iranian Journal of Allergy, Asthma and Immunology, April 17, 2022. http://dx.doi.org/10.18502/ijaai.v21i2.9230.

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LPS-responsive beige-like anchor protein (LRBA) deficiency is a primary immunodeficiency caused by a mutation in the LRBA gene. Affected individuals present with a variety of clinical symptoms including hypogammaglobulinemia, recurrent infections, splenomegaly, hepatomegaly, and autoimmune cytopenias. Except for hypogammaglobulinemia, the remaining features resemble autoimmune lymphoproliferative syndrome (ALPS). Here, we report the case of a 14-year-old boy with the ALPS phenotype, eventually diagnosed with LRBA deficiency. He presented with lymphadenopathy and hepatosplenomegaly, along with autoimmune cytopenia. Due to recurrent infections and worsening gastrointestinal symptoms, whole-exome sequencing was conducted and revealed a novel homozygous pathogenic variant in the LRBA gene (c.534del; p.9Asp179IIef*16). The patient recently suffered from clinical deterioration due to SARS-COV-2 which appears to have triggered an acute worsening of his existing Cytomegalovirus colitis leading to an eventual demise. A literature search for reported LRBA deficient patients with ALPS-like phenotype revealed 11 patients. The most common clinical presentations in LRBA patients with ALPS-like phenotype included autoimmunity (100%), splenomegaly (91%), lymphadenopathy (36.4%), and respiratory tract infections (63.6%). LRBA deficiency is unique in the fact that it encompasses immune deficiency, autoimmunity, and lymphoproliferation. In children with multiple symptoms related to these domains, a genetic diagnosis is necessary to ensure tailored and precise medical therapy.

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Chinello, Matteo, Margherita Mauro, Gaetano Cantalupo, Giacomo Talenti, Sara Mariotto, Rita Balter, Massimiliano De Bortoli, et al. "Acute Cervical Longitudinally Extensive Transverse Myelitis in a Child With Lipopolysaccharide-Responsive-Beige-Like-Anchor-Protein (LRBA) Deficiency: A New Complication of a Rare Disease." Frontiers in Pediatrics 8 (October 16, 2020). http://dx.doi.org/10.3389/fped.2020.580963.

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Trujillo Vargas, Claudia Milena, Melissa Madrid Gallego, and Paula Andrea Restrepo Moreno. "Expresión diferencial de la proteína LRBA en los linfocitos B vírgenes y de memoria humanos." Actualidades Biológicas 42, no. 112 (October 15, 2020). http://dx.doi.org/10.17533/udea.acbi.v42n112a05.

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La deficiencia de LRBA (Lipopolysaccharide-responsive and beige-like anchor protein), es una inmunodeficiencia primaria causada por una expresión defectuosa de la proteína intracelular LRBA, debido a mutaciones, homocigotas y heterocigotas compuestas, en el gen correspondiente. Los pacientes con esta inmunodeficiencia muestran un amplio espectro de manifestaciones clínicas que incluyen, principalmente, inmunodeficiencia y autoinmunidad. La deficiencia de LRBA se asocia con una disminución del recuento de linfocitos B (LB) de memoria con cambio de isotipo en sangre periférica y plasmablastos, y una respuesta defectuosa de anticuerpos específicos, así como un defecto en la apoptosis y la autofagia. En este estudio se evaluó la expresión diferencial intracelular de la proteína LRBA en los LB vírgenes y de memoria de sangre periférica humana, bajo diferentes condiciones por citometría de flujo. Evidenciamos que los LB de memoria presentan una mayor expresión de LRBA; por otra parte, demostramos que la expresión de esta proteína en los LB aumenta considerablemente en condiciones de activación; sin embargo, la magnitud del incremento en la expresión de LRBA bajo esta condición es mayor en los LB vírgenes. En contraste, evidenciamos que la expresión de esta proteína disminuye en LB sometidos a apoptosis, aunque aún en estas condiciones, es mayor en LB de memoria. Estos hallazgos sugieren que LRBA juega un papel importante en el desarrollo de la memoria inmunológica humoral.

