The role of immune regulatory molecules in rheumatoid arthritis: Implication for etiopathogenesis and prospective for treatment.

Rheumatoid arthritis (RA) is considered an autoimmune chronic disorder and the most common inflammatory arthropathy. Disease progression in RA begins with asymptomatic autoimmune responses in cases with a genetic or environmental predisposition, that alters to arthralgia phase as autoantibodies reach the joints and subjects begin demonstrating nonspecific musculoskeletal presentations lacking any clinical symptoms of synovial inflammation. After that, patients' symptoms develop to undifferentiated arthritis (UA)/idiopathic arthritis (IA) whenever the subjects progress to clinical synovitis systemic comorbidities affecting the vasculature, metabolism, and bone, and eventually with augmented immune cell infiltration, IA/UA patients progress to clinically classifiable RA. RA is mainly correlated with different immune cells and each of them contributes variously to the pathogenesis of the disease. The pathogenesis of RA is altered by the contribution of both T and B cells in an autoimmune irregularity. Modulation of the immune responses occurs through regulatory and inhibitory molecules that control activation of the adaptive system as well as immune hemostasis. To confine the exorbitant T cell-associated inflammatory reactions, the immune system provides a system of inhibitory feedbacks, collectively named immune checkpoints. In this review, we aimed to discuss about inhibitory members of immune checkpoint molecules, including programmed cell death 1 (PD-1)/PD-L1, cytotoxic-T-lymphocyte-antigen-4, lymphocyte activation gene-3, T cell immunoglobulin-3, V-domain Ig suppressor of T cell activation, B- and T-lymphocyte attenuator, and T cell immunoglobulin and ITIM domain and their role in RA.

NK cells - Dr. Jekyll and Mr. Hyde in autoimmune rheumatic diseases.

Natural killer (NK) cells belong to innate immune system that are large granular lymphocytes differentiating from the common lymphoid progenitors. These cells were first identified by their functional response against tumor cells and virus-infected cells. That notwithstanding, NK cells are able to affect both adaptive and innate immune arms and modulate a wide range of immune cells. As a consequence, NK cells are capable of bridging between the innate and adaptive immune responses. The effector cytokines as well as direct cell-cell cytotoxicity by NK cells have been shown to be involved in the regulation of the immune responses and might participate in the etiopathogenesis of several disorders, particularly autoimmune rheumatic diseases (AIRDs), such as Ankylosing spondylitis (AS), Rheumatoid arthritis (RA), Systemic lupus erythematosus (SLE), Behcet's disease (BD), Systemic sclerosis (SSc), and psoriasis. Nonetheless, NK cells demonstrate both harmful and protective functions during autoimmune diseases pathogenesis based on the subset of NK cell as well as disease microenvironment and disease phase or genetic/environmental stimuli. Here in this review, we intend to go through the recent findings in the etiology and pathogenesis of AIRDs and discuss about their clinical potential to be utilized as targets for the sake of therapy in the context of such disorders.

MicroRNAs Targeting Programmed Cell Death Protein 1 (PD-1) Promote Natural Killer Cell Exhaustion in Rheumatoid Arthritis.

 Natural killer (NK) cells play a role in the pathogenesis of rheumatoid arthritis (RA). Upregulated levels of programmed cell death protein 1 (PD-1) is a sign of exhausted NK cells that could be regulated by microRNAs (miRNAs). In this investigation, we determined PD­1 expression on NK cells (as a representation of NK cell exhaustion) in RA patients and evaluated if miRNAs are involved in the modulation of PD-1 expression in NK cells. Peripheral blood specimens were obtained from 40 RA patients and 20 healthy subjects. NK cells were isolated by negative selection from a pool of peripheral blood mononuclear cells. The frequency of PD-1-expressing NK cells and the expression of PD-1 on NK cells were analyzed by flow cytometry. Real-time PCR was used to measure the expression levels of PD-1 mRNA and miRNAs in the NK cells. The percentage of the PD-1-expressing NK cells and Mean fluorescence intensity (MFI) of PD-1 expression on the NK cells were significantly higher in the RA cases compared to the controls. The mRNA expression of PD-1 was significantly upregulated in NK cells from RA patients compared to healthy subjects. The expression levels of miR-28, miR-138, and miR-4717 were significantly downregulated in the NK cells from RA patients compared to the healthy group. In RA, miRNAs probably regulate the NK cell exhaustion process through driving PD-1 expression.