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Th2 to Th1 Transition Is Required for Induction of Skin Lesions in an Inducible and Recurrent Murine Model of Cutaneous Lupus–Like Inflammation

ABSTRACT: Cutaneous lupus erythematosus (CLE) is an autoimmune skin disease characterized by a strong IFN signature, normally associated with type I IFNs. However, increasing evidence points to an additional role for IFNγ, or at least a pathogenic T effector subset dependent on IFNγ, for disease progression. Nevertheless, Th2 effector subsets have also been implicated in CLE. We have now assessed the role of specific T cell subsets in the initiation and persistence of skin disease using a T cell-inducible murine model of CLE, dependent on KJ1-26 T cell recognition of an ovalbumin fusion protein. We found that only Th2-skewed cells, and not Th1-skewed cells, induced the development of skin lesions. However, we provide strong evidence that the Th2 disease-initiating cells convert to a more Th1-like functional phenotype in vivo by the time the skin lesions are apparent. This phenotype is maintained and potentiates over time, as T cells isolated from the skin, following a second induction of self-antigen, expressed more IFN-γ than T cells isolated at the time of the initial response. Transcriptional analysis identified additional changes in the KJ1-26 T cells at four weeks post injection, with higher expression levels of interferon stimulated genes (ISGs) including CXCL9, IRF5, IFIH1, and MX1. Further, injection of IFN-γ-/- T cells faied to induce skin disease in mice. We concluded that Th2 cells trigger skin lesion formation in CLE, and these cells switch to a Th1-like phenotype in the context of a TLR7-driven immune environment that is stable within the T cell memory compartment.

SUBMITTER: Haddadi N

PROVIDER: S-EPMC9271959 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Cutaneous lupus erythematosus (CLE) is an autoimmune disease that localizes to the skin and is known to contain elevated glycosaminoglycans (GAGs) on Hale’s stain of skin biopsy specimens. Recently, different GAG species have been shown to have distinct effects on the recruitment and activation of immune cells and stimulation of cytokine production (Taylor and Gallo, FASEB, 2006; 20: 9-22). Thus, we speculate that the elevated GAGs observed in CLE play a role in the local inflammatory process that produces skin lesions in these patients. In order to further investigate a molecular basis for the elevated expression of these GAGs in CLE skin lesions, we would like to determine the gene expression profiles of GAG synthesis, degradation, and modifier genes in lesional and non-lesional skin samples from CLE patients and compare to those from healthy controls. A microarray approach will give us a broader understanding of the genetic regulation of the expression of various GAG species in CLE skin. We will then be able to target future quantitative gene expression experiments by real-time RT-PCR to the genes that are shown to be involved in CLE. In order to accomplish our goal, we would like to examine the GAG gene expression profiles of DLE, TLE, and SCLE subtypes due to the differences in CS and HA staining that we found among these subtypes. Since HA and CS are elevated in DLE and HA in TLE, but not in SCLE, the SCLE samples will also serve as an internal control. We would like to examine both lesional and non-lesional skin biopsies to determine if CLE skin prior to developing a lesion is different at the genetic level from healthy control skin and how it changes once a lesion does develop. We will separate the dermis from the epidermis of the skin biopsies and extract RNA just from the dermis to enrich for dermal fibroblast RNA. We aim to submit four patient biopsies per subtype as well as four samples from healthy control skin for comparison. This number is necessary in order to account for the biologic variability among different patients. We would submit more samples per subtype but are limited by availability of patients in clinic. Thus, we will have a total of 28 samples to submit for microarray. This study design will allow us to analyze the GAG gene expression profiles among different CLE subtypes and enable us to identify which GAc

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Th2 to Th1 Transition Is Required for Induction of Skin Lesions in an Inducible and Recurrent Murine Model of Cutaneous Lupus–Like Inflammation

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