Abstract
The serological presence of autoantibodies is diagnostic of autoimmunity, and these autoantibodies may be present for many years before the presentation of autoimmune disease (AID). Although a pathogenic role has been demonstrated for various autoantibodies reactive with cell surface and extracellular autoantigens, studies using monoclonal antibodies (mAb) show not all antibodies in the polyclonal response are pathogenic. Differences depend on Fab-mediated diversity in epitope specificity, Fc-mediated effects based on immunoglobulin (Ig) class and subclass, activation of complement, and the milieu in which the reaction occurs. These autoantibodies often occur in organ-specific AID and this review illustrates their pathogenic and highly specific effects. The role of autoantibodies associated with intracellular antigens is less clear. In vitro they may inhibit or adversely affect well-defined intracellular biochemical pathways, yet, in vivo they are separated from their autoantigens by multiple cellular barriers. Recent evidence that Ig can traverse cell membranes, interact with intracellular proteins, and induce apoptosis has provided new evidence for a pathogenic role for such autoantibodies. An understanding of how autoantibodies behave in the polyclonal response and their role in pathogenesis of AID may help identify populations of culprit B-cells and selection of treatments that suppress or eliminate them.
Highlights
The first description of a pathogenic autoantibody by Donath and Landsteiner in 1904 [1] was a landmark discovery in the history of clinical medicine
Useful models that are T-cell independent have been developed either by transfer of monoclonal antibodies from an immunized animal, as has been done in collagen antibody induced arthritis (CAIA) [57], or, where human autoantibodies are unreactive with the mouse equivalent, by transfusing mice with anti-mouse antibodies derived by immunizing another species with mouse antigen [27,31]
The most direct evidence for pathogenic effects of Fab binding has come from studies of pemphigus vulgaris (PV), including paraneoplastic pemphigus associated with underlying neoplasms [101], and pemphigus foliaceus (PF), characterized by intra-epidermal blistering of skin and mucosa, with epidermal cell-to-cell detachment, and associated autoantibodies to desmogleins, the cadherin-type cell-cell adhesion molecules in desmosomes
Summary
The first description of a pathogenic autoantibody by Donath and Landsteiner in 1904 [1] was a landmark discovery in the history of clinical medicine. The episode was given the descriptive term paroxysmal cold hemoglobinuria (PCH) but the etiology remained unknown until the elegant laboratory studies of Landsteiner demonstrated the sequence of immunological events that occurred in the blood of three subjects with PCH under the care of Donath. Autoimmunity was first identified as a cause of disease based on the recognition of self-reactive autoantibodies in the sera of patients In these early studies, the autoantigens were not well defined and antibodies were considered in terms of reactivity with whole cells, cell extracts or relatively impure antigen, and disease was attributed to these autoantibodies. Similar autoantibodies were demonstrated in the comparable human disease, Hashimoto’s thyroiditis [3] During the latter half of the 20th century many diseases were identified as autoimmune, poorly understood groups containing such diseases were reclassified and immunosuppression became a standard method of treating the chronic inflammation of autoimmunity. As a template for nominating pathogenic autoantibodies, in this review we sought irrefutable evidence for their pathogenicity in a range of autoimmune diseases, examined the mode of action of antibodies within the polyclonal response, and scrutinized the role of a number of pathogenic autoantibodies in diseases representative of the entire spectrum of autoimmune diseases
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