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Khalili, Mitra, Hossein Farzi, Sepideh Darougar, Fatemeh Hajijoo, Mehrnaz Mesdaghi, Mahboubeh Mansouri, Delara Babaie, Amir Hashemitari, Narges Eslami, and Zahra Chavoshzadeh. "Pulmonary Radiological Manifestations of Humoral and Combined Immunodeficiencies in a Tertiary Pediatric Center." Iranian Journal of Allergy, Asthma and Immunology, December 12, 2021. http://dx.doi.org/10.18502/ijaai.v20i6.8020.

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Respiratory diseases are considered as significant causes of morbidity and mortality in primary immunodeficiencies. This study aimed to reveal the radiologic patterns of thoracic involvement in these disorders. A total of 58 patients, including 38 cases with combined cellular-humoral and 20 cases with humoral immunodeficiencies, were enrolled in this study. The “combined” group consisted of 12 cases with severe combined immunodeficiency (SCID) and 26 cases with combined immunodeficiency. The “humoral” group included seven patients with Hyper IgM syndrome (HIGMs), seven cases with common variable immunodeficiency (CVID), three patients with X-linked agammaglobulinemia, and three patients with other types of humoral primary immunodeficiencies (PIDs). The mean age of patients at the time of evaluation was 3.3±3.8 and 5.3±3.9 years in combined and humoral groups, respectively. The findings of chest X-rays and CT scans were interpreted and compared. There was a significant difference for alveolar opacification between combined and humoral immunodeficiencies (58% vs. 30%). The bronchopneumonia-like pattern was detected as a significant finding in patients with SCID (42%) and HIGMs (43%). Atrophy of the thymus was detected significantly often in cases of SCID (67%). Two patients with CVID and lipopolysaccharide-responsive and beige-like anchor protein deficiency showed parenchymal changes of granulomatous lymphocytic interstitial lung disease. No significant difference was detected for bronchiectasis, bronchitis/bronchiolitis patterns, pleural effusion, and thoracic lymphadenopathy. lymphadenopathy. Distinct subtypes of primary immunodeficiency may provoke differing and comparable radiological patterns of thoracic involvement; which can clue the clinician and radiologist to the diagnosis of the disease.

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Gámez-Díaz, Laura, and Markus G. Seidel. "Different Apples, Same Tree: Visualizing Current Biological and Clinical Insights into CTLA-4 Insufficiency and LRBA and DEF6 Deficiencies." Frontiers in Pediatrics 9 (April 28, 2021). http://dx.doi.org/10.3389/fped.2021.662645.

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Cytotoxic T lymphocyte antigen-4 (CTLA-4) is a crucial immune checkpoint that is constitutively expressed in regulatory T (Treg) cells. Following T-cell activation, CTLA-4 is rapidly mobilized from its intracellular vesicle pool to the cell surface to control the availability of co-stimulatory B7 molecules, thereby maintaining immune homeostasis. Heterozygous mutations in CTLA-4 lead to defects in (i) CTLA-4 ligand binding, (ii) homo-dimerization, (iii) B7-transendocytosis, and (iv) CTLA-4 vesicle trafficking, resulting in an inborn error of immunity with predominant autoimmunity. CTLA-4 vesicle trafficking impairment is also observed in patients with lipopolysaccharide-responsive beige-like anchor protein (LRBA) deficiency or the differentially expressed in FDCP6 homolog (DEF6) deficiency, caused by biallelic mutations in LRBA and DEF6, respectively. Therefore, patients with CTLA-4 insufficiency, LRBA deficiency, and—most recently reported—DEF6 deficiency present an overlapping clinical phenotype mainly attributed to a defective suppressive activity of Tregs, as all three diseases reduce overall surface expression of CTLA-4. In this paper, we describe the clinical phenotypes of these immune checkpoint defects, their patho-mechanisms, and visually compare them to other immune regulatory disorders (IPEX syndrome, CD27, and CD70 deficiencies) by using the immune deficiency and dysregulation (IDDA version 2.1) “kaleidoscope” score. This illustrates the variability of the degrees and manifestations of immune deficiency and dysregulation. Patients characteristically present with an increased risk of infections, autoimmune cytopenias, multi-organ autoimmunity, and inflammation, which are often severe and life-threatening. Furthermore, these patients suffer an increased risk of developing malignancies, especially Non-Hodgkin's lymphoma. Successful treatment options include regular administration of soluble CTLA-4-Ig fusion protein, Treg cell-sparing immune suppressants like sirolimus or mycophenolate mofetil, and hematopoietic stem cell transplantation. This mini-review highlights the most relevant biological and clinical features as well as treatment options for CTLA-4 insufficiency and LRBA and DEF6 deficiencies.

