Systemic lupus erythematosus (SLE) is an autoimmune disease affecting about 1.5 million Americans. At the devastating disease stage, abnormal immune response can target and destroy many vital organs. Neutrophils are at the frontier of innate immunity against infections. Neutrophil activation has also been linked to tissue injury in acute infections and autoimmune conditions. Using our collection of recombinant antibodies generated from single B cells of SLE patients, we found that a high frequency of SLE-derived recombinant antibodies bind to and activate neutrophils as examined by degranulation and oxidative burst. In particular, S4Ab2 antibody recognizes membrane bound protein disulfide isomerase (PDI) and also induces strong Ca++ influx and protein tyrosine phosphorylation in neutrophils;S4Ab4 antibody recognizes a novel pattern recognition receptor NLRC5/NOD27 and induces neutrophil extracellular trap (NET) formation. Furthermore, administration of S4Ab2 or S4Ab4 antibodies in NZB/W F1 mice induces kidney damage. Based on these results, we hypothesize that a subset of autoantibodies from SLE patients recognizes neutrophil antigens and activates neutrophils, which contributes to tissue damage in SLE. To test this hypothesis, (1) we will examine a large number of SLE-derived recombinant antibodies to identify autoantibodies that bind to and activate neutrophils. We will use these autoantibodies to identify their cognate antigens and determine if such autoantibodies can be used as biomarkers to predict tissue damage in SLE patients. (2) We will determine if SLE derived anti-neutrophil antibodies activate neutrophils through the classical Fc3 receptor pathway and further dissect their signaling pathways using different protein kinase inhibitors. We will also determine the specific signaling of S4Ab2 and S4Ab4 antibodies upon binding to their cognate antigens on neutrophils. (3) We will determine if SLE-derived anti-neutrophil autoantibodies induce tissue damage in murine lupus models. We will further test whether depletion of neutrophils or blocking of neutrophil activation can prevent the autoantibody-mediated tissue damage in murine models. Results from our studies will identify potential bio-markers for prediction of tissue damage in SLE and also help to develop novel preventive and therapeutic interventions for tissue damage in SLE patients.
Systemic lupus erythematosus (SLE) is an autoimmune disease affecting more than half a million Americans. At the devastating disease stage, abnormal immune response can target and destroy many vital organs. Although neutrophils are the frontiers of innate immunity against infections, excessive neutrophil activation has been linked to tissue injury in acute infections and autoimmune conditions. Our current studies showed that SLE-derived autoantibodies directly react with neutrophil antigens and activate neutrophils and thus, contribute to tissue damage. Results from our proposed studies will shed new lights on understanding the mechanism of autoantibody-mediated tissue damage and will allow us to design specific treatments to prevent tissue damage in SLE patients.
|Li, Song; Yu, Yangsheng; Yue, Yinshi et al. (2016) Autoantibodies From Single Circulating Plasmablasts React With Citrullinated Antigens and Porphyromonas gingivalis in Rheumatoid Arthritis. Arthritis Rheumatol 68:614-26|
|Yu, Y; Koehn, C D; Yue, Y et al. (2015) Celastrol inhibits inflammatory stimuli-induced neutrophil extracellular trap formation. Curr Mol Med 15:401-10|
|Lange, Miles D; Huang, Lin; Yu, Yangsheng et al. (2014) Accumulation of VH Replacement Products in IgH Genes Derived from Autoimmune Diseases and Anti-Viral Responses in Human. Front Immunol 5:345|
|Li, Song; Yu, Yangsheng; Koehn, Christopher D et al. (2013) Galectins in the Pathogenesis of Rheumatoid Arthritis. J Clin Cell Immunol 4:|
|Yu, Yangsheng; Su, Kaihong (2013) Neutrophil Extracellular Traps and Systemic Lupus Erythematosus. J Clin Cell Immunol 4:|
|Liao, Hongyan; Guo, Jun-tao; Lange, Miles D et al. (2013) Contribution of V(H) replacement products to the generation of anti-HIV antibodies. Clin Immunol 146:46-55|
|Liu, Jing; Lange, Miles D; Hong, Sang Yong et al. (2013) Regulation of VH replacement by B cell receptor-mediated signaling in human immature B cells. J Immunol 190:5559-66|
|Liu, Jing; Xie, Wanqin; Lange, Miles D et al. (2013) Internalization of B cell receptors in human EU12 Î¼HCâº immature B cells specifically alters downstream signaling events. Biomed Res Int 2013:807240|
|Huang, Lin; Lange, Miles D; Yu, Yangsheng et al. (2013) Contribution of V(H) replacement products in mouse antibody repertoire. PLoS One 8:e57877|
|Li, Song; Yu, Yangsheng; Yue, Yinshi et al. (2013) Microbial Infection and Rheumatoid Arthritis. J Clin Cell Immunol 4:|