Autoimmunity should be defined in the strict sense as an immune response by the host to a self-antigen, at either the humoral or cellular level or both. This definition distinguishes the autoimmune response per se from autoimmune disease where the humoral and/or cellular consequences of the immune response have resulted in pathophysiological abnormalities. In this sense, autoimmunity as a phenomenon is not uncommon, but the follow-through to autoimmune disease has been less common. This observation begs the question of whether there are autoimmune responses that are physiological and others that are pathological. In this chapter, I will describe the unique features of the auto-antibody-defined epitope, or the antigenic determinant on the self-antigen, and how perhaps this knowledge might be useful in the context of designing reagents for immunotherapy.
Immunotherapy has been described as any approach aimed at mobilizing or manipulating a patient's immune system to treat or cure disease . This has included therapeutic vaccines consisting of modified or unmodified self-antigens or peptides of such antigens in order to activate the patient's own immune response. Other approaches include the use of monoclonal antibodies targeting autoantigens, cytokines, or cell receptors shown to be involved in tissue pathology. Immunotherapy in the form of monoclonal antibodies to TNFa or as secretory subunits of TNFa have been strikingly successful in the treatment of rheumatoid arthritis , but other forms of immunotherapy have not been as successful. The problems encountered have included unacceptable side effects of autoimmune hyperthyroidism in multiple sclerosis patients treated with monoclonal antibody to CD52 [3, 4] and minimal responsiveness using cancer immunotherapy based on peptide antigens [5, 6]. These and other difficulties have led some investigators to say that human immunotherapy is currently "bewildered" about how to stimulate the immune system and what new directions to pursue .
It is not a point of contention to say that there is very little proven knowledge concerning the mechanisms leading to an autoimmune response to a molecule that is part of self. Our understanding of mechanisms leading to the immune processing of a foreign antigen such as a purified foreign protein is fairly comprehensive, but the knowledge concerning immune processing of a self-protein is at present rudimentary and speculative. There are multiple and complex reasons for this state of our ignorance, not the least of which are uncertainties as to how self-proteins or other self-molecules are recognized as foreign by the immune system. Some of these questions addressed in this book include apoptosis and cell necrosis in the intracellular degradation of potential autoantigens (see Chapters 6 and 7), but these may be but the tip of a hidden iceberg of many mechanisms.
One of the hallmarks of many autoimmune diseases is the production of au-toantibodies to specific cassettes of cellular autoantigens. This is abundantly demonstrated not only in systemic autoimmune diseases such as lupus but also in organ-specific autoimmune diseases such as type 1 diabetes, autoimmune thyroid disease, and others as described by several authors in this book. Autoantibodies to these disease-specific autoantigens have become clinically useful as diagnostic markers in medicine. What has been not as fully appreciated is the fact that there is valuable information to be gained from analyzing the reactive epitopes of autoantigens. In essence, the immune system of the patient is saying that in the case of a particular self-molecule, its own immune system is able to mount an immune response to one particular region but is unable to make a response to another. In the design of antigen-specific immunotherapy, it would be important to capitalize on this information and not design antigens to which the immune system has been non-responsive.
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