B-cell tolerance checkpoints in health and autoimmunity
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.
References (61)
- et al.
Autoreactive IgG memory antibodies in patients with systemic lupus erythematosus arise from nonreactive and polyreactive precursors
Proc Natl Acad Sci U S A
(2008) - et al.
Characterization of a germline Vk gene encoding cationic anti-DNA antibody and role of receptor editing for development of the autoantibody in patients with systemic lupus erythematosus
J Clin Invest
(1996) - et al.
Immunoglobulin kappa chain receptor editing in systemic lupus erythematosus
J Clin Invest
(1998) - et al.
I-PLA(2) activation during apoptosis promotes the exposure of membrane lysophosphatidylcholine leading to binding by natural immunoglobulin M antibodies and complement activation
J Exp Med
(2002) - et al.
Marginal zone and B1 B cells unite in the early response against T-independent blood-borne particulate antigens
Immunity
(2001) - et al.
Efficacy of B cell-targeted therapy with Rituximab in patients with rheumatoid arthritis
N Engl J Med
(2004) - et al.
Rheumatoid factor secretion from human Leu-1+ B cells
Science
(1987) - et al.
Identification and analysis of a novel human surface CD5-B lymphocyte subset producing natural antibodies
J Immunol
(1992) - et al.
Efficient generation of monoclonal antibodies from single human B cells by single cell RT-PCR and expression vector cloning
J Immunol Methods
(2008) Clonal selection and learning in the antibody system
Nature
(1996)