Rubino, Valentina (2015) A study of immune-tolerance control in the pathogenesis of Haematological disorders and Chronic-infection. [Tesi di dottorato]

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Abstract

The main topic of this thesis was to evaluate the relevance of immune-tolerance dys-regulation in the pathogenesis of some haematopoietic disorders and for the occurrence of immune pathological complications in chronic infection models. In Paroxysmal Nocturnal Haemoglobinuria model, we described the occurrence of Treg reduction and NKTi increase in untreated PNH patients as well as the ability of the Complement blocking monoclonal antibody culizumab to selectively restore B and NKTi peripheral concentration without significant interference on NK and Treg numbers. In MyeloDysplastic Syndromes model, the study focused on HLA-E and HLA-I molecules, key elements for NK and Cytotoxic T cell recognition. We consistently found that a subgroup of Low and Int-1 Risk MDS patients, categorised according with their altered immune profile, (low Treg level and high CD54 expression on CD8 T cell effectors in BM) showed significant decrease of HLA-I expression on peripheral PMN. This observation indicate the occurrence of CD8-dependent selection in BM. In addiction, the presence of polyclonal NK expansion bearing an activating receptor able to recognise HLA-E in BM has been observed to associate with the selection of dysplastic precursors lacking HLA-E expression. In chronic infection model, as represented by natural infection by Leishmania Infantum in dogs we described a significant increase of CTL and TH1 cells accompanied by reduction of Tregs. The possibility that such condition might be relevant for the occurrence of autoimmune platelet deficiency, frequently observed in Leishmania infected dogs has been hypothesised. In this model, pharmacological treatment associated with administration of a diet supplemented with nutraceuticals selected for their potential immune modulating properties and rich in essential fatty acids was observed to induce restoration of Treg and a progressive decrease of TH1 CD4+ T cells. The possibility that such immune-modulating effects could affect the occurrence of immune-mediated platelet deficiency is currently under investigation. In SOD1 model, we suggested that SOD-1 is part of the network of molecules involved in antigen-dependent T cell response. Indeed, we described that antigen-dependent activation of human T lymphocytes significantly increased extracellular SOD-1 levels in lymphocyte cultures. This effect was accompanied by the synthesis of SOD-1-specific mRNA and by the induction of microvesicle SOD-1 secretion. Moreover, confocal microscopy showed that antigen-dependent activation was able to modify SOD-1 intracellular localization in T cells, allowing association of the enzyme with the intracellular network of signalling molecules involved in TCR-dependent signal transduction processes. The possibility that such observation might indicate the involvement of peroxide/superoxide balance in fine tuning of TCR triggering, needs further investigation.

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