Molecular approaches in autoimmunity and ageing: potential implications for future therapies.

My researches during my PhD were mainly focused on two aspects. The first one, was to study molecular aspects potentially implicated in autoimmunity pathogenesis, in order to identify new potential risk factors useful as therapeutic target. To this end, we focused on two severe and wasting systemic autoimmune diseases: systemic lupus erythematosus and systemic sclerosis. Pathogenesis of these diseases has still not clear and early diagnosis is difficult to identify because of complex and heterogeneous presentation of symptoms. A strong genetic association between HLA and disease susceptibility is well accept, nevertheless, other factors as oxidative stress, KIR and inflammatory cytokines have a relevant role in disease induction and progression, particularly in predisposed individuals. The aim of this thesis was to observe molecular and genetic variants connected to inflammatory and oxidative status, typical of autoimmune disorders, in order to increase our knowledge about pathogenesis and to find possible diagnostic markers and/or therapeutic targets for improving diagnosis and treatment of these severe diseases. The second aspect was to study potential molecular mechanisms to develop new vaccines or the optimization of immunization in elderly. It is well known, that ageing affects the immune system and its ability to respond pathogens. The current immunological strategies are based on triggering of TLRs on DCs to elicit cytokine production and different immune responses. In this thesis, we evaluated cytokine production in DCs populations after stimulation with combined molecular adjuvants, incorporating complementary TLR agonists. This mechanism may be useful in the new development of vaccine strategy both in young than in elderly. Interestingly, it has been found out that similar strategy could be used in AIDs treatment by the use of negative/positive ligands of TLRs, opening future strategic perspective to adopt in autoimmunity. Indeed, if on the one hand triggering of TLRs may induce increased secretion of inflammatory cytokines to enhance T cell response against pathogens; on the other hand, using TLRs regulators could confer an anti-inflammatory polarizing profile to DCs that could be beneficial in patients with AIDs.