| Summary: | Psoriasiform skin diseases are a poorly understood group of disorders. Recent data has implicated the immune system with a central role in disease pathogenesis. In this thesis, various T cell populations were studied in a TCR transgenic model of psoriasiform disease, whose abnormal interactions culminate in distinctive psoriasiform pathology. The model is based upon the expression of the transgenic 2C TCR on the H-2[sup d] -expressing DBA/2 inbred strain (referred to as D2C mice). The 2C TCR recognizes a peptide (p2Ca) derived from the ubiquitous mitochondrial protein 2-oxoglutarate dehydrogenase, presented by the MHC class I molecule, L[sup d]. In D2C mice, expression of the 2C TCR led to a comprehensive depletion of immature T cell progenitors, which express the 2C TCR, and a resultant lymphopenia of mature peripheral T cells. The lymphopenia of CD8⁺ cytotoxic and CD4⁺ helper T cells predisposes to the overgrowth of opportunistic pathogens, resulting in inflammatory skin disease restricted to the sebum rich areas of the skin, resembling the human psoriasiform disease seborrheic dermatitis. In D2C mice, there is also a deficiency in T regulatory (T[sub reg]) cells as a result of slowed thymic output of mature T cells. The reduced T[sub reg] function results in a lymphoproliferation of polyclonal CD4⁺CD25⁻ cells, many of which home to the aforementioned cutaneous inflammatory sites. This expansion of "helper" cells was likely due to antigenic stimulation, presumably against immunogenic determinants of opportunistic pathogens. Reconstitution of the T[sub reg] compartment by adoptive transfer abrogates the development of psoriasiform pathology and precludes the lymphoproliferation of CD⁺CD25⁻ cells. These data suggest that T[sub reg] may downregulate the response of mature cells to ubiquitous commensal organisms as a means to maintain immunological homeostasis. In TCR transgenic mice which express the cognate Ag of the transgenic TCR, a large population of transgenic cells exist in the peripheral lymphoid tissues. These cells are anergized and fail to respond to stimulation with cognate ligand; however, they express a memory immunophenotype, including the intermediate affinity IL-2 receptor. The expression of this receptor enables these cells to use bystander IL-2 or IL-15 to overcome this inactivation, revealing enhanced functional properties induced by the high-affinity interaction with cognate ligand. These observations suggest that such clonally anergized cells may represent an in vivo autoimmune hazard; and, interestingly, a further consequence of the CD4⁺CD25⁻ lymphoproliferation in D2C mice is the bystander activation of these transgenic T cells. After undergoing acute activation, 2C T cells exacerbate the cutaneous pathology in these animals, a consequence that can be abrogated by the administration of a blocking mAb against the 2C TCR. Interestingly, the combination of immunodeficiency, T[sub reg] lymphopenia, the presence of CD4⁺CD25⁻ cells capable of undergoing vigorous expansion, and a large population of memory phenotype 2C transgenic cells was insufficient to induce disease when D2C bone marrow was adoptively transferred to lethally irradiated syngeneic DBA/2 mice. Examination of these animals revealed that bone marrow transfer did not deplete the skin of DBA/2-derived cutaneous γδ cells. Sentinel intraepithelial γδ lymphocytes have been shown to have an important role in surveying the epithelium for signs of infection and malignancy as well as in maintaining epithelial integrity. The development of these cells is curtailed in D2C mice due to the forced expression of the 2C TCR; however, the persistence of these cells in the aforementioned bone marrow chimeras may have protected these animals from the development of the disease phenotype. While generated DBA/2 TCRδ⁻/⁻ mice did not develop spontaneous disease, the transfer of D2C bone marrow to lethally irradiated DBA/2 TCRδ⁻/⁻ recipients successfully transferred the disease phenotype, confirming the importance of these cells in protecting against the development of psoriasiform pathology. This result also demonstrated that a compromised cutaneous barrier is necessary for disease pathogenesis, as disease does not develop when the skin is populated by sentinel intraepithelial lymphocytes. While considerable research efforts have been focused on human psoriasiform disease, a solid understanding of disease pathophysiology is severely lacking. This limited knowledge of psoriasiform disease is highlighted by the ongoing uncertainty of whether these diseases represent primary diseases of the epithelium, or whether these diseases represent tissue specific autoimmunity occurring in normal skin as a result of dysfunctional immunity. One explanation for this failure to understand basic principles of psoriasiform disease pathophysiology can be attributed to the limited numbers of appropriate model systems to carefully study disease. The D2C model of psoriasiform disease has been shown to be an accurate model system which has demonstrated that a complex interplay between various immunocytes and epithelium culminates in psoriasiform disease. The insight that the D2C model has generated will lead to a better understanding of these poorly characterized psoriasiform conditions. === Science, Faculty of === Microbiology and Immunology, Department of === Graduate
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