Expression of myosin-class II major histocompatibility complexes in the normal myocardium occurs before induction of autoimmune myocarditis.

Abstract

Determining how an autoimmune response is initiated is essential to understanding the mechanisms of autoimmunity. Self-reactive T cells, self-protein, and a failure of tolerance to that self-protein are all involved in the pathogenesis of autoimmune disease; yet it is not clear how self-reactive T cells rind the target self-protein to initiate an autoimmune response. Although a variety of self-proteins have been shown to be presented on both class I and class II major histocompatibility complex (MHC) molecules, the relationship of these self-proteins to autoimmune disease has not been established. To explore this further, we generated a T-cell hybridoma that recognizes mouse cardiac myosin, the self-protein that induces murine autoimmune myocarditis. Using this hybridoma as a probe to detect myosin-class II MHC complexes, we isolated a class II MHC+/CD45+ residential antigen-presenting cell (APC) population directly from the hearts of normal mice and looked for evidence ofendogenous processing ofcardiac myosin by these APC. In this report we show that myosin-class II MHC complexes are found on residential APC in the normal mouse heart. Induction of autoimmune myocarditis increased the expression of myosin-class H MHC in the heart and enhanced their APC functions. This result is a direct demonstration that epitopes of a self-antigen involved in initiating an autoimmune disease are endogenously processed and presented within the target organ.It is vital that the immune system distinguish between selfproteins and foreign protein antigens to elicit an effective immune response. Precisely how this discrimination is made is not completely understood, but negative selection (1-7), clonal anergy (8), peripheral tolerance (9), and downregulation of self-reactive T-cell receptors (10) are all mechanisms shown to function in vivo to sustain tolerance to self-proteins. Work by several investigators has firmly established that self-proteins are processed and presented by antigen-presenting cells (APC) (11)(12)(13)(14)(15). Wekerle et al. (16) reported that Schwann cells could process the self-protein myelin basic protein, known to initiate experimental allergic encephalomyelitis, and present it to myelin basic proteinreactive T cells, but this occurs only if the Schwann cells are first treated with interferon y in vitro. Recently, endogenously processed self-peptides have been eluted from both major histocompatibility complex (MHC) class I and class II molecules, sequenced, and identified (17-21); these selfpeptides represent a spectrum of nuclear, cytoplasmic, and membrane-bound self-proteins. Thus, it is clear that many self-proteins are endogenously processed and complexed with MHC class I or class II molecules. However, none ofthe currently identified self-proteins known to be endogenously processed by APC in vivo has been implicated in an autoimmune disease.Several models of autoimmune disease use a purified self-protein emulsified in complete Freund's adjuvant (CFA) to induce an autoimmune response in suscep...

Spontaneous myocarditis mimicking human disease occurs in the presence of an appropriate MHC and non-MHC background in transgenic mice

“…In vitro spontaneous T cell response to cardiac myosin and derived-peptide could be blocked by anti-DQ antibody thus suggesting it to be DQ-specific. Cardiac myosin MHC class II complexes have been shown to be constitutively expressed on cardiac APCs [27]. There was a marked increase in the expression of DQ8 in these mice similar to what is known from biopsies of myocarditis patients [28].…”

Absence of nonhematopoietic MHC class II expression protects mice from experimental autoimmune myocarditis

“…2A). This MHCII expression appears to be on cardiac professional APCs, mainly macrophages and DCs, which are present in significant numbers in the heart under steady-state conditions [9,27]. Costaining of MHCII molecules with the endothelial cell marker CD31 reveals that mainly endothelial cells of the interstitial capillary network upregulate MHCII expression in inflamed hearts ( Fig.…”

“…MHCII is primarily expressed on professional APCs. Cardiac APCs were suggested to present cardiac myosin before the onset of cardiac pathology [9], and DCs, the major APC subset able to initiate primary immune responses, were shown to be critical for disease induction [5,10]. However, MHCII molecules are also upregulated on nonhematopoietic cells under inflammatory conditions [11,12].…”

Cardiac Myosin and the TH1/TH2 Paradigm in Autoimmune Myocarditis

“…62 Evidence has shown that in normal myocardium myosin-class II major histocompatibility antigen complexes are present before the induction of autoimmune myocarditis. 63 Induction of myocarditis is seen only with cardiac myosin and not skeletal myosin 23 or other ␣-helical coiled-coil proteins such as tropomyosin (Galvin and Cunningham, unpublished data). Streptococcal M protein mimics cardiac myosin sequences or epitopes and immunization with the M protein or peptides leads to myocardial and valvular inflammatory heart lesions in BALB/c mice and Lewis rats.…”