Neuroimmune mediators in rheumatoid arthritis

The mystery of rheumatoid arthritis is plagued by its intricacy. Characterized as a prevalent autoimmune, chronic and progressive systemic disease, rheumatoid arthritis (RA) owes its complexity to its multifactorial etiopathogenesis and clinical heterogeneity. The immune system has the ability to 'sense' pathological influences and relays it to the central nervous system, either directly by crossing the blood brain barrier or indirectly through sensory receptors or the afferent vagus nerve. These afferent signals are synchronized and processed at the central nervous system following which efferent signals are relayed through the efferent vagus nerve and the hypothalamo-pituitary-adrenal axis to influence anti-inflammatory signals back into the immune system. Neuropeptides and cytokines therefore serve as the molecular basis of a neuro-immune axis that, through the autonomic nervous system, provides antiinflammatory feedback to the immune system. Dysregulation of this pathway through the disruption of the synapse between the cholinergic nervous system and the immune system may be an early primary event in the overproduction of cytokines and the pathophysiology of RA, perhaps during the optimal window for aggressive therapeutic strategy in RA. Introducing appropriate therapy early in the course of RA before permanent damage to the joints has occurred can minimize disease severity and may limit pathologic immune system changes later in the course of the disease. This dissertation explored the above hypothesis using clinical, genomic, proteomic and bioinformatic approaches in patients with early RA. This approach has expounded plausible annotations into pathogenic neuroimmune mechanisms and has enabled the identification of novel molecular neuroimmune mediators as potential therapeutic targets in RA.