Putting together the autoimmunity puzzle

Abstract

R e v i e w S e R i e S : A u t o i m m u n i t y2highlighting the evidence for a key role of these suppressor cells in the prevention and suppression of autoimmunity, these authors review the experimental support for the existence of functionally and phenotypically distinct suppressor cell subsets and their complementary role in regulating immune responses. By including considerations of Treg stability under changing environments and the recent immunotherapeutic approaches for the restoration of peripheral immune tolerance, these authors ponder the current challenges in achieving remission of autoimmunity without continuous immune suppression (i.e., by maintaining uncompromised overall immune responses). The restoration of immune homeostasis might be accomplished by enhancing suppressive immune responses, to limit the damage caused by T cells or B cells (or by the cytokines that they produce). George Tsokos and colleagues analyze the central role of T cells in orchestrating autoimmune responses and the characteristics of these cells in a prototypical systemic autoimmune disease (11), while Betty Diamond and Jolien Suurmond address the importance of the mechanisms that drive autoantibody pathogenicity and the mechanisms by which autoantibody production is initiated (12). Autoantibodies appear long before clinical symptoms of autoimmunity, thus representing a marker for potential disease development (13). Their predictive value is also reflected by the finding that there is an approximately six-to eight-fold increase in the risk of developing an autoimmune disease when only one autoantibody is present compared with three autoantibodies present (14).Autoantibodies develop because of inefficient removal of autoreactive B cells, which in healthy individuals are eliminated both at central and peripheral levels. In untreated patients with active autoimmune disease, both central and peripheral B cell tolerance checkpoints can be defective (15). Fritz Melchers describes three checkpoints of central tolerance for B cells in the bone marrow and discusses the importance of the microenvironment in the effective removal of the vast majority of B cell clones that express polyreactive antibodies (16). He then discusses the mechanisms of peripheral B cell tolerance, namely checkpoint 4, which removes peripheral autoreactive new emigrant B cells before they enter the mature naive B cell pool (17), and checkpoint 5, which eliminates accidental products of hypermutation that are created during antibody affinity maturation (18). ConclusionsIn summary, this Review series surveys the complex mechanisms of autoimmunity and the potential new therapies that might target critical disease pathways, cells, and molecules. Much has been learned about the pathogenesis of autoimmune disease since the original formulation of the concept of horror autotoxicus that was forged by Paul Ehrlich during his study of the development of hemolytic antibodies in animals injected with blood of unrelated species (19)(20)(21)(22)(23)(24). The failure to deve...

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