Host response in cutaneous inflammatory disorders: Mechanisms of innate and adaptive immunity

The immune system of the higher vertebrates consists of innate and adaptive immune responses. In this dissertation, we focused on cellular and molecular mechanisms of the host immune response in cutaneous diseases.;We studied the mechanisms of innate immunity by elucidating the role of Toll-like receptor in acne vulgaris. We provided evidence that P. acnes induces monocyte cytokine production through a TLR2-dependent pathway.;In addition to stimulation by microbes, cells of the adaptive immune system can also activate phagocytes. We found that in tuberculoid patients, the resistant form of leprosy, M. leprae upregulated CD40L on T cells and induced a CD40-dependent production of IL-12 in monocytes. This mechanism was not evident in lepromatous patients, the susceptible form of leprosy, suggesting that CD40-CD40L interactions contribute to CMI responses.;Besides secreting immunostimulatory cytokines, the phagocytes also produce inhibitory cytokines. We demonstrated the overexpression of IL-10 in lesions of atopic dermatitis, suggesting that IL-10 may contribute to the pathogenesis of this disease. Furthermore, we demonstrated that skin cancer cells also secrete IL-10 and directly inhibit the function of tumor infiltrating lymphocytes, suggesting that one mechanism by which tumors evade the local host immune response is through the secretion of IL-10.;To study the mechanisms of adaptive immunity, we defined a T-cell epitope of an immunodominant 10 kD M. leprae protein. We correlated the ability of this epitope to activate T cells with the ability of the peptide to bind to the HLA DRB5*0101 molecule, an allele that is overrepresented in tuberculoid patients.;Finally, we studied IL-12 responsiveness in the two polar form of leprosy. We found that T cells derived from the tuberculoid patients express a functional IL-12 receptor and are responsive to IL-12. On the other hand, the lepromatous patients have T cells that lack IL-12 receptor beta2 and therefore do not respond to IL-12.;Although we examined innate and adaptive immune responses independently, these responses are not independent but rather interactive. Throughout this dissertation, our work demonstrates that the innate immune response influences the type of adaptive immune response, while the adaptive immune response influences the function of the innate cells.