Antibody repertoire analysis in polygenic autoimmune diseases

Abstract

High-throughput sequencing of the DNA/RNA encoding antibody heavy- and light-chains is rapidly transforming the field of adaptive immunity. It can address key questions, including: (i) how the B-cell repertoire differs in health and disease; and (ii) if it does differ, the point(s) in B-cell development at which this occurs. The advent of technologies, such as whole-genome sequencing, offers the chance to link abnormalities in the B-cell antibody repertoire to specific genomic variants and polymorphisms. Here, we discuss the current research using B-cell antibody repertoire sequencing in three polygenic autoimmune diseases where there is good evidence for a pathological role for B-cells, namely systemic lupus erythematosus, multiple sclerosis and rheumatoid arthritis. These autoimmune diseases exhibit significantly skewed B-cell receptor repertoires compared with healthy controls. Interestingly, some common repertoire defects are shared between diseases, such as elevated IGHV4-34 gene usage. B-cell clones have effectively been characterized and tracked between different tissues and blood in autoimmune disease. It has been hypothesized that these differences may signify differences in B-cell tolerance; however, the mechanisms and implications of these defects are not clear.

Keywords: B-cell; B-cell receptors; antibodies; autoantibodies; autoimmunity.

Figure 1

Schematic diagram of the processes of B‐cell differentiation and selection, annotated with known human genetic modifiers of the process and the point in selection at which they are thought to act. B‐cells are generated from haematopoietic stem cells. During B‐cell development, V‐D‐J recombination occurs to produce a functional heavy‐chain. Similarly, V‐J recombination occurs in the light‐chain. The resulting B‐cell receptor (BCR) may be expressed as both surface IgD and IgM on naïve B‐cells through alternative splicing. Somatic hypermutation (SHM) can occur during B‐cell activation, in which mutations are introduced into the V‐(D)‐J region of the BCR. Class‐switch recombination (CSR) can also occur during B‐cell activation, which is a chromosomal deletion process leading to the expression of a different antibody isotype.