Defective B cell tolerance checkpoints in systemic lupus erythematosus

Abstract

A cardinal feature of systemic lupus erythematosus (SLE) is the development of autoantibodies. The first autoantibodies described in patients with SLE were those specific for nuclei and DNA, but subsequent work has shown that individuals with this disease produce a panoply of different autoantibodies. Thus, one of the constant features of SLE is a profound breakdown in tolerance in the antibody system. The appearance of self-reactive antibodies in SLE precedes clinical disease, but where in the B cell pathway tolerance is first broken has not been defined. In healthy humans, autoantibodies are removed from the B cell repertoire in two discrete early checkpoints in B cell development. We found these checkpoints to be defective in three adolescent patients with SLE. 25–50% of the mature naive B cells in SLE patients produce self-reactive antibodies even before they participate in immune responses as compared with 5–20% in controls. We conclude that SLE is associated with abnormal early B cell tolerance.

BAFF and the plasticity of peripheral B cell tolerance

“…However, following description of the TR compartment, Fulcher and Basten demonstrated that these 'anergic' B cells achieved entrance to the TR pools, but nonetheless died rapidly before entering mature pools [6]. This relationship holds in humans, as demonstrated by studies showing the loss of autoreactive and polyreactive clonotypes at the TR stages [7••], and apparent failure of this checkpoint in SLE patients [8].…”

Peripheral B cell receptor editing may promote the production of high‐affinity autoantibodies in CD22‐deficient mice

“…Recent studies of individual autoreactive B cells from healthy human subjects and lupus patients [47,48] lend support to the notion that the major failure of self tolerance in spontaneous SLE may take place in the periphery. Although the anti-nuclear autoantibodies were not distinguished on the basis of antigen affinity, these studies have clearly defined two checkpoints, one central and one peripheral, in which autoreactive B cells were controlled by mechanisms of self tolerance.…”

“…Although the anti-nuclear autoantibodies were not distinguished on the basis of antigen affinity, these studies have clearly defined two checkpoints, one central and one peripheral, in which autoreactive B cells were controlled by mechanisms of self tolerance. Strikingly, the only highly significant difference between healthy human subjects and lupus patients was demonstrated in the periphery, where all SLE patients failed to remove B cells that express potentially pathogenic antinuclear autoantibodies [48].…”

B cell tolerance: Putting the horse before the cart

“…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)(18)(19)(20). Interestingly, immature B cells in the BM of healthy subjects are frequently autoreactive, with as many as 75% of recovered IgH ϩ IgL pairs exhibiting self-binding (e.g., antinuclear antibody, DNA, or insulin reactivity) and/or polyreactivity (10).…”

“…The high frequency of poly-reactive membrane IgMϪ B cells in human BM is surprising, given the characteristic specificity (Յ5% polyreactivity) of mature peripheral B cell populations (10,18), and these cells are associated with BCRs bearing long IgH in the third complementarity-determining region, containing positively charged and/or aromatic amino acids (10,21,22). In humans, perhaps even more than in mice (3), random V-D-J rearrangements frequently generate autoreactive/polyreactive BCRs and B cells with a potential role in autoimmune disease (10,(17)(18)(19).…”