BAFF selectively enhances the survival of plasmablasts generated from human memory B cells

The generation of Ig-secreting cells (ISCs) from memory B cells requires interactions between antigen-specific (Ag-specific) B cells, T cells, and dendritic cells. This process must be strictly regulated to ensure sufficient humoral immunity while avoiding production of pathogenic autoantibodies. BAFF, a member of the TNF family, is a key regulator of B cell homeostasis. BAFF exerts its effect by binding to three receptors — transmembrane activator of and CAML interactor (TACI), B cell maturation antigen (BCMA), and BAFF receptor (BAFF-R). To elucidate the contribution of BAFF to the differentiation of B cells into ISCs, we tracked the fate of human memory B cells stimulated with BAFF or CD40L. BAFF and CD40L significantly increased the overall number of surviving B cells. This was achieved via distinct mechanisms. CD40L induced proliferation of nondifferentiated blasts, while BAFF prevented apoptosis of ISCs without enhancing proliferation. The altered responsiveness of activated memory B cells to CD40L and BAFF correlated with changes in surface phenotype such that expression of CD40 and BAFF-R were reduced on ISCs while BCMA was induced. These results suggest BAFF may enhance humoral immunity in vivo by promoting survival of ISCs via a BCMA-dependent mechanism. These findings have wide-ranging implications for the treatment of human immunodeficiencies as well as autoimmune diseases.This work was supported by the National Health and Medical Research Council of Australia. S.G. Tangye was supported by a U2000 Postdoctoral Fellowship awarded by the University of Sydney. P.D. Hodgkin is a Senior Research Fellow of the National Health and Medical Research Council of Australia. F. Mackay is a Wellcome Trust Senior Research Fellow

Identification of a pathogenic variant in TREX1 in early-onset cerebral systemic lupus erythematosus by whole-exome sequencing

Objective: Systemic lupus erythematosus (SLE) is a chronic and heterogeneous autoimmune disease. Both twin and sibling studies indicate a strong genetic contribution to lupus, but in the majority of cases the pathogenic variant remains to be identified. The genetic contribution to disease is likely to be greatest in cases with early onset and severe phenotypes. Whole-exome sequencing now offers the possibility of identifying rare alleles responsible for disease in such cases. This study was undertaken to identify genetic causes of SLE using whole-exome sequencing.\ud \ud Methods: We performed whole-exome sequencing in a 4-year-old girl with early-onset SLE and conducted biochemical analysis of the putative defect.\ud \ud Results: Whole-exome sequencing in a 4-year-old girl with cerebral lupus identified a rare, homozygous mutation in the three prime repair exonuclease 1 gene (TREX1) that was predicted to be highly deleterious. The TREX1 R97H mutant protein had a 20-fold reduction in exonuclease activity and was associated with an elevated interferon-α (IFNα) signature in the patient. The discovery and characterization of a pathogenic TREX1 variant in our proband has therapeutic implications. The patient is now a candidate for neutralizing anti-IFNα therapy.\ud \ud Conclusion: Our study is the first to demonstrate that whole-exome sequencing can be used to identify rare or novel deleterious variants as genetic causes of SLE and, through a personalized approach, improve therapeutic options