Regulatory Molecules of Inflammatory Processes
Understanding peripheral mechanisms operating in autoinmmune and chronic inflammatory diseases is critical for the design and development of novel therapies against these immunological disorders.
Autoimmune diseases are characterized by a breakdown in the mechanisms of tolerance to self antigens. Autoimmune diseases, which include conditions such as arthritis, asthma, contact dermatitis and myocarditis, affect millions of people worldwide, and there is no definitive treatment for their eradication. Our group seeks to identify new regulatory cells and molecules involved in the control of these diseases.
The early leukocyte activation antigen CD69 is a membrane receptor ascribed to the family of type II C-type lectins. It is rapidly induced after cell activation in all bone marrow derived cells except erythrocytes. Expression in vivo is restricted to positively selected thymocytes and leukocytes undergoing activation, particularly at inflammatory sites. Engagement of CD69 with monoclonal antibodies in the presence of phorbol esters induces Ca2+ influx that leads to the activation of ERK, induction of IL-2 and IFN-? genes, and T cell proliferation. Our recent work shows that the cytoplasmic tail of CD69 interacts with Jak3/Stat5 proteins, which regulate the transcription of ROR?t in human and mouse Th17 cells, thus establishing a mechanistic link between CD69 and the regulation of Th17 differentiation. The balance between Th17 cells and regulatory T cells determines the net balance between pro- and anti-inflammatory cytokines at inflammatory foci, and is thus critical for the regulation of the immune response. CD69 might also regulate the function or differentiation of regulatory T cells, thus affecting the outcome of Th17 responses indirectly. This is supported by the finding that mice lacking CD69 develop exacerbated forms of contact dermatitis, allergic asthma and autoimmune myocarditis. Our data demonstrate that CD69, through the regulation of Th17 effector responses, limits myocardial inflammation and subsequent heart failure. It is likely that a similar process occurs in humans with myocarditis and subsequent dilated cardiomyopathy. These findings reveal the involvement of a novel molecular actor in the immunopathogenesis of myocarditis, which could be a potential therapeutic target.