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Chawla, Sanchi, Prabal Barman, Rahul Tyagi, Ankur Kumar Jindal, Saniya Sharma, Amit Rawat, and Surjit Singh. "Autoimmune Cytopenias in Common Variable Immunodeficiency Are a Diagnostic and Therapeutic Conundrum: An Update." Frontiers in Immunology 13 (June 20, 2022). http://dx.doi.org/10.3389/fimmu.2022.869466.

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Common variable immunodeficiency (CVID) is the most common symptomatic primary immunodeficiency (PID). CVID is a heterogenous condition and clinical manifestations may vary from increased susceptibility to infections to autoimmune manifestations, granulomatous disease, polyclonal lymphoproliferation, and increased risk of malignancy. Autoimmune manifestations may, at times, be the first and only clinical presentation of CVID, resulting in diagnostic dilemma for the treating physician.Autoimmune cytopenias (autoimmune haemolytic anaemia and/or thrombocytopenia) are the most common autoimmune complications seen in patients with CVID. Laboratory investigations such as antinuclear antibodies, direct Coomb’s test and anti-platelet antibodies may not be useful in patients with CVID because of lack of specific antibody response. Moreover, presence of autoimmune cytopenias may pose a significant therapeutic challenge as use of immunosuppressive agents can be contentious in these circumstances. It has been suggested that serum immunoglobulins must be checked in all patients presenting with autoimmune cytopenia such as immune thrombocytopenia or autoimmune haemolytic anaemia.It has been observed that patients with CVID and autoimmune cytopenias have a different clinical and immunological profile as compared to patients with CVID who do not have an autoimmune footprint. Monogenic defects have been identified in 10-50% of all patients with CVID depending upon the population studied. Monogenic defects are more likely to be identified in patients with CVID with autoimmune complications. Common genetic defects that may lead to CVID with an autoimmune phenotype include nuclear factor kappa B subunit 1 (NF-kB1), Lipopolysaccharide (LPS)-responsive beige-like anchor protein (LRBA), cytotoxic T lymphocyte antigen 4 (CTLA4), Phosphoinositide 3-kinase (PI3K), inducible T-cell costimulatory (ICOS), IKAROS and interferon regulatory factor-2 binding protein 2 (IRF2BP2).In this review, we update on recent advances in pathophysiology and management of CVID with autoimmune cytopenias.

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Ma, Jingyao, Lingling Fu, Hao Gu, Zhenping Chen, Jialu Zhang, Shasha Zhao, Xiaojing Zhu, Huiqing Liu, and Runhui Wu. "Screening for Genetic Mutations for the Early Diagnosis of Common Variable Immunodeficiency in Children With Refractory Immune Thrombocytopenia: A Retrospective Data Analysis From a Tertiary Children's Center." Frontiers in Pediatrics 8 (December 3, 2020). http://dx.doi.org/10.3389/fped.2020.595135.

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Aim: This study aimed to identify common variable immunodeficiency (CVID) by high-throughput next-generation sequencing (NGS) in children with refractory immune thrombocytopenia (RITP) to facilitate early diagnosis.Methods: CVID-related genetic mutations were explored in patients with RITP during 2016–2019. They were tested consecutively through NGS by the ITP team of the tertiary children hospital in China. An evaluation system was devised based on the phenotype, genetic rule, and serum immunoglobulins (Igs) of all patients with RITP. The patients were divided into highly suspicious, suspicious, and negative groups using the evaluation system.Results: Among 176 patients with RITP, 16 (9.1%) harbored CVID-related genetic mutations: 8 (4.5%) were highly suspicious of CVIDs. Five had mutations in tumor necrosis factor receptor superfamily 13B (TNFRSF13B), one in lipopolysaccharide responsive beige-like anchor protein (LRBA), one in nuclear factor kappa-B2 (NF-κB2), and one in caspase recruitment domain11 (CARD11). Others were classified into the suspicious group because the clinical phenotype and pedigree were suggestive, yet insufficient, for diagnosis. Repeated infection existed in all patients. Two had an allergic disease. Positive autoimmune serologies were noted in 62.5%. Five had a definite positive family history. The median serum immunoglobulin (Ig)A, IgG, and IgM levels were 0.3875, 6.14, and 0.522 g/L, respectively. Nearly 85.7% of patients had insufficient serum IgA levels, while 37.5% had low IgG and IgM levels.Conclusions: High-throughput NGS and a thorough review of the medical history are beneficial for the early diagnosis of patients without any significant clinical characteristics, distinguishing them from those with primary pediatric ITP. The cases suspicious of CVID need further investigation and follow-up to avoid deterioration.

