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Infections often precede the onset of autoimmune disease and molecular (or epitope) mimicry is a plausible link. Cross-reacting epitopes are common between an infecting microorganism and the host because negative selection of self-reactive T-cells and B-cells is frequently incomplete. Complete eradication could lead to major voids in the immunologic repertoire. The association of an autoimmune disease with a microbial epitope may signify a causal relationship with the organism, an indirect connection through bystander effects, persistent infection or coincidence. There are well-established examples of a microbial mimic inducing a defined model of autoimmune disease in experimental animals but such instances are still relatively rare in humans. Establishing epitope mimicry as a direct cause opens opportunities for preventing the disease. Current approaches to cancer immunotherapy provides new examples of epitope mimicry between cancer antigens and normal tissue antigens. [ABSTRACT FROM AUTHOR]

Abstract: Most of our current understanding of the genetic predisposition to autoimmune disease can be traced to experiments performed in the decade from 1971 to 1981. Chella David was a key contributor to this research. Many of these early steps came from studies of experimental autoimmune thyroiditis. This model has been especially valuable because essentially the same disease can occur spontaneously in selected strains of animals or can be induced by deliberate immunization. From a genetic point of view, the disease has been investigated in three different species: mice, rats and chickens. The same antigen, thyroglobulin, initiates the disease in all three species. Among the main discoveries were the relationship of autoimmune disease to the major histocompatibility complex (MHC), the interplay of different subregions within the MHC in promoting or retarding development of disease, the differing roles of MHC class II and MHC I class genes in induction and effector phases, respectively, and the cumulative effect of non-MHC genes, each of which represents a small addition to overall susceptibility. Other experiments revealed that genetic differences in thyroglobulin allotypes influence susceptibility to thyroiditis. Thyroid glands differed in different strains in vulnerability to passive transfer of antibody. The first evidence of modulatory genes on the sex-related X chromosome emerged. All of these genetic findings were concurrently translated to the human disease, Hashimoto’s thyroiditis, where thyroglobulin is also the initiating antigen. [Copyright &y& Elsevier]

Examines the role of dichotomous helper T cell subset model in immunology. Mediation of delayed type hypersensitivity; Phenomenon of polarization in cytokine secretion patterns; Generation of ovalbumin specific T cells which secrete interleukins in response to antigenic stimulation.

The mechanism of polyclonal activation suggested that it was the indirect and nonspecific result of cytokine release by either B cells stimulated by antigen or T cells stimulated by viral peptide bound to major histocompatibility complexes (MHCs) on antigen-presenting cells (APCs). The mechanism proposed by researchers however, differs by postulating that virusspecific CD4 cells interact with viral peptide-MHC complexes exposed on the surface of B cells acting as APCs and directly stimulate these B cells to differentiate, regardless of their BCR specificity. Authors suggest that the phenomenon of polyclonal B cell activation is much more general and wish also to comment on some further theoretical implications of their study. T cells may also be engaged in non-specific polyclonal activation. Thus, only a small proportion of passively administered specific T cells is found in the infiltrates that mediate skin graft rejection or delayed-type hypersensitivity. The implication of these findings is that any specific antigenimmunocyte interaction may serve the purpose. Researchers have suggested that this phenomenon is an important contributor to the luxuriant mononuclear infiltrates found in all immunogenic inflammatory reactions involving B and T cells.

Abstract: Autoimmune myocarditis, a chronic stage of myocardial inflammation, occurs in a small subset of patients after acute cardiotropic viral infection and can lead to dilated cardiomyopathy (DCM). This disease can be recapitulated in susceptible mouse strains by infection with coxsackievirus B3, or by immunization with cardiac myosin or cardiac troponin I. The etiologies of myocarditis are multifactorial and genetically complex. Genetic linkage between susceptibility to myocarditis/DCM and the major histocompatibility complex (MHC) genes has been reported in both humans and experimentally induced mouse models. However, unlike other autoimmune diseases, the non-MHC genes seem to have greater impact than MHC genes on disease susceptibility. Several myocarditis-related non-MHC loci have been identified by our laboratory and others in different models. Most of these loci overlap with other autoimmune disease susceptibility loci, suggesting common or shared genetic traits influencing general autoimmunity. For example, we have demonstrated that Eam1 and Eam2 may influence disease susceptibility via regulating T cell apoptosis at different developmental stages. Blockade of signaling through specific genes, such as CTLA4, ICOS and PD-1, can either enhance or prevent the development of experimental autoimmune myocarditis, but it remains unclear whether functional polymorphisms in these genes are involved in predisposition to disease. In humans, mutations/deletions in immunologically important genes such as CD45, and genes encoding cardiac proteins, have been reported in patients with recurrent myocarditis or DCM. Identification of genetic polymorphisms controlling autoimmune myocarditis will help us understand the mechanisms underlying autoimmune diseases in general, thereby improving potential therapies in patients. [Copyright &y& Elsevier]

