Investigating Disease Related Factors and Mechanisms Associated with Autoimmune Myocarditis and Multiple Sclerosis
This thesis is divided into two sections, the first section investigates a therapeutic approach to attenuate progression of myocarditis to inflammatory dilated cardiomyopathy (DCMi) and molecular mechanisms associated with disease progression. The second section addresses the role of Aire in regulating multiple sclerosis (MS) in the context of disease associated risk factors.
Myocarditis and associated sequalae, DCMi account for 45% of heart transplantations which is the only intervention currently available. Due to heterogeneity in clinical presentation of myocarditis and since precise mechanisms governing transition to DCMi are unknown there are no treatment strategies to delay progression or improve long term survival. Glucocorticoids (GCs) are commonly prescribed for autoimmune conditions and are known to limit initial inflammatory response but cannot prevent disease progression. Also, GC resistance is a significant problem that restricts GC usage. We investigated one such factor, MIF which has been associated with resistance to GCs. MIF has a unique relationship with GCs, it is induced by GCs and it counter-acts immune-suppressive effects exerted by GCs. Hence, we studied whether absence of MIF and administration of GCs attenuated disease by abolishing pro-inflammatory effects of MIF. Our studies revealed a novel treatment approach for myocarditis and DCMi. Importantly, our findings also shed light on probable molecular pathways involved in progression of the disease.
The HLA alleles HLA-DR2b (DRB11501) and HLA-DR4 (DRB10401) are strongly linked to increased susceptibility for multiple sclerosis (MS) and rheumatoid arthritis (RA), respectively. Though underlying mechanisms are not fully understood, these MHC alleles may shape the pathogenic T cell repertoire via central tolerance. The transcription factor autoimmune regulator (AIRE) promotes central T cell tolerance via ectopic expression of tissue-specific antigens (TSAs). Aire−/− HLA-DR2b and HLA-DR4 tg mice were generated to investigate the contribution of Aire deficiency on manifestation of autoimmunity in the context of autoimmunity associated risk alleles. Aire−/− HLA-DR tg mice displayed reduced thymic expression of tissue-specific genes which corresponded with mild inflammatory infiltrates observed in the salivary glands, liver and pancreas and autoantibodies. Deficiency of Aire in these mice induced a mild increase in disease severity and a slightly earlier disease onset upon active EAE induction. Our results support a role for the transcription factor Aire in modulating autoimmune pathology but argue against its essential role in regulating autoimmunity in the context of the human HLA-DR2b and -DR4 alleles associated with MS and RA, respectively.