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Driouk, Lina, Robert Schmitt, Anke Peters, Sabine Heine, Hermann Josef Girschick, Brigitte Strahm, Charlotte M. Niemeyer, and Carsten Speckmann. "Daratumumab therapy for post-HSCT immune-mediated cytopenia: experiences from two pediatric cases and review of literature." Molecular and Cellular Pediatrics 8, no. 1 (April 29, 2021). http://dx.doi.org/10.1186/s40348-021-00114-y.

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Abstract Background Immune-mediated cytopenias (AIC) are challenging complications following allogeneic hematopoietic stem cell transplantation (HSCT). While broad-acting immunosuppressive agents like corticosteroids are often standard of care, several novel therapies which target specific immunological pathways have recently been developed and provide hope for patients with steroid-refractory courses and may limit long-term toxicity. The successful off-label use of the plasma cell depleting anti-CD38 antibody daratumumab was published in several case reports, suggesting efficacy, i.e., in patients with antibody-mediated AIC refractory to previous B cell depletion. We want to share our experience with two children, whom we treated with daratumumab, including one fatal course with uncontrolled disease. Given the absence of substantial data from HSCT registries or prospective trials, we furthermore provide a critical review of the literature on daratumumab treatment of AIC. Case presentations Patient 1 (P1), an 11-year-old girl with lipopolysaccharide-responsive and beige-like anchor protein (LRBA) deficiency who developed immune-mediated thrombocytopenia (AIT) from day +58 after HSCT, showed a complete response to daratumumab after the fourth of six total daratumumab doses. She remains transfusion independent for over a year of follow-up. Previously, her thrombocytopenia was refractory to corticosteroids, rituximab, intravenous immunoglobulins (IVIG), eltrombopag, cyclosporine A, and sirolimus. Patient 2 (P2), a 6-year-old boy with CD40 ligand (CD40L) deficiency, developed both AIT and hemolytic anemia (AIHA) after HSCT on days +58 and +83, respectively, and was also treated with daratumumab after being previously refractory to prednisolone, rituximab, and IVIG. Yet, he did neither respond to daratumumab nor the concomitantly administered methyprednisolone pulse, plasmapheresis, and eculizumab and succumbed due to refractory disease. Conclusion Reviewing the literature on the use of daratumumab for refractory AIC post-HSCT, we consider daratumumab a promising agent for this life-threatening disorder: ten of the twelve patients reached transfusion independency in the literature. However, treatment failures are likely to be underreported. Thus, controlled trials are needed to explore the safety and efficacy of daratumumab in this rare post-HSCT complication.

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Gámez-Díaz, Laura, Elena C. Sigmund, Veronika Reiser, Werner Vach, Sophie Jung, and Bodo Grimbacher. "Rapid Flow Cytometry-Based Test for the Diagnosis of Lipopolysaccharide Responsive Beige-Like Anchor (LRBA) Deficiency." Frontiers in Immunology 9 (April 23, 2018). http://dx.doi.org/10.3389/fimmu.2018.00720.

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Ghaini, Mehdi, Mohammad Taghi Arzanian, Bibi Shahin Shamsian, Saeed Sadr, Pejman Rohani, Mohammad Keramatipour, Mehrnaz Mesdaghi, et al. "Identifying Novel Mutations in Iranian Patients with LPS-responsive Beige-like Anchor Protein (LRBA) Deficiency." Immunological Investigations, June 1, 2020, 1–7. http://dx.doi.org/10.1080/08820139.2020.1770784.

