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Cvid-Associated B Cell Activating Factor Receptor Variants Change Receptor Oligomerization, Ligand Binding, and Signaling Responses Publisher Pubmed



Block V1, 2 ; Sevdali E1, 2 ; Recher M3 ; Abolhassani H4, 5 ; Hammarstrom L4 ; Smulski CR1, 6 ; Baronio M7 ; Plebani A7 ; Proietti M2, 8 ; Speletas M9 ; Warnatz K1, 2 ; Voll RE1, 2 ; Lougaris V7 ; Schneider P10 Show All Authors
Authors
  1. Block V1, 2
  2. Sevdali E1, 2
  3. Recher M3
  4. Abolhassani H4, 5
  5. Hammarstrom L4
  6. Smulski CR1, 6
  7. Baronio M7
  8. Plebani A7
  9. Proietti M2, 8
  10. Speletas M9
  11. Warnatz K1, 2
  12. Voll RE1, 2
  13. Lougaris V7
  14. Schneider P10
  15. Eibel H1, 2
Show Affiliations
Authors Affiliations
  1. 1. Department of Rheumatology and Clinical Immunology, Medical Center and Faculty of Medicine, University of Freiburg, Freiburg, Germany
  2. 2. Center for Chronic Immunodeficiency, Medial Center and Faculty of Medicine, University of Freiburg, Freiburg, Germany
  3. 3. Immunodeficiency Clinic and Laboratory, Medical Outpatient Unit and Department Biomedicine, University Hospital and University of Basel, Basel, Switzerland
  4. 4. Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden
  5. 5. Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran
  6. 6. Medical Physics Department, Centro Atomico Bariloche, Comision Nacional de Energia Atomica (CNEA), Consejo Nacional de Investigaciones Cientificas Y Tecnicas (CONICET), San Carlos de Bariloche, Rio Negro, Argentina
  7. 7. Department of Clinical and Exp. Sciences, University of Brescia, Brescia, Italy
  8. 8. Institute for Immunodeficiency, Medical Center and Faculty of Medicine, University of Freiburg, Freiburg, Germany
  9. 9. Department of Immunology & Histocompatibility, Faculty of Medicine, University of Thessaly, Larissa, Greece
  10. 10. Department of Biochemistry, University of Lausanne, Epalinges, Switzerland

Source: Journal of Clinical Immunology Published:2023


Abstract

Purpose: Binding of the B cell activating factor (BAFF) to its receptor (BAFFR) activates in mature B cells many essential pro-survival functions. Null mutations in the BAFFR gene result in complete BAFFR deficiency and cause a block in B cell development at the transition from immature to mature B cells leading therefore to B lymphopenia and hypogammaglobulinemia. In addition to complete BAFFR deficiency, single nucleotide variants encoding BAFFR missense mutations were found in patients suffering from common variable immunodeficiency (CVID), autoimmunity, or B cell lymphomas. As it remained unclear to which extent such variants disturb the activity of BAFFR, we performed genetic association studies and developed a cellular system that allows the unbiased analysis of BAFFR variants regarding oligomerization, signaling, and ectodomain shedding. Methods: In addition to genetic association studies, the BAFFR variants P21R, A52T, G64V, DUP92-95, P146S, and H159Y were expressed by lentiviral gene transfer in DG-75 Burkitt’s lymphoma cells and analyzed for their impacts on BAFFR function. Results: Binding of BAFF to BAFFR was affected by P21R and A52T. Spontaneous oligomerization of BAFFR was disturbed by P21R, A52T, G64V, and P146S. BAFF-dependent activation of NF-κB2 was reduced by P21R and P146S, while interactions between BAFFR and the B cell antigen receptor component CD79B and AKT phosphorylation were impaired by P21R, A52T, G64V, and DUP92-95. P21R, G64V, and DUP92-95 interfered with phosphorylation of ERK1/2, while BAFF-induced shedding of the BAFFR ectodomain was only impaired by P21R. Conclusion: Although all variants change BAFFR function and have the potential to contribute as modifiers to the development of primary antibody deficiencies, autoimmunity, and lymphoma, P21R is the only variant that was found to correlate positively with CVID. © 2022, The Author(s).
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