B cell tolerance: putting the horse before the cart.

In immunology, and especially in clinical immunology, it is seldom easy to put carts and horses in their proper order. In this issue of Arthritis & Rheumatism, Menard et al (1) demonstrate that the defective central B cell tolerance observed in patients with rheumatoid arthritis (RA) is not resolved by effective treatment regimens that reduce inflammation. Based on this finding, Menard et al conclude that the impairment in central B cell tolerance is causal for disease and predates the onset of pathogenesis and immune dysregulation. This simple observation provides a firm answer to years of debate and provides a secure framework for new discovery and therapy. During their development in the bone marrow (BM), the antigen receptors of B lymphocytes (B cell receptors [BCRs]) are generated by random genomic rearrangements of Ig variable (V), diversity (D), and joining (J) gene segments at the heavy-chain (IgH) and light-chain (IgL) loci. The very randomness of this process ensures a B cell repertoire capable of responding to virtually any antigen, including self antigens. Whether this property of latent autoreactivity is a feature or a bug of combinatorial diversity remains an issue of considerable importance and debate, but significant autoimmunity is normally blocked by several mechanisms of immunologic tolerance that operate at distinct checkpoints in the BM and periphery (for review, see refs. 2 and 3). At least 3 distinct mechanisms of immune tolerance can operate to purge developing B cell populations of autoreactivity: clonal deletion by apoptosis (4), secondary V–D–J gene rearrangements that alter BCR specificity (5,6), and the induction of cellular unresponsiveness or anergy (7). Estimates on the relative contributions of each of these processes indicate that secondary V–D–J gene rearrangements that result in the editing of autoreactive BCRs is the preeminent mechanism of B cell tolerance, with deletion and anergy playing relatively minor roles in silencing self-reactive B cells (8). Even though these mechanisms of central B cell tolerance are efficient, significant numbers of autoreactive B cells emigrate from the BM and enter peripheral lymphoid tissue as transitional (9) or new emigrant B cells (10). These newly arrived populations exhibit decreased frequencies of autoreactivity compared to phenotypically indistinguishable BM cells, but contain more self-reactive cells than do fully mature, naive B cell populations (10). This secondary reduction of autoreactivity that follows the incorporation of transitional new emigrant B cells into the mature B cell pools in the periphery reveals a second checkpoint for B cell tolerance (10,11). Acting together, these tolerance checkpoints ensure that depletion of B lymphocytes, which avidly bind self antigens present in both the BM and the peripheral tissue, is sufficient to preclude pathogenic autoimmunity while retaining the capacity to respond effectively to any and all pathogens (Figure 1). Whereas B cell tolerance has been extensively studied in mice for decades (4–7), 8 years ago Wardemann and colleagues assembled a technology for recovering and expressing IgH IgL rearrangements from single human B cells, to determine the specificity and affinity of each reconstituted BCR (10). Although the core methods of this approach were not novel (12–16), its scale was unprecedented, and consequently, great precision and much new insight has been brought to studies of human B cell biology. In particular, this experimental system has been used with great effect to enumerate self-reactive B cells in healthy subjects and in patients with systemic autoimmune disease (10,17–20). Interestingly, immature B cells in the BM of healthy subjects are frequently autoreactive, with as many as 75% of recovered IgH IgL pairs exhibiting self-binding (e.g., antinuclear antibody, DNA, or insulin reactivity) and/or polyreactivity (10). The high frequency of polyGarnett Kelsoe, DSc: Duke University and Duke University Medical Center, Durham, North Carolina. Address correspondence to Garnett Kelsoe, DSc, Department of Immunology, Duke University Medical Center, 116 Jones Building, Box 3010, Durham, NC 27710. E-mail: ghkelsoe@duke.edu. Submitted for publication November 1, 2010; accepted in revised form November 16, 2010.