嗜中性白血球上MDL-1(CLEC5A)在類風性關節炎中的角色

Abstract

Rheumatoid arthritis is a chronic systemic autoimmune disease which is characterized by synovitis. And it will gradually develop into poly-articular arthritis with the passage of time. The manifest symptoms of rheumatoid arthritis are joint pain; swelling; stiffness; deformation, moreover, the most prominent symptoms are joint swelling and pain. In late stages of RA, deformity of joint and defective joints expanded due to severely damage. Hence, patient could not be self-management further cause adverse effects in family and society. Rheumatoid arthritis processes involving dys-regulation of multiple components of immune system including the adaptive and the innate immune system. Compared to adaptive immunity, the role of innate immunity in the pathogenesis of rheumatoid arthritis is not well being elucidated yet. C-type lectin is as an effector molecule in the innate immune system, expressed on immune cells specifically. MDL-1 /CLEC5A is a type II trans-membrane protein belonging to the C type lectin superfamily. According to previous publications, MDL-1 be found participate in osteoclastogenesis when partnered with DAP12 and DAP10 in osteoclasts and bone marrow-derived macrophages in mice. Moreover, In animal model of rheumatoid arthritis shows that MDL-1 as key regulator of synovial injury and bone erosion during Rheumatoid Arthritis joint inflammation. Functional blockade of MDL-1 receptor via Mdl1 deletion or treatment with MDL-1-Ig fusion protein reduces the incidence and severity of autoimmune joint inflammation in mice. Neutrophils presence extraordinary numbers in the synovial fluid of patients with RA when disease flares up. But whether MDL-1 could be detect on neutrophil in RA synovial fluid or whether MDL-1 could modulate neutrophil function are uncertainly. Our data displays neutrophils from synovial fluid in RA patients the MDL-1 expression increased compared with the neutrophil from healthy volunteers peripheral blood. This observation also exist in AS and Gout patient. Therefore, immunehistochemical analyses disclosed MDL-1 positive cells in human RA synovial tissue but not in Osteoarthritis (OA) synovial tissue. Further investigation supporting that MDL-1 expression could be promoted by G-CSF in the present of TNF-α which cytokines are related to RA and neutrophil. Although anti-MDL-1 mAb did not have capacity to stimulate neutrophil to secrete TNF-α and IL-10, TLR4 ligands has been shown to stimulate the raise of RANKL on neutrophil in the present of anti-MDL-1 mAb. Moreover, RANKL could promote osteoclastogenesis. In our results show MDL-1 could enhance Ca2+ influx on neutrophil and enhance generation of neutrophil chemotactic activities. All of evidences indicate MDL-1 have some capacity to modulate the pathogenesis of rheumatoid arthritis. The aim and contribution of this research are to investigate what kind of function mediated by MDL-1 on neutrophil in Rheumatoid arthritis. In the future, expecting that apply MDL-1 related molecule to pharmacological application in RA therapy and further improve patient’s quality of life.