Selective clinical and immune response of the oligoclonal autoreactive T cells in Omenn patients after cyclosporin A treatment

Abstract

SummaryThe immunological hallmark of Omenn syndrome (OS) is the expansion and activation of an oligoclonal population of autoreactive T cells. These cells should be controlled rapidly by immunosuppressive agents, such as cyclosporin A (CsA), to avoid tissue infiltration and to improve the general outcome of the patients. Here we studied the clinical and the immune response to CsA in two Omenn patients and also examined the gene expression profile associated with good clinical response to such therapy. T cell receptor diversity was studied in cells obtained from OS patients during CsA therapy. Characterization of gene expression in these cells was carried out by using the TaqMan low-density array. One patient showed complete resolution of his symptoms after CsA therapy. The other patient showed selective response of his oligoclonal T cell population and combination therapy was required to control his symptoms. Transcriptional profile associated with good clinical response to CsA therapy revealed significant changes in 26·6% of the tested genes when compared with the transcriptional profile of the cells before treatment. Different clinical response to CsA in two OS patients is correlated with their immunological response. Varying clonal expansions in OS patients can cause autoimmune features and can respond differently to immunosuppressive therapy; therefore, additional treatment is sometimes indicated. CsA for OS patients causes regulation of genes that are involved closely with self-tolerance and autoimmunity.

Somatic Reversion of a Novel IL2RG Mutation Resulting in Atypical X-Linked Combined Immunodeficiency

“…Puzzlingly, the phenotypes of the three individuals are highly similar in Vβ families that are missing and those reduced to a single peak they are almost completely identical. Moreover, many families reduced to single peaks and highly overexpressed is highly suggestive for oligo or even monoclonal expansion as reported before [ 32 , 33 ]. We speculate that the skewed TCR repertoire may mainly consist of public TCRs that are virus specific.…”

Embryonic lymphocytes contribute to a genetic form of autoimmune inflammation

“…As the major clinical OS manifestations are caused by an aberrant activation of T-cells in the periphery, with preferential localization in skin and gut 8,12,33,34 , we looked more closely at peripheral T-cell compartments in adult Rag2 R229Q OS mice. In Rag2 R229Q large intestines, the overall proportion of T-lymphocytes amongst hematopoietic cells was increased by 2-fold compared to Rag2 +/+ controls (Figure S1C) and composed by both TCRβ T-cells, representing the major T-cell type with a 2-fold increased frequency compared to Rag2 +/+ , and TCRγδ T-cells (Figures 1E and 1F).…”

“…OS T-cells in peripheral tissues express markers of activation (such as CD45RO and HLA-DR), but display a depressed response to foreign antigens, thus not contributing to a functional immune response 10 . In contrast, the TCR clonotypes shared among OS patients are enriched for self-reactive specificities, thus making the residual OS T-cells prone to get activated against the tissues they populate [11][12][13] .…”

Recent advances in understanding RAG deficiencies

“…These infections should be treated aggressively. Calcineurin inhibitors and other systemic immunosuppression may improve the inflammation 69 , which may affect any and all organs. Serotherapy may be required to remove auto-inflammatory cells, although immunosuppression in the presence of active infection can present specific challenges.…”