CD4+ T cells play a central role in inflammatory heart disease, implicating a cytokine product associated with Th cell effector function as a necessary mediator of this pathophysiology. IFN-γ-deficient mice developed severe experimental autoimmune myocarditis (EAM), in which mice are immunized with cardiac myosin peptide, whereas IL-17A-deficient mice were protected from progression to dilated cardiomyopathy. We generated IFN-γ-/-IL-17A-/- mice to assess whether IL-17 signaling was responsible for the severe EAM of IFN-γ-/- mice. Surprisingly, IFN-γ-/-IL-17A-/- mice developed a rapidly fatal EAM. Eosinophils constituted a third of infiltrating leukocytes, qualifying this disease as eosinophilic myocarditis. We found increased cardiac production of CCL11/eotaxin, as well as Th2 deviation, among heart-infiltrating CD4+ cells. Ablation of eosinophil development improved survival of IFN-γ-/-IL-17A-/- mice, demonstrating the necessity of eosinophils in fatal heart failure. The severe and rapidly fatal autoimmune inflammation that developed in the combined absence of IFN-γ and IL-17A constitutes a novel model of eosinophilic heart disease in humans. This is also, to our knowledge, the first demonstration that eosinophils have the capacity to act as necessary mediators of morbidity in an autoimmune process. [ABSTRACT FROM AUTHOR]

Background and Aims: Immune-mediated, drug-induced liver injury (DILI) triggered by drug haptens is more prevalent in women than in men. However, mechanisms responsible for this sex bias are not clear. Immune regulation by CD4+CD25+FoxP3+ regulatory T-cells (Tregs) and 17β-estradiol is crucial in the pathogenesis of sex bias in cancer and autoimmunity. Therefore, we investigated their role in a mouse model of immune-mediated DILI. Methods: To model DILI, we immunized BALB/c, BALB/cBy, IL-6–deficient, and castrated BALB/c mice with trifluoroacetyl chloride-haptenated liver proteins. We then measured degree of hepatitis, cytokines, antibodies, and Treg and splenocyte function. Results: BALB/c females developed more severe hepatitis (p<0.01) and produced more pro-inflammatory hepatic cytokines and antibodies (p<0.05) than did males. Castrated males developed more severe hepatitis than did intact males (p<0.001) and females (p<0.05). Splenocytes cultured from female mice exhibited fewer Tregs (p<0.01) and higher IL-1β (p<0.01) and IL-6 (p<0.05) than did those from males. However, Treg function did not differ by sex, as evidenced by absence of sex bias in programmed death receptor-1 and responses to IL-6, anti-IL-10, anti-CD3, and anti-CD28. Diminished hepatitis in IL-6-deficient, anti-IL-6 receptor α-treated, ovariectomized, or male mice; undetectable IL-6 levels in splenocyte supernatants from ovariectomized and male mice; elevated splenic IL-6 and serum estrogen levels in castrated male mice, and IL-6 induction by 17β-estradiol in splenocytes from naïve female mice (p<0.05) suggested that 17β-estradiol may enhance sex bias through IL-6 induction, which subsequently discourages Treg survival. Treg transfer from naïve female mice to those with DILI reduced hepatitis severity and hepatic IL-6. Conclusions: 17β-estradiol and IL-6 may act synergistically to promote sex bias in experimental DILI by reducing Tregs. Modulating Treg numbers may provide a therapeutic approach to DILI. [ABSTRACT FROM AUTHOR]

