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

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.

Systemic Activation of NRF2 Alleviates Lethal Autoimmune Inflammation in Scurfy Mice

“…This result is consistent with a previous report revealing that NRF2 activation in T cells shifts the Th1/Th2 balance toward Th2-skewed immunity (41). Because IFN-␥ has been reported to enhance the autoimmune response through increasing the numbers of activated effector T and B cells and the production of autoantibodies (42,43), a reduction of IFN-␥ contributes, at least partially, to the attenuation of the autoimmune response by NRF2. Consistent with this idea, a previous study showed that deletion of the Ifng gene prolongs the life span of Sf mice to 6 to 7 weeks and alleviates inflammation in the skin, lungs, and liver (36).…”

Inhibition of experimental Sjögren's syndrome through immunization with HSP60 and its peptide amino acids 437–460

“…In our study, induction of anti-M3R IgG1 production was strongly related to immunization with Hsp60. However, although IgG1 has previously been reported to be the anti-M3R isotype that can mediate hyposalivation (37), in our study the induction of the anti-M3R IgG1 isotype, generally considered to be an antiinflammatory isotype (38), did not seem to be related to manifestation of or protection against hyposalivation.…”

Toll‐like receptor 2 induces Th17 myeloperoxidase autoimmunity while Toll‐like receptor 9 drives Th1 autoimmunity in murine vasculitis

“…We found that addition of either of the TLR ligands to MPO enhanced autoantibody production. MPO and TLR-9 ligand promoted production of the Th1-associated IgG2b and IgG2c subclasses, which fix complement and enhance glomerular injury (34). Conversely, the combination of MPO and TLR-2 ligand was associated with enhanced IgG1 subclass production.…”