A B cell explanation for autoimmune disease: the forbidden clone returns

Abstract

More than 60 years ago, Burnet first proposed the 'forbidden clone' hypothesis postulating that autoimmune disease arises as a result of persistence of self-reactive clones of lymphocytes that should have been deleted via immune tolerance. These autoreactive clones could effect immune-mediated end-organ damage via peripheral selfantigen recognition. Recent evidence that stretches across the boundaries of many medical specialties supports this proposal, implicating a B cell precursor as the culprit. The success of B cell depleting therapy in rheumatoid arthritis, anti-neutrophil cytoplasmic antibodies (ANCA) associated vasculitis, polymyositis, lupus and autoimmune diseases as diverse as multiple sclerosis and idiopathic thrombocytopenic purpura supports this proposal. Clonality of B cells and plasma cells has been described in a number of autoimmune disorders and the presence of autoantibodies, which may arise years before the onset of clinical disease, supports the notion of autoreactivity within the B cell lineage. T cell activation within the end-organ would be predicted by cognate BeT cell interactions and resultant tissue inflammation and destruction could produce diverse clinical manifestations dictated by the original specificity of the autoimmune B cell.

Bone marrow edema and osteitis in rheumatoid arthritis: the imaging perspective

“…There was a also a strong correlation with the receptor activator of nuclear factor kappa B (RANKL) score (r = 0.59, P = 0.004). B-cell aggregates were identified in some samples, which were reminiscent of the ectopic lymphoid tissue that can be found in active rheumatoid synovium [51]. The conclusion from these findings was that the rheumatoid bone marrow is a site of active pathology with a histology similar to that found within synovial membrane but with the addition of osteoclasts closely apposed to trabecular bone and likely to be mediating the erosive process.…”

Hypergammaglobulinemia is a marker of extraintestinal manifestations in pediatric inflammatory bowel disease

“…Polyclonal B-cell activation by inflammatory cytokines, including B-cell activating factor and interleukin 6 (IL-6), plays an important role in lupus and other autoimmune conditions (12,13). IL-6 overexpression is a common feature of many autoimmune disorders, including IBD and autoimmune joint diseases (14,15); thus, it is probably a key determinant in the etiology of elevated IgG levels in IBD and EIM patients.…”

Decreased CD5+ B Cells in Active ANCA Vasculitis and Relapse after Rituximab

“…These autoantibodies can cause disease in mouse models (3)(4)(5). Recently, rituximab (a B cell-depleting mAb) has been shown to be effective in treating ANCA-SVV, suggesting that B cells play an important role in the pathophysiology of this disease (6,7).…”