Sex differences in a NOD.H2h4 murine model of Sjögren's syndrome were analyzed. Compared to males, female NOD.H2h4 mice have increased severity of sialoadenitis and have a significantly increased percentage of CD4+ T cells in salivary gland infiltrates. CD4+ T cells in female infiltrates produce more Th2 and Th17 cytokines than in males, while males have greater Th1 responses. Females also have enhanced B cell responses, with higher levels of SSA and SSB serum antibodies, and B cell activation factor F (BAFF). Thus, sex has a strong impact on the severity of murine Sjögren's syndrome by affecting the immune mechanisms driving the autoimmune inflammation. [ABSTRACT FROM AUTHOR]

Abstract: MIP-2 and IFN-γ inducible protein-10 (IP-10) and their respective receptors, CXCR2 and CXCR3, modulate tissue inflammation by recruiting neutrophils or T cells from the spleen or bone marrow. Yet, how these chemokines modulate diseases such as immune-mediated drug-induced liver injury (DILI) is essentially unknown. To investigate how chemokines modulate experimental DILI in our model we used susceptible BALB/c (WT) and IL-4−/− (KO) mice that develop significantly reduced hepatitis and splenic T cell priming to anesthetic haptens and self proteins following TFA-S100 immunizations. We detected CXCR2+ splenic granulocytes in all mice two weeks following immunizations; by three weeks, MIP-2 levels (p <0.001) and GR1+ cells were elevated in WT livers, suggesting MIP-2-recruited granulocytes. Elevated splenic CXCR3+CD4+T cells were identified after two weeks in KO mice indicating elevated IP-10 levels which were confirmed during T cell priming. This result suggested that IP-10 reduced T cell priming to critical DILI antigens. Increased T cell proliferation following co-culture of TFA-S100-primed WT splenocytes with anti-IP-10 (p <0.05) confirmed that IP-10 reduced T cell priming to CYP2E1 and TFA. We propose that MIP-2 promotes and IP-10 protects against the development of hepatitis and T cell priming in this murine model. [Copyright &y& Elsevier]

Complement receptors type 1 and 2 (CR1 (CD35)/CR2 (CD21)) are known to enhance the adaptive immune response. In mice, CR1/CR2 are expressed on B cells, follicular dendritic cells, and activated granulocytes. Recently, we showed that a subset of CD44high and CD62Llow T cells also expresses CR1 and CR2. We now report that CR1/CR2 are detectable on both CD4+ and CD8+ subsets of T cells. Lipopolysaccharide (LPS) from Gram-negative bacteria causes polyclonal activation of B cells and stimulation of macrophages and other antigen-presenting cells. We further demonstrate that LPS induced marked up-regulation of CD25 and CD69 on T cells from CR1/CR2 sufficient (Cr+/+), but significantly lower up-regulation on T cells from CR1/CR2 deficient (Cr–/–) mice. These findings point to a novel mechanism by which CR1/CR2 modulates the activation of T cells by LPS. [ABSTRACT FROM AUTHOR]

Inflammation has been recognized increasingly as a critical pathologic component of a number of heart diseases. A mouse model of autoimmune myocarditis was developed to study the role of immune mediators in the development of cardiac dysfunction. We have found previously that IFN-'y deficiency promotes inflammation in murine myocarditis. It has been unclear, however, how IFN-γ deficiency in myocarditis affects cardiac function and what underlying immune mechanisms are responsible for these effects. In this work, we show that IFN-γ knockout (KO) mice have more pronounced systolic and diastolic dysfunction and greater frequency of progression to dilated cardiomyopathy and heart failure compared with WT mice. Cardiac dysfunction in the KO mice is associated with the expansion of activated (CD44high) CD3+ T cells due to reduced apoptosis of CD4+, but not CD8+, T cells. CD4+ T cells in the KO mice show impaired up-regulation of CD25 upon activation, resulting in the expansion of CD4+CD44+CD25- T cells and their infiltration into the heart. CD4+CD25- T cells are less apoptosis-prone compared with the CD25+ population, and their infiltration into the heart is associated with greater severity of myocarditis. We conclude that IFN-γ deficiency in autoimmune myocarditis is associated with preferential expansion of CD4+CD44+CD25- T cells resulting in increased cardiac inflammation. An exaggerated inflammatory response in IFN-γ KO mice causes cardiac dysfunction, leading to dilated cardiomyopathy and heart failure. [ABSTRACT FROM AUTHOR]