ABSTRACT
Mostly for convenience, a large number of animal and human diseases have been grouped under the category of autoimmune diseases. This group is extremely heterogeneous in nature. First, there are broad differences in the nature of some of these diseases, and large biological discrepancies within each disease. The level of heterogeneity extends from the symptomatology to the etiology, to the T or B cell nature of the autoreactive response, and to the response to immunosuppressive therapies. Nonetheless, it appears that in most of these diseases, the cells of the immune system are involved in tissue damage. Also common to all of these diseases is the absence of a unique causative agent. Viral, bacteria and environmental antigens have been suspected in many cases, but no correlation has been established directly between these factors and a particular disease. In this context, the question is how tolerance to self-antigens is disrupted? Hypotheses are numerous, but again definitive proof is absent. To address some of the most relevant questions, we and others have chosen a reductionist approach by analyzing the T cell receptor-self-peptide MHC complex at the molecular level. This very basic approach answers three questions: 1) Are autoimmune TCRs peculiar in their structure? 2) Are self-peptide MHC complexes structurally unusual? 3) Is the interaction of these molecules different from the interaction of normal TCR/MHC pairs? It is very likely that the answer to all three questions is negative. However, answering these questions allows us to move forward in the understanding of the autoimmune process. In the unexpected case that all autoimmune TCRs display a high affinity for their ligand, further research in thymic negative selection as a cause for autoimmunity would be warranted. Alternatively, very low affinities would focus our attention on positive selection. In any case, structural information on autoimmune peptideMHC and TCR molecules could also guide the design of small molecule compounds that can specifically alter this interaction. From a more general perspective, these studies will help in understanding the linkage between human autoimmune diseases, particular major histocompatibility complex (MHC) class I or II haplotypes. This correlation, which was established three decades ago, is still poorly understood. For some diseases, the linkage is established through the nature of the peptide that associates with a given haplotype, while for others, the MHC itself is the culprit in bearing distinctive structural features that could lead to poor peptide binding, high autoreactivity, and instability. These structural studies have been greatly helped by new protein expression systems, but structural studies remain difficult, confidential and are limited in their advances. To date, there is a small
set of structural data on MHC molecules associated with autoimmunity, but information on the TCRs that recognize these structures is lacking thus far. We will discuss the conclusions of these initial findings in the following chapter.
