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Molecular and cellular basis for pathogenicity of autoantibodies: lessons from murine monoclonal autoantibodies

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Abstract

The pathogenesis of autoantibody-mediated cellular and tissue lesions in autoimmune diseases is most straightforwardly attributable to the combined action of self-antigen binding properties and effector functions associated with the Fc regions of the different immunoglobulin (Ig) isotypes. The analysis of two different sets of monoclonal autoantibodies derived from lupus-prone mice revealed remarkable differences in the pathogenic potentials of different IgG subclasses: (1) the IgG2a and IgG2b subclasses of anti-red blood cell (RBC) autoantibodies are the most pathogenic and efficiently activate two classes of activating IgG Fc receptors (FcγRIII and FcγRIV) and complement; (2) the IgG3 subclass is less pathogenic and activate only complement; and (3) the IgG1 subclass is the least pathogenic and interact only with FcγRIII. In addition, because of the unique property of IgG3 to form self-associating complexes and generate cryoglobulins, this subclass of rheumatoid factor and anti-DNA autoantibodies became highly pathogenic and induced lupus-like nephritis and/or vasculitis. Since the switch to IgG2a and IgG3 is promoted by Th1 cytokine interferon γ, these results strongly suggest that Th1 autoimmune responses could be critically involved in the generation of more pathogenic autoantibodies in systemic lupus erythematosus. This finding is consistent with the observation that the progression of murine lupus nephritis is correlated with the relative dominance of Th1 autoimmune responses. Finally, the analysis of IgG glycosylation pattern revealed that more sialylated IgG autoantibodies remained poorly pathogenic because of limited Fc-associated effector functions and loss of cryoglobulin activity. This suggests that the terminal sialylation of the oligosaccharide side chains of IgG could be a significant factor determining the pathogenic potential of autoantibodies. Our results thus underline the importance of subpopulations of autoantibodies, induced by the help of Th1 cells, in the pathogenesis of autoantibody-mediated cellular and tissue injuries.

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Acknowledgment

The studies from the authors’ laboratory discussed in this review were supported by a grant from the Swiss National Foundation for Scientific Research.

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Authors and Affiliations

  1. Department of Pathology and Immunology, University of Geneva, 1211, Geneva 4, Switzerland

    Lucie Baudino, Samareh Azeredo da Silveira & Shozo Izui

  2. Department of Applied Biochemistry, Tokai University, Hiratsuka, Kanagawa, Japan

    Munehiro Nakata

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  1. Lucie Baudino
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  2. Samareh Azeredo da Silveira
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  3. Munehiro Nakata
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  4. Shozo Izui
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Correspondence to Shozo Izui.

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Baudino, L., Azeredo da Silveira, S., Nakata, M. et al. Molecular and cellular basis for pathogenicity of autoantibodies: lessons from murine monoclonal autoantibodies. Springer Semin Immun 28, 175–184 (2006). https://doi.org/10.1007/s00281-006-0037-0

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