B-cell tolerance checkpoints in health and autoimmunity

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The enormous diversity of the antibody repertoire is generated by two mechanisms: recombination of immunoglobulin (Ig) gene variable (V), diversity (D), and joining (J) gene segments during the early stages of B-cell development in the bone marrow and somatic hypermutation (SHM) of functional Ig genes from antigen-activated B cells within secondary lymphoid organs. Diversity by V(D)J recombination and SHM not only provides protective humoral immunity but also generates potentially harmful clones expressing autoantibodies. Under normal circumstances, several mechanisms regulate the removal of autoreactive B cells and defects in central and peripheral B cell tolerance checkpoints are associated with the development of autoimmunity in humans.

Introduction

A prerequisite for the generation of effective humoral immune responses is the diversity and specificity of the antibody repertoire. Diversity of the nascent B cell pool in the bone marrow (BM) is generated by the random recombination of immunoglobulin (Ig) variable (V), diversity (D), and joining (J) gene segments at the heavy (H) and light (L) chain locus. In addition, antibody specificity of antigen-challenged B cells in the periphery is further improved by random somatic hypermutations (SHM) on IgH and IgL genes and subsequent selection of B-cell clones expressing Igs with increased affinity for the stimulating antigen. Because V(D)J recombination and SHM are random mechanisms, the resulting Ig repertoire cannot be predicted and includes the generation of B-cell receptors (BCRs) that can recognize the body’s own selfantigens [1]. Attempts to thwart autoimmunity are ensured by several B-cell tolerance checkpoints at which developing autoreactive B cells are counterselected. Although transgenic mice carrying prerearranged selfreactive Ig genes were instrumental in understanding the mechanisms that regulate developing selfreactive B cells, these models did not allow estimates on the frequency at which selfreactive BCRs are generated by V(D)J recombination in normal mice or healthy humans with a quasi-unlimited Ig gene repertoire [2, 3, 4, 5, 6, 7]. In the last five years, insight in the contribution of autoreactive B cells to the normal human B cell repertoire and their regulation at selftolerance checkpoints came from the analysis of monoclonal antibodies cloned from single purified B cells at different stages during their development [8••, 9, 10, 11•, 12•, 13, 14, 15, 16••, 17, 18•, 19].

Section snippets

Selection of the naïve B cell repertoire

The naïve B cell repertoire is devoid of SHMs and its BCR diversity relies entirely on random Ig V(D)J gene recombination in developing B-cell precursors. Early immature B cells are the first precursors in the BM that express functionally rearranged Ig gene transcripts but lack detectable surface IgMs (Figure 1). In healthy donors, we found that more than 75% of the recombinant antibodies cloned from single early immature B cells were autoreactive that is polyreactive with several individual

Defective early B cell tolerance checkpoints in SLE and RA

Systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA) are autoimmune diseases characterized by high serum IgG autoantibody titers [26]. Hence, B-cell tolerance is broken and ultimately results in the production of antibody-secreting plasma cells in these patients. However, active nontreated SLE and RA patients already showed elevated frequencies of autoreactive B cells in the naïve B cell compartments suggesting an early break of B-cell tolerance even before antigen-mediated

Regulation of the peripheral B cell tolerance checkpoint

Transgenic mouse models have suggested that CD4+ T cells may play an important role in the elimination of peripheral autoreactive B cells through MHC class II/T cell receptor; CD40/CD40L and Fas/FasL interactions [41•, 42]. By studying CD40L-deficient and MHC class II-deficient (bare lymphocyte syndrome, BLS) patients, we found that antibody reactivity from CD40L-deficient and MHC class II-deficient new emigrant B cells was similar to those from healthy donors, suggesting that CD40/CD40L

Autoreactivity and tolerance in memory B cells in health and autoimmunity

T-cell-dependent antigen-mediated activation of naïve B cells induces Ig gene somatic mutations and class switching in germinal centers followed by differentiation into antibody-secreting cells and memory B cells. Somatic mutations are random Ig gene modifications and may not be beneficial in most cases but antigen-experienced B cells that leave the GC under physiological circumstances are selected for high reactivity and specificity to foreign antigens. Surprisingly, we found that circulating

Conclusion

It has long been known that low levels of serum autoantibodies are present under normal circumstances and studies on hybridomas and EBV transformed B cell clones demonstrated that autoreactive B cells are expressed by naïve and antigen-experienced B cells in mice and humans [57, 58, 59, 60]. The analysis of antibodies cloned from single human B cells at different stages of development determined for the first time the frequency at which V(D)J recombination generates selfreactivity that is

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

  • • of special interest

  • •• of outstanding interest

Acknowledgements

This work is supported by National Institutes of Health grants P01 AI061093 and R01 AI071087 to EM and by the German Research Foundation (DFG WA-2590) to HW.

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