Small GTPase RAS in multiple sclerosis - exploring the role of RAS GTPase in the etiology of multiple sclerosis.

Abstract

Ras: signaling is involved in the development of autoimmunity in general. Multiple sclerosis (MS) is a T cell-mediated autoimmune disease of the central nervous system. It is widely recognized that a reduction of Foxp3+ regulatory T (Treg) cells is an immunological hallmark of MS, but the underlying mechanisms are unclear. In experimental autoimmune models, N-Ras and K-Ras inhibition triggers an anti-inflammatory effect up-regulating, via foxp3 elevation, the numbers and the functional suppressive properties of Tregs. Similarly, an increase in natural Tregs number during Experimental Autoimmune Encephalomyelitis (EAE) in R-RAS -/- mice results in attenuated disease. In humans, only KRAS GTPase isoform is involved in mechanism causing tolerance defects in rheumatoid arthritis (RA). T cells from these patients have increased transcription of KRAS (but not NRAS). RAS genes are major drivers in human cancers. Consequently, there has been considerable interest in developing anti-RAS inhibitors for cancer treatment. Despite efforts, no anti-RAS therapy has succeeded in the clinic. The major strategy that has so far reached the clinic aimed to inhibit activated Ras indirectly through blocking its post-translational modification and inducing its mis-localization. The disappointing clinical outcome of Farnesyl Transferase Inhibitors (FTIs) in cancers has decreased interest in these drugs. However, FTIs suppress EAE by downregulation of myelin-reactive activated T-lymphocytes and statins are currently studied in clinical trials for MS. However, no pharmacologic approaches to targeting Ras proteins directly have yet succeeded. The therapeutic strategy to recover immune function through the restoration of impaired Tregs function with the mounting evidences regarding KRAS in autoimmune mediated disorder (MS, SLE, RA, T1D) suggest as working hypothesis the direct targeting KRAS activation using cancer-derived small molecules may be clinically relevant.

Abbreviations: FTIs: Farnesyl Transferase Inhibitors; MS: Multiple Sclerosis; RRMS: Relapsing Remitting Multiple Sclerosis; PPMS: Primary Progressive Multiple Sclerosis; Tregs: regulatory T-cells; Foxp3: Forkhead box P3; EAE: Experimental Autoimmune Encephalomyelitis; T1D: Type 1 Diabete; SLE: Systemic Lupus Erythematosus; RA: Rheumatoid Arthritis; CNS: Central Nervous System; TMEV: Theiler's murine encephalomyelitis virus; FTS: farnesyl thiosalicylic acid; TCR: T-Cell Receptor; AIA: Adjuvant-induced Arthritis; EAN: experimental autoimmune neuritis; HVR: hypervariable region; HMG-CoA: 3-hydroxy-3-methylglutaryl coenzyme A reductase; PBMC: Peripheral Blood Mononuclear Cells.