Immune response againstMycobacterium aviumsubsp.paratuberculosis, Epstein-Barr virus, HERV-K and IRF5 in rheumatoid arthritis

Rheumatoid arthritis (RA) is an inflammatory disease characterized by synovitis, systemic inflammation, autoantibodies that causes joint damage, disability, decreased quality of life, and cardiovascular and other comorbidities. Its aetiology as well the exact etiopathogenetic mechanisms are not well clear so far. RA is triggered by an interplay between genes and environmental factors.Several studies showed that microorganisms play an important role in triggering autoimmunity through different mechanisms of action. Viral and bacterial infections, such as those caused by Epstein-Barr virus (EBV), Human Endogenous Retrovirus (HERVs) and mycobacteria, may play a pathogenetic role in RA through immunological cross-reactivity or molecular mimicry. Sardinians have a peculiar genetic background resulting from a long lasting geographical isolation with a strong incidence and prevalence of different autoimmune disease such as RA, multiple sclerosis (MS) and diabetes.During this PhD course, I have studied the role of EBV, HERV-K andMycobacterium aviumsubsp.paratuberculosis(MAP) in RA pathogenesis and other rheumatic diseases for a better understanding of how these infectious agents can lead to a deregulation of transcription factors such as Interferon Regulatory Factor 5 (IRF5) that is important in the regulation of different cells type like macrophages and neutrophils.Finally, in order to better understand the etiopathogenesis of RA, an animal model has been used to study the molecular mechanisms involved in the above-mentioned diseases and to better understand the link between the environment and genes in RA with an objective to develop new therapeutic strategies.