Changes in Soluble CD18 in Murine Autoimmune Arthritis and Rheumatoid Arthritis Reflect Disease Establishment and Treatment Response

Abstract

IntroductionIn rheumatoid arthritis (RA) immune activation and presence of autoantibodies may precede clinical onset of disease, and joint destruction can progress despite remission. However, the underlying temporal changes of such immune system abnormalities in the inflammatory response during treat-to-target strategies remain poorly understood. We have previously reported low levels of the soluble form of CD18 (sCD18) in plasma from patients with chronic RA and spondyloarthritis. Here, we study the changes of sCD18 before and during treatment of early RA and following arthritis induction in murine models of rheumatoid arthritis.MethodsThe level of sCD18 was analyzed with a time-resolved immunoflourometric assay in 1) plasma from early treatment naïve RA patients during a treat-to-target strategy (the OPERA cohort), 2) plasma from chronic RA patients, 3) serum from SKG and CIA mice following arthritis induction, and 4) supernatants from synovial fluid mononuclear cells (SFMCs) and peripheral blood mononuclear cells (PBMCs) from 6 RA patients cultured with TNFα or adalimumab.ResultsPlasma levels of sCD18 were decreased in chronic RA patients compared with early RA patients and in early RA patients compared with healthy controls. After 12 months of treatment the levels in early RA patients were similar to healthy controls. This normalization of plasma sCD18 levels was more pronounced in patients with very early disease who achieved an early ACR response. Plasma sCD18 levels were associated with radiographic progression. Correspondingly, the serum level of sCD18 was decreased in SKG mice 6 weeks after arthritis induction compared with healthy littermates. The sCD18 levels in both SKG and CIA mice exhibited a biphasic course after arthritis induction with an initial increase above baseline followed by a decline. Shedding of CD18 from RA SFMC and RA PBMC cultures was increased by TNFα and decreased by adalimumab.ConclusionsThe plasma sCD18 levels were altered in patients with RA, in mice with autoimmune arthritis and in cell cultures treated with TNFα and adalimumab. Decreased levels of plasma sCD18 could reflect autoimmunity in transition from early to chronic disease and normalization in response to treatment could reflect autoimmunity in remission.

Altered levels of soluble CD18 may associate immune mechanisms with outcome in sepsis

“…We have shown increased CD18 shedding previously in response to TNF‐α stimulation . Here, we found increased CD18 shedding in response to several inflammatory mediators relevant in sepsis, indicating that CD18 shedding is the result of many inflammatory pathways.…”

“…In consequence, causes and effects are poorly resolved. Thirdly, the onset of disease was unknown in the septic group of patients, potentially obscuring comparisons, especially when considering that the level of sCD18 seems to stabilize during inflammatory disease . Fourthly and finally, immunosuppression with steroid therapy may have influenced our results, although patients who received high‐dose glucocorticoid treatment were excluded prior to the study.…”

“…CD18 is found both in a surface-bound form expressed exclusively by leucocyte cell membranes and in a shed, soluble form (sCD18) in peripheral blood and other extracellular fluids [13][14][15][16]. Shedding of CD18 can be induced by TNF-a [14,15]. LFA-1 binds ICAM-1 as part of the process, enabling transendothelial migration of leucocytes from the circulation into the extravascular tissue contributing to inflammation and tissue damage [17][18][19][20][21].…”

Responses to Cytokine Inhibitors Associated with Cellular Composition in Models of Immune‐Mediated Inflammatory Arthritis

“…The SFMC 48-hour culture is an in vitro model of IMIA dominated by lymphocytes and monocytes (20,29). The SFMC 48-hour culture is an in vitro model of IMIA dominated by lymphocytes and monocytes (20,29).…”

“…Therefore, we used in vitro models that mimic different pathotypes of IMIA to study potential associations between the treatment effect of different cytokine inhibitors and the cellular composition of the cultures. Therefore, this culture was used as a model of a lymphocyte-and monocyte-dominated environment (20). SFMCs have previously been shown to consist of primarily lymphocytes and cells of the monocyte and macrophage lineage (17).…”