Adenosine deaminase and cytokines associated with infectious diseases as risk factors for inflammatory arthritis and methotrexate as a potential prophylactic agent

Rheumatoid arthritis (RA), is an autoimmune disease resulting in inflamed joints with erosions and deformities. A complex interaction of genetic factors concomitant with a specific immune response against a variety of environmental factors might play a pivotal role in determining susceptibility to RA. RA is known to have infections as trigger points to develop autoimmunity and antibodies prior to the presentation of symptoms clinically. Infections beckon both the innate and the adaptive immune systems. The inflammatory cells such as macrophages and lymphocytes secrete Adenosine deaminase (ADA), an important enzyme in purine metabolism, which through deamination converts the extracellular adenosine to inosine causing a dip in adenosine levels and shifting the immune balance towards pro-inflammatory response. ADA induces production of inflammatory cytokines such as tumor necrosis factor alpha (TNF alpha), transforming growth factor beta (TNF beta), and interferon gamma (IFN gamma). Infections parse as well as ADA activity can also lead to citrullination (deamination) which enhances auto-antibody production and can lead to systemic inflammation prior to the clinical symptoms of RA. So, the conversion of arginine to citrulline by peptidyl arginine deiminase enzyme (PAD) may be an important precursor to the development of RA. These antibody titers are maintained by ADA even after post infection by keeping the pro-inflammatory bias making it a chronic condition in RA. This eventually leads to joint erosions by enhanced osteoclastic activity, cartilage degradation, synoviocyte proliferation and reduced differentiation of osteoblasts from mesenchymal stem cells and also their mineralization. Methotrexate, a disease-modifying antirheumatic drug (DMARD) used for RA treatment can be used as a prophylactic agent to prevent the patients of high ADA activity, elevated cytokines and high anti-CCP antibodies titers from developing RA.

Automated summary

Rheumatoid arthritis (RA) is an autoimmune disease with a complex interaction of genetic factors and immune response to environmental factors involved in determining susceptibility. Infections and ADA activity can lead to citrullination, increase auto-antibody production, and cause systemic inflammation. The conversion of arginine to citrulline by PAD enzyme is a key precursor to the development of RA. Methotrexate can be used as a prophylactic agent to prevent RA in patients with high ADA activity, elevated cytokines, and high anti-CCP antibody titers.