B Cells and Immunological Tolerance

Abstract

Work from multiple groups continues to provide additional evidence for the powerful and highly diverse roles, both protective and pathogenic, that B cells play in autoimmune diseases. Similarly, it has become abundantly clear that antibody-independent functions may account for the opposing influences that B cells exercise over other arms of the immune response and ultimately over autoimmunity itself. Finally, it is becoming apparent that the clinical impact of B cell depletion therapy may be to a large extent determined by the functional balance between different B cell subsets that may be generated by this therapeutic intervention. In this review, we postulate that our perspective of B cell tolerance and our experimental approach to its understanding are fundamentally changed by this view of B cells. Accordingly, we shall first discuss current knowledge of B cell tolerance conventionally defined as the censoring of autoantibody-producing B cells (with an emphasis on human B cells). Therefore, we shall discuss a different model that contemplates B cells not only as targets of tolerance but also as mediators of tolerance. This model is based on the notion that the onset of clinical autoimmune disease may require a B cell gain-of-pathogenic function (or a B cell loss-of-regulatory-function) and that accordingly, disease remission may depend on the restoration of the physiological balance between B cell pathogenic and protective functions.

Autoimmune Markers in Diabetes

“…Whereas autoantibodies are excellent and predictive markers of ␤-cell autoimmunity, B lymphocytes may play a more important role as antigen-presenting cells (64 ) and/or regulatory cells in the genesis of T1DM (65)(66)(67). B lymphocytes (such as B10 cells) may produce regulatory cytokines such as interleukin-10 and transforming growth factor-␤ (68 ).…”

Molecular Basis of 9G4 B Cell Autoreactivity in Human Systemic Lupus Erythematosus

“…The canonical anti-i B cell binding (BCB) of 9G4 Abs is further documented by presence of this reactivity IgM 9G4 Abs derived from fetal spleen B cells representing the innate repertoire without previous antigenic selection. Of great relevance for our work, both the expression of the 9G4 idiotype and the 9G4 canonical LN autoreactivity are determined by a framework 1 (FR1) hydrophobic patch (HP) formed by residues Q 6 W 7 and A 23 V 24 Y 25 of the VH4-34 germline sequence (13,21,22).…”

Reducing Epitope Spread during Affinity Maturation of an Anti-Ganglioside GD2 Antibody

“…B cell tolerance, whether central or peripheral, is a complex process for preventing the development of autoimmunity during an immune response to an epitope on a foreign pathogen. In germinal center follicles of peripheral lymphoid tissues, self-reactive BCRs are continually generated through somatic hypermutation (29,30). With affinity maturation, autoimmunity, if not prevented, can be severe, especially because follicular B-cells differentiate into long-lived memory cells and plasma cells that in turn will produce autoantibodies indefinitely.…”