Pathogenesis and treatment of autoimmune rheumatic diseases

Abstract

Purpose of review: Autoimmune diseases are of unknown origin, and they represent significant causes of morbidity and mortality. Here, we review new developments in the understanding of their pathogenesis that have led to development of well tolerated and effective treatments.

Recent findings: In addition to the long-recognized genetic impact of the HLA locus, interferon regulatory factors, PTPN22, STAT4, and NOX have been implicated in pathogenesis of systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). Smoking, ultraviolet light, diet, and microbiota exert strong environmental influence on development of RA and SLE. Metabolism has been recognized as a critical integrator of genetic and environmental factors, and it controls immune cell differentiation both under physiological and pathological conditions.

Summary: With the advent of high-throughput genetic, proteomic, and metabolomic technologies, the field of medicine has been shifting towards systems-based and personalized approaches to diagnose and treat common conditions, including rheumatic diseases. Regulatory checkpoints of metabolism and signal transduction, such as glucose utilization, mitochondrial electron transport, JAK, mTOR, and AMPK pathway activation, and production of pro-inflammatory cytokines IL-1, IL-6, and IL-17 have presented new targets for therapeutic intervention. This review amalgamates recent discoveries in genetics and metabolomics with immunological pathways of pathogenesis in rheumatic diseases.

Figure 1.

Brief view of the immunologic network depicting common CD4+T cells, B-cells, pathways (regulatory genes, proteins and transcription factor), cytokines and functions of the immune system (blue). Targeted biologic therapies as well as the inhibitory effect of Treg cells is shown as well (red). IL: Interleukin; IFN: Interferon; TNF: Tumor necrosis factor; TGF: Tumor growth factor; Th: Helper T-cells; Treg: Regulatory T-cells, STAT: Signal Transducer and Activator of Transcription proteins; GATA3 gene; Foxp3: Forkhead box p3 protein; T-bet: T-Box transcription factor; RORγt: RAR-related orphan receptor gamma protein.