Abnormal B Cell Development in Systemic Lupus Erythematosus: What the Genetics Tell Us.

Abstract

Although the immunologic abnormalities in SLE are complex, numerous, and not fully understood, B cells have a central role in the development of the disease, from driving immune complex production to secretion of proinflammatory cytokines. Since SLE is an archetypal complex disease, the genetic association data reflect that complexity, with many variants, affecting several areas of the immune system 13, 14. The advent of GWAS has identified many potential abnormal pathways relevant to the breaking of self tolerance in SLE (summarized in Table 1). The data emphasize the central role of B cells, with a significant proportion of identified genes affecting B cell function and epigenetic annotation reinforcing this 13, 14, 65, 66. GWAS have also helped to explain clinical variability between individuals—it is easy to see how each patient is likely to have a different combination of risk variants resulting in a pattern of immune dysfunction unique to that individual. We can already see how variants in TLR genes can help predict disease and serologic markers, or how variants in the gene for Lyn can protect against hematologic involvement 36, 49. Traditionally, B cell–targeted therapy has mostly been focused on depletion of numbers (e.g., through targeting CD20‐mediated depletion through rituximab), but with our growing understanding, less crude approaches are being investigated. For example, Aiolos depletion therapy with the CC‐220 molecule results in down‐regulation of genes mediating B cell differentiation, reduces proliferation, and inhibits antibody secretion in B cells from SLE patients 69. Emerging therapy such as epratuzumab (a monoclonal antibody to CD22) has been shown to block B cell differentiation and activation directly through selective inhibition of BLIMP‐1 (encoded by PRDM1), demonstrating how data from GWAS can inform future drug therapy 70. Although the results from GWAS confirm the complexity of SLE pathogenesis and show that different intrinsic B cell abnormalities are likely to drive disease in each individual case, the principles underlying the loss of central tolerance (deficient BCR signaling) and peripheral tolerance (dysregulated T cell–B cell interaction) are universal. Genetic information helps us to personalize therapy, whereby relevant molecules can be targeted through understanding the exact pathways involved in an individual's disease.