Soluble CD137 and Autoimmune Diseases

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CD137 has been detected in both membrane-bound (mCD137) and soluble forms (sCD137). Expression level of soluble forms of CD137 does not always correlate with that of mCD137, since they are generated by alternative splicing (Setareh et al., 1995) instead of a proteolytic product of mCD137. Two splice variants of sCD137 has been identified (Michel et al., 1998). Expression of both membrane-bound and soluble isoforms is activation-dependent (Schwarz et al.,

1996), while the production of sCD137 seems to be restricted to activated lymphocytes (Michel etal., 1998).

The elevated levels of sCD137 have been observed in sera of patients with multiple autoimmune disorders such as rheumatoid arthritis (Jung et al., 2004; Michel etal., 1998), multiple sclerosis (Sharief, 2002), systemic lupus erythematosus (SLE) and Behcet's disease (BD) (Jung et al., 2004). Michel et al. (1998) first observed dramatic increased levels of sCD137 in sera of patients with rheumatoid arthritis. Later studies (Jung et al., 2004) showed that both sCD137 and sCD137L serum levels were significantly higher in RA patients compared with healthy controls, and their concentration correlated with rheumatoid factor (RF) values and the disease severity. Moreover, the levels were markedly decreased at the quiescent stage following immunosuppressive therapy, compared with patients at disease onset (Jung et al., 2004). Sharief observed significantly higher levels of sCD137 in serum and the intrathecal compartment of patients with clinically active multiple sclerosis (MS), which is a demyelinating disease of the central nervous system (CNS), when compared with patients with clinically stable MS or healthy individuals (Sharief, 2002). It indicates that eminent release of sCD137 is related to clinically active MS. Substantially higher serum levels of sCD137 were also detected in patients with active SLE and BD (Jung et al., 2004). So far, elevated levels of sCD137 and sCD137L have been detected in multiple autoimmune disease and they may mirror the clinical symptoms of the disease. So the levels of sCD137 and sCD137L in sera may help the diagnosis and prognosis of certain autoimmune diseases.

Although lots of evidence indicates CD137/CD137L interactions may be involved in the pathogenesis of autoimmune disease, their precise role is far from well dissected. Soluble CD137 and sCD137L may be implicated in the negative feedback control of the ongoing inflammation (Michel et al., 1998). Since activation of lymphocytes through mCD137 delivers a potent costimulatory signal, sCD137L may retard the function of mCD137 by competing the ligand and receptor, leading to restricted lymphocyte activation. In support of this, soluble recombinant CD137 protein has been shown to suppress the T cell responses (DeBenedette et al., 1995; Hurtado et al., 1995). On the other hand, CD137L is expressed on professional APCs, and crosslinking of the ligand by CD137 receptor induces activation of the ligand-expression cells (Alderson etal., 1994; Goodwin etal., 1993; Pollok etal., 1994). Interfering CD137/CD137L interaction by soluble receptor and ligand may also slake the activity of their stimulating cells. So for therapeutic purpose, the disruption of autoreactive lymphocyte activation by sCD137 may be helpful for treatment of deleterious inflammatory diseases.

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