Role of the IL-23/IL-17 Axis in a Mouse Model of Psoriasiform Disease: An Immunological Approach
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Date
2012-11-23
Authors
Gosselin, Timothy
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Abstract
Psoriasiform disorders, are a group of skin diseases characterized by thickened skin (acanthosis). Psoriasis and seborrheic dermatitis, prototypical examples of this disease class, affect up to 4% of the population (Johnson, 1978). The D2C T-cell receptor transgenic mouse model
demonstrates severe lymphopenia and an immune reconstitution phase that models the immune
dysregulation occuring in the setting of immune reconstitution syndromes. This includes patients with the acquired immunodeficiency syndrome (AIDS) undergoing HARRT therapy, a group of patients whom develop a high frequency of concommittant psoriasiform diseases (Reveille et al,
1990). D2C skin pathology closely mimics the clinicopatholgical features of human seborrheic dermatitis (Oble, 2006), a disease which is believed to have a multifactorial etiology but a poorly understood immune contribution. Previously it was shown that the pathophysiology in D2C mice was in part attributable to a lymphoproliferation of effector T-cells (Teffector) due to a
lymphopenia of regulatory T-cells (Treg ) since the development of disease could be abrogated by the adoptive transfer of syngeneic Treg. It was hypothesized that this lymphoproliferation of Teffector was accompannied by a greater polarization of T-cells to the TH17 lineage and a greater
liberation of IL-23/IL-17 axis cytokines. We demonstrated by enzyme-linked immunosorbent
assay (ELISA) that there is in fact an increase in IL-23/IL-17 axis cytokines in the serum of D2C mice. Similalry, we demonstrated by RT-PCR analysis that there is an increased message level of these IL-23/IL-17 axis cytokines in lesional skin of D2C mice and that there is a vague correlation of these cytokine levels with disease stage. Given the intimate relationship between the TH17 and Treg lineages (antagonistic yet capable of reciprocal transmutation) and the
previously ascertained role of Treg in the model system, we also conducted pilot studies to examine in greater detail how Treg subsets are altered by the process of transgenesis, and how these effects might effect disease pathogenesis. These preliminary results demonstrtaed that that
both natural and induced Treg are deficient in D2C mice however CD25+ natural Treg are
particularly deficient in prediseased D2C animals and that disease progression and ultimately disease convalescence is associated with an expansion of both Treg subsets, but with a preportionally greater expansion of the self-antigen specific natural Treg, perhaps reflecting the
self-reactive nature of the 2C-TCR on the H-2d expressing DBA/2 inbred strain, and the need to regulate self-reactive cells in this model system.
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Medicine