Overexpression of IFN-Induced Protein 10 and Its Receptor CXCR3 in Myasthenia Gravis

Abstract

Myasthenia gravis (MG) and its animal model, experimental autoimmune MG (EAMG), are autoimmune disorders in which the acetylcholine receptor (AChR) is the major autoantigen. Microarray technology was used to identify new potential drug targets for treatment of myasthenia that would reduce the need for the currently used nonspecific immunosuppression. The chemokine IFN-γ-inducible protein 10 (IP-10; CXCL10), a CXC chemokine, and its receptor, CXCR3, were found to be overexpressed in lymph node cells of EAMG rats. Quantitative real-time PCR confirmed these findings and revealed up-regulated mRNA levels of another chemoattractant that activates CXCR3, monokine induced by IFN-γ (Mig; CXCL9). TNF-α and IL-1β, which act synergistically with IFN-γ to induce IP-10, were also up-regulated. These up-regulations were observed in immune response effector cells, namely, lymph node cells, and in the target organ of the autoimmune attack, the muscle of myasthenic rats, and were significantly reduced after suppression of EAMG by mucosal tolerance induction with an AChR fragment. The relevance of IP-10/CXCR3 signaling in myasthenia was validated by similar observations in MG patients. A significant increase in IP-10 and CXCR3 mRNA levels in both thymus and muscle was observed in myasthenic patients compared with age-matched controls. CXCR3 expression in PBMC of MG patients was markedly increased in CD4+, but not in CD8+, T cells or in CD19+ B cells. Our results demonstrate a positive association of IP-10/CXCR3 signaling with the pathogenesis of EAMG in rats as well as in human MG patients.

Microarrays Reveal Distinct Gene Signatures in the Thymus of Seropositive and Seronegative Myasthenia Gravis Patients and the Role of CC Chemokine Ligand 21 in Thymic Hyperplasia

“…Like CCL21, CCL19 acts through CCR7, but no up-regulation of CCL19 was observed. An increased expression of CXCL10, a chemoattractant for activated T cells, was also detected, as previously described (23). However, we did not notice any MH-specific increase in the expression of CXCL12 known to contribute to the T cell homing and GC organization (22,24).…”

Antagonist of interferon‐inducible protein 10/CXCL10 ameliorates the progression of autoimmune sialadenitis in MRL/lpr mice

“…Expression of IP-10 and its receptor CXCR3 has been shown to be associated with the development of several Th1-type human inflammatory diseases, including psoriasis, multiple sclerosis, atherosclerosis, rheumatoid arthritis, and myasthenia gravis (41)(42)(43)(44)(45)(46). In addition, elevated IP-10 gene expression has been found in association with rejection of human cardiac allografts and mouse cardiac, small bowel, and pancreatic islet allografts (47,48).…”

Microarray Analysis of Gene Expression Profiles in Response to Treatment with Melatonin in Lipopolysaccharide Activated RAW 264.7 Cells

“…CXCL10 is induced by LPS in RAW macrophage cells [20]. Feferman et al [21] found increased expression of Cxcl10 and its receptor, Cxcr3, in lymph node cells of rats with experimental autoimmune myasthenia gravis. In the present study, Cxcl10 expression increased 10.50 fold in response to LPS treatment, but decreased −7.54 fold in response to melatonin treatment.…”