Abstract
Granulocyte monocyte colony-stimulating factor (GM-CSF) is currently considered a crucial inflammatory mediator and a novel therapeutic target in rheumatoid arthritis (RA), despite the fact that its precise cellular sources remain uncertain. We studied the expression of GM-CSF in peripheral lymphocytes from RA patients and its change with antirheumatic therapies. Intracellular GM-CSF expression was assessed by flow cytometry in stimulated peripheral B (CD19+) and T (CD3+) cells from RA patients (n = 40), disease (n = 31 including osteoarthritis n = 15, psoriatic arthritis n = 10, and systemic rheumatic diseases n = 6) and healthy (n = 16) controls. The phenotype of GM-CSF+ B cells was assessed as well as longitudinal changes in GM-CSF+ lymphocytes during methotrexate (MTX, n = 10) or anti-tumor necrosis factor (anti-TNF, n = 10) therapy. Among untreated RA patients with active disease (Disease Activity Score 28-C-reactive protein = 5.6 ± 0.89) an expanded population of peripheral GM-CSF+ B (4.1 ± 2.2%) and T (3.4 ± 1.6%) cells was detected compared with both disease (1.7 ± 0.9%, p < 0.0001 and 1.7 ± 1.3%, p < 0.0001, respectively) and healthy (0.3 ± 0.2%, p < 0.0001 and 0.6 ± 0.6%, p < 0.0001) controls. RA GM-CSF+ B cells displayed more commonly a plasmablast or transitional phenotype (37.12 ± 18.34% vs. 14.26 ± 9.46%, p = 0.001 and 30.49 ± 15.04% vs. 2.45 ± 1.84%, p < 0.0001, respectively) and less a memory phenotype (21.46 ± 20.71% vs. 66.99 ± 16.63%, p < 0.0001) compared to GM-CSF- cells. GM-CSF expression in RA patients did not correlate to disease duration, activity or serological status. Anti-TNF treatment led to a statistically significant decrease in GM-CSF+ B and T cells while MTX had no significant effect. This is the first study showing an expanded population of GM-CSF+ B and T lymphocytes in patients with active RA which declined after anti-TNF therapy.
Highlights
Rheumatoid arthritis (RA) is a chronic autoimmune disease associated with joint and systemic inflammation and autoantibody production [rheumatoid factor (RF) and anticyclic citrullinated peptide antibodies], which untreated leads to cartilage and bone destruction as well as to systemic complications [1]
Anti-tumor necrosis factor (TNF) treatment led to a statistically significant decrease in Granulocyte macrophage colony-stimulating factor (GM-CSF)+ B and T cells while MTX had no significant effect. This is the first study showing an expanded population of GM-CSF+ B and T lymphocytes in patients with active RA which declined after anti-TNF therapy
An expanded range of immune cells recruited from the circulation as well as resident cells through the secretion of various cytokines [such as tumor necrosis factor (TNF), interleukin-1 (IL-1), IL-6, and IL-17A] contribute to joint and systemic inflammation that characterizes the disease and which untreated leads to chronic joint damage [2]
Summary
Rheumatoid arthritis (RA) is a chronic autoimmune disease associated with joint and systemic inflammation and autoantibody production [rheumatoid factor (RF) and anticyclic citrullinated peptide (anti-CCP) antibodies], which untreated leads to cartilage and bone destruction as well as to systemic complications [1]. GM-CSF is elevated in the serum [5] and synovial fluid [6, 7] of RA patients, is expressed in rheumatoid synovium [8], its in vivo administration can induce RA exacerbation [9] while its inhibition has beneficial effects in animal models of arthritis [10] and patients with RA [11,12,13,14] It appears that GM-CSF is involved in the generation of inflammatory and arthritic joint pain [15]
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