Genetic contributors and soluble mediators in prediction of autoimmune comorbidity

Abstract

Comorbidities including subclinical atherosclerosis, neuropsychological aberrations and lymphoproliferation represent a major burden among patients with systemic autoimmune diseases; they occur either as a result of intrinsic disease related characteristics including therapeutic interventions or traditional risk factors similar to those observed in general population. Soluble molecules recently shown to contribute to subclinical atherosclerosis in the context of systemic lupus erythematosus (SLE) include among others B-cell activating factor (BAFF), hyperhomocysteinemia, parathormone (PTH) levels and autoantibodies against oxidized lipids. Variations of the 5, 10- methylenetetrahydrofolate reductase (MTHFR) gene -the main genetic determinant of hyperhomocystenemia in humans-as well the interferon regulatory factor-8 (IRF8), FcγRIIA and BAFF genes have been all linked to subclinical atherosclerosis in SLE. BAFF variants have been also found to confer increased risk for subclinical atherosclerosis and lymphoma development in Sjogren's syndrome (SS) patients. Other genes shown to be implicated in SS lymphoproliferation include genes involved a. in inflammatory responses such as the NFκB regulator Tumor necrosis factor alpha-induced protein 3 (TNFAIP3) and the Leukocyte immunoglobulin-like receptor A3 (LILRA3) immunoreceptor, b. B cell activation and signaling (BAFF/BAFF-receptor), c. type I IFN pathway such as three-prime repair exonuclease 1 (TREX1), d. epigenetic processes including DNA methylation (MTHFR rs1801133, 677T allele) and e. genomic instability (MTHFR rs1801131, 1298C allele). Emerging soluble biomarkers for SS related lymphoma include mediators of B cell growth and germinal center formation such as BAFF, FMS-like tyrosine kinase 3 ligand (Flt-3L) and CXCL13 as well as inflammatory contributors such as inteleukin (IL)-17, IL-18, ASC, LILRA3 and the extracellular lipoprotein-associated phospholipase A2 (Lp-PLA2). In regard to fatigue and neuropsychologic features in the setting of SS, contributing factors such as BAFF variants, antibodies against neuropeptides, proteins involved in nervous system function as well as inflammatory cytokines have been reported.

Keywords: Atherosclerosis; Autoimmune diseases; Cardiovascular disease; Comorbidities; Lymphomagenesis; Neuropsychological disturbances; Sjogren's syndrome; Systemic lupus erythematosus.