Pathogenic mechanisms in systemic lupus erythematosus

Abstract

Systemic lupus erythematosus (SLE) is a chronic inflammatory disease characterized by the dysfunction of T cells, B cells, and dendritic cells and by the production of antinuclear autoantibodies. This editorial provides a synopsis of newly discovered genetic factors and signaling pathways in lupus pathogenesis that are documented in 11 state-of-the-art reviews and original articles. Mitochondrial hyperpolarization underlies mitochondrial dysfunction, depletion of ATP, oxidative stress, abnormal activation, and death signal processing in lupus T cells. The mammalian target of rapamycin, which is a sensor of the mitochondrial transmembrane potential, has been successfully targeted for treatment of SLE with rapamycin or sirolimus in both patients and animal models. Inhibition of oxidative stress, nitric oxide production, expression of endogenous retroviral and repetitive elements such as HRES-1, the long interspersed nuclear elements 1, Trex1, interferon alpha (IFN-α), toll-like receptors 7 and 9 (TLR-7/9), high-mobility group B1 protein, extracellular signal-regulated kinase, DNA methyl transferase 1, histone deacetylase, spleen tyrosine kinase, proteasome function, lysosome function, endosome recycling, actin cytoskeleton formation, the nuclear factor kappa B pathway, and activation of cytotoxic T cells showed efficacy in animal models of lupus. Although B cell depletion and blockade of anti-DNA antibodies and T–B cell interaction have shown success in animal models, human studies are currently ongoing to establish the value of several target molecules for treatment of patients with lupus. Ongoing oxidative stress and inflammation lead to accelerated atherosclerosis that emerged as a significant cause of mortality in SLE.

HDAC Inhibition in Lupus Models

“…Substantial evidence exists that histone proteins may play a critical role in the regulation of a wide variety of normal cellular functions and pathologies (14). For genes to be transcribed, DNA must uncoil from around the histone proteins.…”

Nutrient signaling pathways and rheumatic diseases

“…Системная красная волчанка Хотя точные причины активации Т-, В-лимфоцитов, дендритных клеток (ДК) и макрофагов неясны, имеются доказательства, что активация mTOR играет центральную роль в дисфункции лимфоцитов при системной красной волчанке (СКВ), а сам mTOR рассматривается как новый общий биомаркер дисфункции Т-и В-лимфоцитов при этом заболевании [175][176][177][178]. Это предполагается, посколь-ку ингибитор mTOR рапамицин оказался очень эффекти-вен для нормализации функционирования Т-лимфоцитов при СКВ.…”

“…Поскольку mTOR локализуется на внешней мембране митохондрий и служит сенсором митохондри-ального трансмембранного потенциала [63], он, вероятно, активируется вследствие персистентной гиперполяриза-ции митохондрий, наблюдаемой при СКВ [176,178].…”

Regulatory T Cells Compensation Failure Cause the Dysregulation of Immune Response in Pristane Induced Lupus Mice Model

“…Systemic lupus erythematosus (SLE) is a systemic autoimmune inflammatory disease that has a complex pathogenesis (1). Recent studies have discovered that the pathogenesis of SLE is correlated with the abnormal response of CD4 + T cells, including regulatory T cells (Tregs) and T helper (Th) cell subsets (2)(3)(4).…”