Integration of phosphatidylinositol 3-kinase (PI3K) activity and inflammatory signaling pathways in autoimmune disease

Abstract

Autoimmune disorders arise from the dysregulation of the immune system and the subsequent abnormal immune response to self-antigens. Genetic factors and environmental factors contribute to the pathogenesis of autoimmune disorders, but the triggers that initiate disease remain to be elucidated. Rheumatoid arthritis (RA) is a chronic and progressive inflammatory disease characterized by the recruitment and accumulation of activated immune cells along with hyperplastic growth of intimal lining layer fibroblast-like synoviocytes (FLS) in the synovial compartment. The initiation of RA likely involves antigen-presenting cell (APC) activation due to so-called dangers signals, and the recognition of autoantigens by B and T cells and their subsequent production of autoantibodies. Autoantibody formation can precede clinical signs and symptoms by years and this does not coincide with subclinical inflammation in the joint, suggesting that multiple pathological events (hits) are needed to develop chronic synovitis. When synovitis does occur and pro- inflammatory cytokines are produced, in combination with the formation of immune complexes, this can lead to the activation of synovium-infiltrating and tissue resident myeloid cells, like macrophages, monocytes, dendritic cells (DCs), neutrophils and mast cells. Eventually, synovitis leads to erosion of the joint surface, causing deformity and loss of function. The prevalence rate is approximately 1% of the population, with women affected three to five times as often as men. Commonly used animal models of RA include the murine collagen induced arthritis (CIA), adjuvant-induced arthritis (AIA) and K/BxN serum transfer models.

Immune-mediated inflammatory diseases are characterized by deregulated processes in immune and stromal cells such as migration, survival, proliferation and differentiation. Phosphatidylinositol 3-kinases (PI3Ks) play a crucial role in these cellular processes, which include control of cell growth and survival, nutrient uptake, proliferation, migration and differentiation. In the last 20 years our understanding of how lipid products are regulated and interact with downstream effectors to exert their biological roles, has developed rapidly. The contribution of PI3Ks in the development of several inflammatory and autoimmune diseases, such as type 1 diabetes, cancer, atherosclerosis and rheumatological autoimmune diseases, has generated a great interest in targeting these enzymes in the clinic. With a growing knowledge of the role of PI3K lipid products, and the downstream proteins they activate, targeting PI3K signaling is becoming of increasing interest. By blocking or inhibiting individual components of the PI3K signaling pathway, multiple cellular processes could be influenced and could provide novel targets for therapeutic interventions in RA and other immune-mediated inflammatory disorders.