Cellular requirements for antibody production in a novel LPS-enhanced model of autoimmune myasthenia gravis



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Bacterial lipopolysaccharide (LPS) is a T cell-independent adjuvant known to abrogate peripheral tolerance. For the first time, the potential of LPS to induce antigenspecific B cell responses to acetylcholine receptor (AChR) in myasthenia gravis (MG) was evaluated in wild type (WT), CD4-/-, and CD8-/- C57BL/6 mice. Historically, MG\r\nhas been induced in mice by immunization with AChR emulsified in complete Freund’s\r\nadjuvant (CFA). WT mice immunized with AChR in LPS developed an MG-like disease\r\n(LPS-EAMG) similar to a disease induced by immunization with AChR in complete\r\nFreund’s adjuvant (CFA-EAMG). The CD4-/- mice were resistant to the development of\r\nCFA-EAMG, but had significantly higher frequencies of IgG expressing AChR-binding\r\nB cells than WT mice. However, CFA-AChR immunization of CD4-/- mice failed to\r\ndifferentiate these cells to secrete anti-AChR IgG. The CD4-/- mice were susceptible to\r\nthe development of LPS-EAMG and also had significantly higher frequencies of IgG\r\nexpressing AChR-binding B cells than WT mice. WT and CD4-/- mice in the LPSEAMG\r\nmodel had significant amounts of secreted high-affinity anti-AChR IgG2,\r\nimmune complex deposits (IgG, C3, MAC) in muscle, and elevated sera levels of the Bcell survival factor, BAFF. Our results indicate that LPS abrogated B cell differentiation\r\nto antibody secreting cells in the LPS-EAMG model. Furthermore, CD8-/- mice were\r\nalso susceptible to the development of LPS-EAMG, but were resistant to the development of moderate or severe signs of EAMG. While CD8 deficiency did not affect the quantity or avidity of secreted anti-AChR antibodies, it significantly reduced the\r\nsurvival of circulating IgG expressing AChR-binding B cells. The findings, accordingly\r\nhave allowed us to identify an alternate cellular mechanism for the development of EAMG.



Myasthenia Gravis, B cells, autoimmunity, antibody