Overexpression of IFN-induced protein 10 and its receptor CXCR3 in myasthenia gravis.
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-gamma-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-gamma (Mig; CXCL9). TNF-alpha and IL-1beta, which act synergistically with IFN-gamma 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.
Feferman
Tali
T
Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel.
Maiti
Prasanta K
PK
Berrih-Aknin
Sonia
S
Bismuth
Jacky
J
Bidault
Jocelyne
J
Fuchs
Sara
S
Souroujon
Miriam C
MC
D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D015815:Cell Adhesion Molecules / Q000096:biosynthesis; D054357:Chemokine CXCL10; D019743:Chemokines, CXC / Q000096:biosynthesis* / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D007371:Interferon-gamma / Q000502:physiology*; D008198:Lymph Nodes / Q000276:immunology / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000276:immunology / Q000378:metabolism; D009157:Myasthenia Gravis / Q000235:genetics / Q000276:immunology / Q000473:pathology; D020720:Myasthenia Gravis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control; D020411:Oligonucleotide Array Sequence Analysis; D021122:Protein Subunits / Q000008:administration & dosage / Q000276:immunology; D051381:Rats; D011917:Rats, Inbred Lew; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine / Q000096:biosynthesis* / Q000235:genetics* / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000008:administration & dosage / Q000276:immunology; D015854:Up-Regulation / Q000276:immunology
C515187:CXCR3 protein, human; D015815:Cell Adhesion Molecules; D054357:Chemokine CXCL10; D019743:Chemokines, CXC; C515189:Cxcr3 protein, rat; D021122:Protein Subunits; D054367:Receptors, CXCR3; D019707:Receptors, Chemokine; D011978:Receptors, Nicotinic; D007371:Interferon-gamma