Circulating immune complexes augment severity of antibody-mediated myasthenia gravis in hypogammaglobulinemic RIIIS/J mice.
Experimental autoimmune myasthenia gravis (EAMG) is severe in RIIIS/J mice, despite a significant B cell immunodeficiency and a massive TCR V beta gene deletion. Severity of EAMG in RIIIS/J mice is greater than MHC-identical (H-2(r)) B10.RIII mice, suggesting the influence of non-MHC genes as an EAMG-potentiating factor in this strain. To delineate the role of deleted TCR V beta genes in RIIIS/J mice, we obtained (RIIIS/J x B10.RIII)F(1) (V beta(b/c)) x RIIIS/J (V beta(c)) backcross mice using Mendelian genetic methods and immunized them with acetylcholine receptor. EAMG susceptibility was not elevated in mice with V beta(c) genotype having 70% V beta gene deletion. Next, we performed microarray analysis on 12,488 spleen cDNAs obtained from spleens of naive RIIIS/J and B10.RIII mice. In RIIIS/J mice, 263 cDNAs were overexpressed and 303 cDNAs were underexpressed greater than 2-fold, compared with B10.RIII mice. TCR gene expression was augmented, whereas NK receptor, C1q, and C3 gene expressions were diminished in RIIIS/J mice. RIIIS/J mice also had increased lymph node T cell counts, elevated serum anti-AChR Ab levels, and serum C3 and C1q-conjugated circulating immune complex levels. A direct correlation between increased serum C1q-conjugated circulating immune complex levels and disease severity was observed in RIIIS/J mice.
Tüzün
Erdem
E
Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA.
Scott
Benjamin G
BG
Yang
Huan
H
Wu
Bo
B
Goluszko
Elzbieta
E
Guigneaux
Michelle
M
Higgs
Stephen
S
Christadoss
Premkumar
P
D000276:Adjuvants, Immunologic / Q000096:biosynthesis / Q000097:blood* / Q000502:physiology; D000361:Agammaglobulinemia / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D000818:Animals; D000936:Antigen-Antibody Complex / Q000096:biosynthesis / Q000097:blood* / Q000502:physiology; D000954:Antigens, Surface / Q000032:analysis; D001323:Autoantibodies / Q000096:biosynthesis / Q000502:physiology*; D016175:B-Lymphocyte Subsets / Q000473:pathology; D015922:Complement C1q / Q000096:biosynthesis; D003176:Complement C3 / Q000096:biosynthesis; D017353:Gene Deletion; D018858:Germinal Center / Q000473:pathology; D006183:H-2 Antigens / Q000235:genetics; D006650:Histocompatibility Testing; D007074:Immunoglobulin G / Q000097:blood; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D018655:Lymphocyte Count; D008231:Lymphopenia / Q000235:genetics / Q000276:immunology / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D020720:Myasthenia Gravis, Autoimmune, Experimental / Q000453:epidemiology / Q000235:genetics / Q000276:immunology* / Q000473:pathology*; D020411:Oligonucleotide Array Sequence Analysis; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000096:biosynthesis / Q000235:genetics; D011950:Receptors, Cholinergic / Q000008:administration & dosage / Q000276:immunology; D011971:Receptors, Immunologic / Q000096:biosynthesis / Q000235:genetics; D054340:Receptors, KIR; D012720:Severity of Illness Index; D013154:Spleen / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000473:pathology
D000276:Adjuvants, Immunologic; D000936:Antigen-Antibody Complex; D000954:Antigens, Surface; D001323:Autoantibodies; D003176:Complement C3; D006183:H-2 Antigens; D007074:Immunoglobulin G; D016693:Receptors, Antigen, T-Cell, alpha-beta; D011950:Receptors, Cholinergic; D011971:Receptors, Immunologic; D054340:Receptors, KIR; D015922:Complement C1q