Circulating Immune Complexes Augment Severity of Antibody-Mediated Myasthenia Gravis in Hypogammaglobulinemic RIIIS/J Mice

Abstract

Experimental autoimmune myasthenia gravis (EAMG) is severe in RIIIS/J mice, despite a significant B cell immunodeficiency and a massive TCR Vβ gene deletion. Severity of EAMG in RIIIS/J mice is greater than MHC-identical (H-2r) 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 Vβ genes in RIIIS/J mice, we obtained (RIIIS/J × B10.RIII)F1 (Vβb/c) × RIIIS/J (Vβc) backcross mice using Mendelian genetic methods and immunized them with acetylcholine receptor. EAMG susceptibility was not elevated in mice with Vβc genotype having 70% Vβ 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.

Effect of complement and its regulation on myasthenia gravis pathogenesis

“…Despite a significant B-cell deficiency, RIIIS/J mice have severe EAMG that is associated with increased lymph node cell counts, elevated anti-AChR antibodies, and C3-and C1q-conjugated circulating immune complexes. There is direct correlation between increased circulating immune complex levels and disease severity [71]. Deficiency in Fcγ RIII did not impair primary immune response to AChR but caused a reduction in serum levels of C1q and C3 circulating immune complexes.…”

Complement and cytokine based therapeutic strategies in myasthenia gravis

“…While a correlation between serum complement levels and EAMG severity has not been identified, C3-and C1q-conjugated immune complex levels have been shown to be correlated with the severity of muscle weakness in C57BL/6 (B6) and RIIIS/J mouse strains [16,17]. The components of the classical (C1q) and common (C3, C9) pathways are abundantly deposited at the NMJs of EAMG mice in colocalization with IgG deposits [13,16] supporting the notion that AChR antibodies activate the classical pathway upon binding their target antigens at the NMJ and thus trigger the complement cascade ultimately leading to the formation of MAC (Figs.…”

Classical Complement Pathway in Experimental Autoimmune Myasthenia Gravis Pathogenesis

“…7). 29 In other words, similar to AChR-immunized B6 mice, AChR-immunized RIIIS/J mice with higher serum CIC levels tend to have more severe muscle weakness. There are also a few anecdotal clinical reports showing a similar correlation in MG patients.…”

“…7). 29 In other words, similar to AChR‐immunized B6 mice, AChR‐immunized RIIIS/J mice with higher serum CIC levels tend to have more severe muscle weakness.…”