The levels of soluble granzyme A and B are elevated in plasma and synovial fluid of patients with rheumatoid arthritis (RA)

Abstract

Cytotoxic cells possess specialized granules which contain perforin and a group of serine proteinases termed granzymes. Granzyme-positive cells have been identified in synovial fluid and tissue of patients with RA, where they may play an important role as mediators of granule-mediated apoptosis, extracellular proteolysis, and cytokine induction. The aim here was to define further the involvement of cytotoxic cells in RA. Plasma and synovial fluid samples from the knee joint were obtained from 31 RA patients. The disease controls included 20 osteoarthritis (OA) patients and 10 reactive arthritis (ReA) patients. A recently developed capture ELISA was used to detect soluble granzymes A and B in all patients. Compared with OA and ReA disease controls, markedly increased levels of soluble granzymes A and B were detected in both plasma and synovial fluid of RA patients (P < 0.00001). When values for soluble granzymes A and B in plasma and synovial fluid were used simultaneously as independent variables, logistic regression analysis indicated that a diagnosis of RA could be predicted correctly in 84% of the RA patients and a diagnosis of non-RA in 90% of the controls. The markedly elevated levels of soluble granzymes A and B in plasma and synovial fluid of RA patients strongly suggest that cytotoxic cells are active participants in the pathogenesis of RA. Moreover, the results suggest that measurement of granzymes may assist the laboratory evaluation of patients with arthritis. Larger studies in patients with early disease may clarify the role of this test system in differential diagnosis.

Death by a Thousand Cuts: Granzyme Pathways of Programmed Cell Death

“…During inflammation and infection, elevated levels of granzymes exist in both serum and other bodily fluids. Examples in which extracellular granzymes have been detected include the serum of patients undergoing acute cytomegalovirus infection or chronic HIV infection, the joints of rheumatoid arthritis patients, and the bronchoalveolar lavage fluid of allergen-challenged patients with asthma and patients with chronic obstructive pulmonary disease (9,114,(179)(180)(181)(182)(183). Elevated granzyme levels also occur in the serum of patients with endotoxemia and bacteremia, supporting the idea that granzymes are expressed and secreted by activated leukocytes, not just by lymphocytes (184).…”

Granzyme B is expressed in mouse mast cells in vivo and in vitro and causes delayed cell death independent of perforin

“…Arrows indicate apoptotic-(a) or non apoptotic-(c) like dead cells rheumatoid arthritis (RA). 13,41,42 The finding of degranulated mast cells in joint tissue of mice with experimentally induced erosive synovitis and the observation that two strains of mice deficient in mast cells were resistant to the development of this type of joint inflammation 43 points to a likely role of mast cells in the pathogenesis of inflammatory arthritides, including RA. 44 Thus, mast cell-derived gzmB may contribute, together with other granule-associated effector molecules and mediators, to the pathogenic mechanisms of joint destruction by facilitating recruitment of leukocytes from the circulation, 31,32 degrading cartilage proteoglycan 14 and/or by killing synovial membrane lining cells, most probably via anoikis.…”

“…These extracellular activities of gzms are implicated in inflammation and processes of leukocyte extravasation. 10,12,13 Both, gzmA and/or gzmB cleave extracellular proteins such as fibronectin, collagen IV, vitronectin and/or laminin. 8,10,11 GzmB also degrades the cartilage proteoglycan aggrecan, 14 induces perf-independent cell detachment and delayed cell death (anoikis) in adherent smooth muscle cells (SMCs) 11 and in EC.…”

A quarter century of granzymes

“…Physiological evidence of GrA extracellular proteolytic activities originates from the observation that GrA levels are elevated in synovial fluid of rheumatoid arthritis patients. 103 Additionally, a number of plasma inhibitors of GrA have been reported, further supporting a potential GrA extracellular function. But, a direct causative effect of GrA and immunopathology has not been clearly established.…”