B cells in autoimmune diseases: Insights from analyses of immunoglobulin variable (Ig V) gene usage

Abstract

The role of B cells in autoimmune diseases has not been fully elucidated. It is also unclear whether breaking of B cell tolerance in patients with autoimmune diseases is due to underlying defects in the molecular mechanisms involved in the arrangement of antibody genes or deficiencies in the subsequent selective influences that shape the antibody repertoire. Analysis of immunoglobulin (Ig) variable (V) gene usage is beginning to provide answers to some of these questions. Such analyses have identified some differences in the basic Ig V gene repertoire of patients with autoimmune diseases compared to healthy controls, even though none of these differences can be considered major. Defects in positive and negative selection, mutational targeting and, in some cases, receptor editing have also been detected. In addition, analysis of Ig V gene usage in target organs and tissues of patients with autoimmune diseases has clearly demonstrated that there is a highly compartmentalized clonal expansion of B cells driven by a limited number of antigens in these tissues. Great progress has been made in the structural and functional characterization of disease-associated antibodies, largely because of the development of the combinatorial library technique. Use of antibodies generated by this technique offers great promise in identifying B cell epitopes on known target antigens and in gaining greater insights into the pathogenic role of B cells in both B and T cell mediated autoimmune diseases.

Autoantibodies in primary sclerosing cholangitis

“…Nevertheless, the study points to the possible need for the application of broader screening methods in the search for autoantigens in PSC. The role of autoantibodies and B-cells in other autoimmune diseases has gained renewed interest the last few years [134] , not only as pathogenetic factors [135] , but also as therapeutic targets (e.g. Rituximab) [136] .…”

Overexpression and unique rearrangement of VH2 transcripts in immunoglobulin variable heavy chain genes in ankylosing spondylitis patients

“…Such differences could be derived from intrinsic abnormalities in the generation of Ig V genes or B cell development and functions (Foreman et al, 2007). Thus, the analysis of Ig V gene usages can offer new insights into possible pathogenic role of B cells in diseases.…”

The immunoglobulin heavy chain locus: genetic variation, missing data, and implications for human disease

“…While there are several compelling examples of such biases for IGHV genes (for review of V gene usage biases in autoimmune disease, see Foreman et al 54 ), we discuss one of these to illustrate the potential importance of these effects. Three surveys of anti-HIV antibodies (Abs) have shown biased usage of IGHV1-69, 55-57 and 9 of 12 Abs against the CD4-induced binding site of the HIV-1 epitope, gp120 (CD4i Abs), used this gene.…”