Could TCR antagonism explain associations between MHC genes and disease? Stanislav Vukmanovic ´ 1 , Thomas A. Neubert 2 and Fabio R. Santori 1 1 Michael Heidelberger Division of Immunology, Department of Pathology and NYU Cancer Center, NYU School of Medicine, New York, NY 10016, USA 2 Skirball Institute of Biomolecular Medicine, Department of Pharmacology, NYU School of Medicine, New York, NY 10016, USA Alleles of major histocompatibility complex (MHC) loci are associated with certain types of diseases, including those of infectious and autoimmune origin. MHC products can promote susceptibility or resistance to disease by stimulating or inhibiting immune responses. Recent evidence suggests that MHC-associated peptides derived from self-proteins can act as antagon- ists of T-cell activation, thereby inhibiting immune responses to antigens. We suggest that self-peptide- promoted antagonism might explain some associations between MHC alleles and particular chronic diseases. Immune responses are initiated when short peptide antigens derived from lysosomal or proteasomal proteo- lytic processing, in association with major histocompati- bility complex (MHC) molecules, are presented to T lymphocytes. In every species analyzed to date, MHC genes are the most polymorphic genes found in the genome, and this polymorphism is maintained by selection [1]. Allelic variants of MHC gene products bind different peptides from any given protein (Fig. 1). The presence of multiple alleles in a population increases the probability of foreign-antigen presentation in at least some individuals (Fig. 2), and consequently enhances the likelihood of species survival [2]. Associations between MHC alleles and AUTOIMMUNE (see Glossary) diseases [3–6], infectious diseases [7], allergic disorders [8] and tumors [9–11] have been observed. One common characteristic of these diseases is their chronic nature, suggesting that MHC exerts its influence over relatively long time periods. Both susceptibility and resistance to disease can be mediated by stimulatory or inhibitory influences of MHC molecules on the intensity of the immune response, depending on the nature of the disease (Fig. 3 and Table 1). Immune responses can contribute to either resistance or susceptibility to disease Stimulation of an immune response can protect the host against infections or tumors, but can also promote autoimmune and/or inflammatory (IMMUNOPATHOLOGI- CAL) diseases. An illustrative example of MHC-mediated protection is resistance to the development of severe (cerebral) malaria [12]. Presentation of a peptide derived from Plasmodium falciparum by human leukocyte antigen (HLA)-B53 has enabled preferential survival of HLA-B53 þ individuals in areas of Africa in which severe malaria in endemic. HLA genes are also associated with the speed of development of AIDS following infection with HIV-1. Most untreated HIV-1-infected humans develop clinical AIDS within 5 – 10 years of initial infection [13]. However, a small group of seropositive long-term survivors develop benign disease with much slower progression to AIDS [14], and HLA-B57 and HLA-B27 are over-represented alleles in this group of individuals [15,16]. Productive immune responses can also be harmful. Some of the strongest associations between HLA and diseases are with autoimmune and/or immunopatho- logical conditions. For example, . 90% of patients with ankylosing spondylitis, coeliac disease, narcolepsy or birdshot chorioretinopathy are carriers of HLA-B27, -DQ2, -DR2 or -A29, respectively (Table 1). Although associations between MHC genes and diseases could potentially be the result of ‘squatter’ genes placed by chance in the MHC locus, evidence for a specific and direct role for MHC alleles in disease has been provided in some cases. For example, in experimental animals transgenic for the appropriate allele, HLA-B27 [17,18] and HLA-A29 [19] promote the development of pathology that is Glossary Anergy: A state of unresponsiveness to antigen. Autoimmunity: Damage done to the tissue as a consequence of an immune response to self antigens, which should not normally occur. Determinant capture: Prevention of binding of an epitope to a major histocompatibility complex (MHC) molecule, caused by binding of the same epitope or its large portion to another MHC molecule. Epitope: The portion of an antigen that interacts with antibody or the T-cell receptor (TCR). Immunodominance: The capacity of an immune system to focus the response on one or few of the many potential epitopes. Immunopathology: Damage done to the tissue as a consequence of a protracted immune response to foreign antigens. Negative selection: Physical removal or functional silencing of autoreactive T cells, which occurs during maturation of T cells in the thymus. Positive selection: Functional and phenotypic maturation of T cells in the thymus based on the ability of their TCRs to interact with self-peptide– MHC complexes. Corresponding author: Stanislav Vukmanovic ´ (vukmas01@med.nyu.edu). Opinion TRENDS in Molecular Medicine Vol.9 No.4 April 2003 139 http://tmm.trends.com 1471-4914/03/$ - see front matter q 2003 Elsevier Science Ltd. All rights reserved. doi:10.1016/S1471-4914(03)00029-7