Autoimmunogens, autoantigens, autoantibodies and autoimmune diseases: one-to-one or many-to-many relationships?

Abstract

Cells with receptors capable of binding self-antigens constitute a normal component of the B cell repertoire; these specificities appear to be represented in low levels within the expressed antibody population. In autoimmune disease, this potential-actual repertoire is skewed in favor of exaggerated autoantibody expression. The clones or specificities affected are characteristic, even diagnostic of the particular disease, yet individuals express but a relatively small subset of this complexity. "Marker" autoantibodies may or may not be included, but autoantibodies more typical of other, related diseases are usually present. Certain specificities are clearly implicated in the pathogenesis of the corresponding disease; others contribute to- or exacerbate pre-existing pathological conditions, and still others appear at present as epiphenomena. Organ-/tissue-specific autoantibodies largely fall into the first or perhaps second categories; those associated with the systemic rheumatic diseases fit better into the latter or latter two categories. As we learn eventually more about these antibodies and the full spectra of autoantigens with which they react, many more may be found to exert more central roles in pathogenesis. The distortion of the expressed repertoire represents but one aspect of a far more complex set of pre-dispositions, conditions, stimuli, contributory factors and perhaps coincidences involved in the onset and perpetuation of the disease. The AAb arise within the context of a disease more pervasive than just the autoantibodies themselves, however, in certain diseases the subsequent autoimmune response may surpass all other variables to constitute the single most clinically significant factor. In attempting to account for these individual specificities and their disease associations, certain models seem applicable to selected autoantibodies but not to others. Even in these selected cases, the models remain speculative; in no case can we categorically state how the specificities arose. Non-specific activation may contribute to- and expand the expressed autoantibodies, but such mechanisms generally fall short in terms of adequately explaining the specificities of autoantibodies, the overlapping sets, the polyclonality of the response against single autoantigens or the specific disease associations. Despite this theoretical criticism, empirically, non-specific mechanisms have given rise to mixtures of autoantibodies which appear identical at least in terms of specificities to their spontaneous counterparts in various rheumatic diseases.(ABSTRACT TRUNCATED AT 400 WORDS)