Catálogo de publicaciones - libros

Autoimmune myocarditis can be induced in susceptible strains of mice by infection with coxsackievirus B3. The most prominent antibody elicited by the viral infection reacts with the cardiac isoform of myosin and immunization of susceptible mice with cardiac myosin replicates the autoimmune disease. A number of traits determine whether a particular strain of mice is susceptible to autoimmune myocarditis, but the critical decision is made early after infection during the innate immune response. Four of the major components of the innate response have been investigated and found to contribute to susceptibility: the complement system; NK cells; early-acting proinflammatory cytokines and chemokines.

The discovery that TLR9 can promote the production of autoantibodies by synergistically activating B cells in conjunction with BCR raises the intriguing possibility that self-DNA is immunostimulatory in a T cell-independent manner. Furthermore, TLRs can no longer be regarded as recognition systems in the innate immune system that shows exclusive selectivity for pathogen-associated molecules. TLR9 compromises the capacity for absolute distinction between self and nonself. Our current molecular appreciation of the TLR9 signaling pathway provides hope for therapeutic manipulation and the design of novel strategies for treating autoimmune diseases.

The studies summarized in this chapter demonstrate that the failure to maintain DNA methylation patterns in mature CD4^+ T cells causes aberrant expression of several methylation-sensitive genes, including LFA-1, perforin, CD70, and likely others, and that their overexpression alters T cell function, promoting autoreactivity, monocyte/macrophage killing, and B cell overstimulation. Furthermore, T cells experimentally demethylated with DNA methyltransferase or ERK signaling pathway inhibitors cause a lupus-like disease in murine models. Procainamide and hydralazine are DNA methylation inhibitors and cause a lupus-like disease in genetically susceptible individuals. Patients with idiopathic lupus have hypomethylated DNA, overexpress the same genes due to the same changes in DNA methylation patterns as in the methylation inhibition model, and demonstrate identical changes in CD4^+ T cell function including autoreactive, perforin-mediated monocyte killing and B cell overstimulation. Thus, similar changes in DNA methylation and chromatin structure likely contribute to the pathogenesis of autoimmunity in the DNA hypomethylation model as in idiopathic lupus. The DNA hypomethylation model may also provide an approach to predict additional aberrantly expressed genes in human lupus T cells, since CD11a, perforin, and CD70 were predicted by this model. Finally, these studies also suggest that environmental agents may act by mechanisms analogous to those seen in DIL, triggering changes in chromatin structure and affecting gene expression through signaling inhibition or direct DNA methyltransferase inhibition. Clearly, there is a fundamental role for a failure to maintain DNA methylation patterns and chromatin structure in this disease.

The knowledge of the pathogenesis of RF/RHD makes it is possible to delineate a new picture of the disease that involves the remarkable points. First, molecular mimicry mechanism between streptococcal antigens and human tissues, mainly heart tissue, leads to rheumatic heart lesions in RHD patients. Second, CD4^+ T lymphocytes are the major effectors of heart lesions. Third, several streptococcal immunodominant peptides generate cross-recognition of several heart tissue-derived proteins. Fourth, several HLA class II molecules are associated with the disease worldwide, and HLA-DR7/DR53, combined with some HLA-DQ molecules, seem to be associated with the development of MVLs and/or MVR in RHD patients. Fifth, Th1 type cytokines seem to be predominant in heart lesions and the small numbers of mononuclear cells able to produce IL-4 (a regulatory cytokine) may account for the more severe tissue destruction in valves seen in RHD.