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Totsune, Eriko, Tomohiro Nakano, Kunihiko Moriya, Daichi Sato, Dai Suzuki, Akinobu Miura, Saori Katayama, et al. "Case Report: Infantile-Onset Fulminant Type 1 Diabetes Mellitus Caused by Novel Compound Heterozygous LRBA Variants." Frontiers in Immunology 12 (April 12, 2021). http://dx.doi.org/10.3389/fimmu.2021.677572.

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Lipopolysaccharide-responsive beige-like anchor (LRBA) deficiency is a subtype of common variable immune deficiency (CVID). Numerous case reports and cohort studies have described a broad spectrum of clinical manifestations and variable disease phenotypes, including immune dysregulation, enteropathy, and recurrent infections. Although LRBA deficiency is an autosomal recessive primary immunodeficiency resulting in a phenotype similar to CVID, it is a monogenic disease and separate from CVID. Recently, in a report of monogenic primary immunodeficiency disorder associated with CVID and autoimmunity, the most common mutated gene was LRBA. We report the case of a girl who presented with fulminant type 1 diabetes at age 7 months. She later experienced recurrent bacterial infections with neutropenia and idiopathic thrombocytopenic purpura. Clinical genome sequencing revealed compound heterozygosity of the LRBA gene, which bore two novel mutations. A genetic basis should be considered in the differential diagnosis for very young patients with fulminant autoimmunity, and the diagnostic work-up should include evaluation of markers of immunodeficiency.

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Sudan, Raki, Sandra Fernandes, Neetu Srivastava, Chiara Pedicone, Shea T. Meyer, John D. Chisholm, Robert W. Engelman, and William G. Kerr. "LRBA Deficiency Can Lead to Lethal Colitis That Is Diminished by SHIP1 Agonism." Frontiers in Immunology 13 (May 4, 2022). http://dx.doi.org/10.3389/fimmu.2022.830961.

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Humans homozygous for inactivating LRBA (lipopolysaccharide (LPS)-responsive beige-like anchor) mutations or with compound heterozygous mutations exhibit a spectrum of immune-related pathologies including inflammatory bowel disease (IBD). The cause of this pathology remains undefined. Here we show that disruption of the colon epithelial barrier in LRBA-deficient mice by dextran sulfate sodium (DSS) consumption leads to severe and uniformly lethal colitis. Analysis of bone marrow (BM) chimeras showed that susceptibility to lethal colitis is primarily due to LRBA deficiency in the immune compartment and not the gut epithelium. Further dissection of the immune defect in LRBA-deficient hosts showed that LRBA is essential for the expression of CTLA4 by Treg cells and IL22 and IL17 expression by ILC3 cells in the large intestine when the gut epithelium is compromised by DSS. We further show that SHIP1 agonism partially abrogates the severity and lethality of DSS-mediated colitis. Our findings indicate that enteropathy induced by LRBA deficiency has multiple causes and that SHIP1 agonism can partially abrogate the inflammatory milieu in the gut of LRBA-deficient hosts.

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Ren, Yanling, Feng Xiao, Fei Cheng, Xin Huang, Jianhu Li, Xiaogang Wang, Wei Lang, Xinping Zhou, Jianping Lan, and Hongyan Tong. "Whole exome sequencing reveals a novel LRBA mutation and clonal hematopoiesis in a common variable immunodeficiency patient presented with hemophagocytic lymphohistiocytosis." Experimental Hematology & Oncology 10, no. 1 (June 13, 2021). http://dx.doi.org/10.1186/s40164-021-00229-y.

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AbstractCommon variable immunodeficiency (CVID) was a kind of primary immunodeficiency disorders with heterogeneous phenotype and genotype. Lipopolysaccharide-responsive and beige-like anchor (LRBA) mutation was identified as disease associated in CVID, advanced genetic method will help to detect atypical cases. We report a case of adult patient manifested as hemophagocytic lymphohistiocytosis (HLH), bone marrow examination suggested prosperity to MDS, manifested as increased immature myeloid cells and dysplastic hematopoiesis. Whole exome sequencing (WES) identified a novel heterogeneous c.1876T > C (p.W626R) mutation in LRBA and four somatic mutations: ASXL1 (c.1967dupA); PTPN11 (c.226G > A), U2AF1 (c.101C > T and c.470A > G), among which ASXL1 was a high-risk marker of clonal hematopoiesis. Combined with her recurrent severe infections and immune abnormalities such as hypoimmunoglobulinemia, the patient was diagnosed with CVID. Subsequent hematopoietic stem cell transplantation saved her from severe cytopenia and immune deficiency. This case report highlights the great promise of utilization of WES for diagnosing rare disease with atypical manifestations and guiding further treatment.

