It is well known that
It is well known that the thymus plays an important function in the complex pathogenesis and perpetuation of MG. We compared resistin levels between patients with MG with or without thymoma and found that those with thymoma had higher levels than those without thymoma. It has been previously recognized that some adipose tissue-derived peptides may significantly influence the growth and proliferation of tumorous stroma and malignant cells and that resistin is involved in the pathology of malignant tumors (Di Simone et al., 2006, Housa et al., 2008). Thus, we speculate that resistin is also involved in the pathophysiology of thymoma, and resistin levels may represent a biomarker for thymoma in MG and other disorders. Providing further evidence for a potential diagnostic and disease monitoring role for resistin in MG, when we investigated the relationship between resistin levels and disease severity, we observed significant correlations between serum resistin and MG-ADL scores in patients with AChR-GMG or AChR-MG with thymoma. Taken together, these data suggest that resistin may be a useful inflammation marker for disease symptom severity in AChR-MG and a diagnostic indicator of thymoma.
Finally, we found that resistin levels decreased in patients with GMG after treatment. Due to the small sample size, determining if the effect of immunosuppression on resistin is directly related to MG regression will require further study. Nevertheless, 2 other observational studies have demonstrated that decreased resistin levels are a marker of successful therapy in patients with inflammatory bowel disease (Karmiris et al., 2007, Konrad et al., 2007). In addition, in an experimental model of autoimmune arthritis, resistin levels were downregulated after treatment with high doses of the anti-diabetic drugs thiazolidinediones (TZDs), and this reduced bone erosions and prevented inflammatory bone loss (Koufany et al., 2008). Given that reduced resistin levels correlate with improvement in various human pathologies, resistin might be a potential target for MG treatment.
Conflict of interest
Acknowledgments This was supported in part by the National Science Foundation of China (81471221, 81171183 to L.Y.) and the National Key Clinical Specialty Construction Project of China.
Introduction Myasthenia gravis (MG), a disease with impaired neuromuscular transmission, is a T cell dependent, antibody and complement mediated autoimmune disease (Turner, 2007). MG patients usually have clinical manifestations of fatigue and fluctuating weakness of voluntary muscles (McGrogan et al., 2010). The pathogenesis of MG involves genetic and environmental factors which cause aberrant generation of autoreactive antibodies against tetracaine hydrochloride receptor (AchR) (McGrogan et al., 2010). Approximately 85–90% of autoreactive antibodies in MG are anti-AchR antibodies (Bateman et al., 2007). The antibodies bind with AchRs in the neuromuscular junction (NMJ), activate the complement system, and lead to postsynaptic membrane damage as well as accelerating the degradation of the AchRs thus leading to fatigue of voluntary muscles (Tüzün et al., 2008, Souroujon et al., 2010, Tüzün et al., 2010). Alexa-conjugated AChR was used as a probe for AchR specified B cells (B220+Ig+). Mice with experimental autoimmune myasthenia gravis (EAMG) had significantly elevated frequencies of AchR specified IgG2+ (IgG1 in human) and IgM+ B cells. The frequencies of AchR specified B cells significantly correlated with the clinical grade of disease and loss of limb muscle strength (Allman et al., 2011). These results indicated that significantly elevated frequencies of AchR specified peripheral blood B cells could be a potential biomarker for MG disease severity. However, there are no studies on the characterization of AchR specified B cells in the periphery of MG patients. The complement system, which plays a pivotal role in innate and adaptive immune responses (Holers, 2005, Isaák et al., 2006, Holers and Kulik, 2007, Roozendaal and Carroll, 2007), has been investigated extensively in MG (Wagner and Frank, 2010). In the mouse model of EAMG, complements, such as C3 and C5b–C9, were accumulated on the postsynaptic membrane of NMJ, and more the C5b–C9 deposits less the functional AchR (Tüzün et al., 2003, Tüzün et al., 2004, Christadoss et al., 2008). Previous study has shown that membrane damage of NMJ was initiated by anti-AchR antibody mediated complement damage (Tüzün et al., 2003, Tüzün et al., 2004, Christadoss et al., 2008). Complements exert their effects through binding with complement receptors (CRs). CRs, including CR1, CR2, CR3, CR4, are expressed widely on immunocytes, such as T lymphocytes, B lymphocytes, dendritic cells (Fischer et al., 1991, Roozendaal and Carroll, 2007, Erdei et al., 2009, Twohig et al., 2009). CD21, also called CR2, mainly expressed on B lymphocytes, is responsible for B cell survival and activation (Erdei et al., 2009, Dunkelberger and Song, 2010). CD21 on peripheral B cells could reduce the threshold of B cell activation, stop surface IgM (sIgM) mediated B cell apoptosis, favor antigen presentation, stabilize BCR “flip-flop”, regulate the expression of costimulatory molecules, and transport immune complexes (ICs) to germinal centers (Patterson et al., 2006, Dunkelberger and Song, 2010). Recently, several lines of evidence demonstrated that the levels of CD21 were decreased on serum and synovial B cells of patients suffering from systemic lupus erythematosus or rheumatoid arthritis (Wehr et al., 2004, Patterson et al., 2006, Isaák et al., 2008). It has also been found that CD21 may be correlated positively with the maturity of newborn immune system, which further helps to explain the feasibility of infectious diseases in newborns (Zhang et al., 2007). All the evidence suggests that CD21 has a close relationship with immune disorders.