Interplay between inflammation, autoimmunity and regeneration in the NOD mouse model of type 1 diabetes and Sjogren’s Syndrome.
A continuous process of tissue remodelling and regeneration is a fundamental feature of the homeostatic response of the target organ of several autoimmune diseases. In type 1 diabetes (T1D) the β cell mass is in a constant process of death and renewal in order to regenerate the islets damaged by the autoimmune process. The relationship linking inflammation and regeneration during autoimmunity remains elusive. Reg genes, a multigene family discovered using cDNA libraries derived from rat regenerating islets, have been suggested to play an important role in epithelial regeneration not only in the pancreas but also in the salivary glands (SG) of Sjogren’s Syndrome (SS) during autoimmune sialoadenitis. Both in patients and animal models of T1D and SS, the chronic inflammatory/autoimmune process is heterogeneous and display high immunological variability. In particular, in a sizeable subset of cases, inflammatory lesions display ectopic lymphoid structures (ELS) characterised by T/B cell segregation, follicular dendritic cells networks and differentiation of germinal center B cells. However, there is limited evidence on the cellular and molecular mechanisms underlying ELS formation and their contribution to autoimmunity in the pancreas during autoimmune insulitis and in SG during autoimmune sialoadenitis. In this PhD project, I used the NOD mouse model of T1D and SS in order to investigate i) the cellular and molecular mechanisms regulating ELS formation, ii) the functionality of ELS in supporting in situ autoreactive B cell differentiation and iii) the relationship between formation of ELS and the expression of REG genes. In this work I showed that ELS formation was preceded by local up-regulation of lymphotoxins (LTαβ) and lymphoid chemokines CXCL13 and CCL19 and that, once formed, ELS were fully functional in promoting autoreactive B cell activation. Importantly, inhibition of the LT-β pathway prevented the formation of ELS and B cell autoimmunity. Finally, I showed that the expression pattern of Reg genes was strictly related to the development of inflammatory infiltrates in NOD 7 mice and that Reg proteins were target of the autoimmune process itself, as shown by the development of anti-Reg1 antibodies in patients with T1D. Overall, these results suggest that the processes of destruction and regeneration occurring in chronic autoimmune/inflammatory diseases are strongly interdependent whereby autoimmunity may be further enhanced by the attempt to regenerate.
- Theses