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"Case Report: An Unreported Homozygous Variant within Lipopolysaccharide Responsive Beige-Like Anchor (LRBA) Gene in a Child Exhibiting with Infantile Type 1 Diabetes Mellitus." Journal of Vaccines, Immunology and Immunopathology 7, no. 4 (December 26, 2022). http://dx.doi.org/10.29011/2575-789x.000183.

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Merico, Daniele, Yehonatan Pasternak, Mehdi Zarrei, Edward J. Higginbotham, Bhooma Thiruvahindrapuram, Ori Scott, Jessica Willett-Pachul, et al. "Homozygous duplication identified by whole genome sequencing causes LRBA deficiency." npj Genomic Medicine 6, no. 1 (November 18, 2021). http://dx.doi.org/10.1038/s41525-021-00263-z.

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AbstractIn more than one-third of primary immunodeficiency (PID) patients, extensive genetic analysis including whole-exome sequencing (WES) fails to identify the genetic defect. Whole-genome sequencing (WGS) is able to detect variants missed by other genomics platforms, enabling the molecular diagnosis of otherwise unresolved cases. Here, we report two siblings, offspring of consanguineous parents, who experienced similar severe events encompassing early onset of colitis, lymphoproliferation, and hypogammaglobulinemia, typical of lipopolysaccharide-responsive and beige-like anchor (LRBA) or cytotoxic T lymphocyte antigen 4 (CTLA4) deficiencies. Gene-panel sequencing, comparative genomic hybridization (CGH) array, and WES failed to reveal a genetic aberration in relevant genes. WGS of these patients detected a 12.3 kb homozygous tandem duplication that was absent in control cohorts and is predicted to disrupt the reading frame of the LRBA gene. The variant was validated by PCR and Sanger sequencing, demonstrating the presence of the junction between the reference and the tandem-duplicated sequence. Droplet digital PCR (ddPCR) further confirmed the copy number in the unaffected parents (CN = 3, heterozygous) and affected siblings (CN = 4, homozygous), confirming the expected segregation pattern. In cases of suspected inherited immunodeficiency, WGS may reveal a mutation when other methods such as microarray and WES analysis failed to detect an aberration.

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Semo Oz, Rotem, and Melissa S. Tesher. "Arthritis in children with LRBA deficiency – case report and literature review." Pediatric Rheumatology 17, no. 1 (December 2019). http://dx.doi.org/10.1186/s12969-019-0388-4.

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Abstract Background Lipopolysaccharide (LPS)-responsive and beige like anchor (LRBA) deficiency is categorized as a subtype of common variable immune deficiency (CVID). A growing number of case reports and cohorts reveal a broad spectrum of clinical manifestations and variable phenotype expression, including immune dysregulation, enteropathy and recurrent infections. The association between rheumatic disease and CVID generally has been well established, arthritis has been less frequently reported and minimal data regarding its clinical features and characteristic in LRBA deficiency has been published. This case report and literature review evaluates the characteristics and features of arthritis in LRBA deficiency patients. Case presentation and review results Herein, we describe a unique case of LRBA deficiency first presented with poly articular arthritis. Alongside the report, a literature review focusing on LRBA deficiency, rheumatic disease and arthritis has been conducted. We reviewed 43 publications. Among these, 7 patients were identified with arthritis. Age of first presentation was six weeks to 3 years. Male to female ratio was 4/3. Two patients were diagnosed with polyarticular Juvenile idiopathic arthritis (JIA) and three with oligoarticular JIA. Each patient was found to have different genomic mutation. The treatment was diverse and included corticosteroids, cyclosporine, methotrexate, adalidumab and abatacept. Conclusion Joint involvement is variable in LRBA deficiency, hence it should always be kept in mind as a differential diagnosis for a patient with combination of juvenile arthritis and clinically atypical immune dysregulation and / or immunodeficiency.

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Journal articles on the topic 'LIPOPOLYSACCHARIDE RESPONSIVE BEIGE-LIKE ANCHOR PROTEIN'

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