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680 Immunology—Autoimmunity

arenas. To appreciate fully the significant roles these tech- clones are activated during an autoimmune response. In
niques have played it is necessary first to review briefly the systemic autoimmune diseases many autoantigens are
some of the fundamental features of autoimmunity and complexes of nucleic acid and/or protein, and an autoim-
autoantibodies. mune response may target several of the components of
a complex. It is unknown whether the autoantibody re-
sponses to the components of a complex arise simul-
I. AUTOIMMUNITY AND AUTOANTIBODIES taneously, sequentially, independently, or through some
interrelated mechanism. Immunization studies in mice
Autoimmune responses constitute an attack by the im- have suggested that some autoantibody responses may
mune system on the host. The responsible effector mech- arise sequentially, a process termed epitope spreading.
anisms appear to be no different from those used to combat Whether this mechanism is applicable to humans is under
exogenous agents and include soluble products such as an- investigation.
tibodies (humoral immunity), as well as direct cell-to-cell In only a few instances have autoantibodies been
interaction leading to specific cell-lysis (cell-mediated im- shown to be the causative agents of pathogenesis (e.g.,
munity). Autoantibodies are therefore defined as antibod- anti-acetylcholine receptor autoantibodies in myasthe-
ies produced by the host which recognize cellular or tissue nis gravis, anti-thyroid stimulating hormone receptor au-
constituents of the host. No single mechanism has been toantibodies in Graves’ disease). It is noteworthy that
described that can account for the diversity of autoimmune these diseases are usually organ specific and that their
responses or the production of autoantibodies. Perhaps the autoantigens are extracellular or on the surface of cell
most perplexing and challenging aspect of autoimmunity membranes and therefore easily targeted by the immune
and autoantibody elicitation is the identification of the system. In the non-organ-specific autoimmune disease
events involved in the initiation of the response. Although systemic lupus erythematosus (SLE) anti-double-stranded
these early events are poorly understood for most autoim- DNA (dsDNA) autoantibodies have been shown to partic-
mune diseases, it is thought that an exogenous trigger may ipate in pathogenic events by way of complexing with
provide the first step in the initiation of some autoimmune their cognate antigen to cause immune complex medi-
responses. It is also uncertain how T and B cells, with re- ated inflammation. These examples show that in both
ceptors for autoantigen, emerge from primary lymphoid organ-specific and systemic autoimmune diseases, in vivo
tissues, having escaped the regulatory mechanisms that deposition of autoantibody in tissues and organs has
normally delete them or keep them in check, and make clinical significance, as it indicates sites of inflamma-
their way to secondary lymphoid tissues where they can tion and possible pathological lesions. Detection of au-
be activated to respond in an inappropriate manner. Stud- toantibody/autoantigen deposits in organ-specific autoim-
ies involving transgenic mice expressing neoautoantigens mune diseases has particular significance because passive
suggest that possible mechanisms for emergence of au- infusion of some organ-specific autoantibodies has been
toractive cells include avoidance of apoptotic elimination, found directly to mediate pathological sequelea. In most
escape from tolerance induction, and reversal of an anergic autoimmune diseases, however, it has not been deter-
state. Molecular identification of autoantigens, their pres- mined whether autoantibodies cause or contribute in any
ence in macromolecular complexes, the occurrence of au- way to disease. It is possible that autoantibodies are an
toantibodies to different components of the same complex, indicator of the primary event or a secondary conse-
and the appearance of somatic mutations in the variable quence of the underlying clinical condition; autoantibod-
regions of autoantibodies have suggested that autoantigen ies have been described as potential “reporters” of disease
drives the autoimmune response. These findings support mechanisms.
the argument that activation of autoreactive cells occurs Diseases associated with autoantibodies can be divided
in secondary lymphoid tissues. It remains unclear how into two broad groups: multisystem autoimmune diseases,
autoantigens, particularly intracellular autoantigens, are in which autoantibodies react with common cellular com-
made available to the immune system and what molec- ponents that appear to bear little relationship to the clin-
ular forms of these complex macromolecular structures ical syndrome, and organ-specific autoimmune diseases,
interact with autoreactive lymphoid cells. in which autoantibodies have the ability to react with au-
An important component in humoral autoimmune re- toantigens from a particular organ or tissue. In both sit-
sponses is the appearance of autoantibody-secreting B uations the specificity of the autoantibody can serve as a
cells. The antibody secreted by a B cell is directed against diagnostic marker (Table I). There are several features of
a single region (or epitope) on an antigen. An autoanti- the relationship between autoantibody specificity and di-
body response can target a number of epitopes on any one agnostic significance within the multisystem autoimmune
antigen, clearly showing that multiple autoreactive B-cell diseases that bear consideration. Autoantigens in these