With the support of the National Natural Science Foundation of China (NSFC grant number: 81730043, 81621002 and 31530020), a joint team in Beijing led by Dr. Wanli Liu from the School of Life Sciences, Institute for Immunology, at Tsinghua University, and by Dr. Zhanguo Li from the Department of Rheumatology and Immunology of Peking University People's Hospital, recently published a paper in Science entitled "Autoimmune disease variant of IgG1 modulates B Cell activation and differentiation" on October 4^th 2018 (http://science.sciencemag.org/content/362/6415/700.long). In this paper, the authors reported a single-nucleotide polymorphism (SNP) within the intracellular domain of human membrane-bound immunoglobulin IgG1 heavy chain that is positively correlated with systemic lupus erythematosus (SLE). The authors also revealed that this SNP is involved in the regulation of antigen-binding induced B cell activation and subsequent B cell fate determination. This finding provides new potential drug targets and theoretical supports for the study of B cell associated pathogenic mechanisms for the treatment of autoimmune diseases including SLE.

SLE is one of the most common autoimmune diseases, and its pathogenesis is still unclear, leading to limited treatments and inability to cure. By collaborating with three clinical hospitals in Beijing and Shenzhen respectively, the authors identified a SNP (rs117518546) within the gene coding the intracellular domain of human membrane-bound immunoglobulin IgG1 heavy chain, which was substantially enriched in SLE patients compared to criteria-matched controls. This SNP results in a glycine-to-arginine substitution at position 396 in human IgG1 (hIgG1-G396R). Further analyses indicated that this SNP drives an autoantibody subclass profile shift towards IgG1 isotype predominance in G396R patients, and is also associated with a more severe disease phenotype, including earlier onset, multiple organ involvement, higher SLE disease activity and inflammation. Thus, hIgG1-G396R is a risk locus for SLE. By analyzing the human genome sequences from “1000 Genomes Project” database,  the authors also found that this SNP is mainly carried in the East Asian population with high minor allele frequency (MAF), but rarely in the Caucasus and African population. The unique MAF of this SLE susceptible SNP in Chinese population may be one of the factors that determine the distinct clinical manifestations and responses upon treatment of SLE patients in Chinese and other populations.

This joint study is a representative example of a multi-level complex project supported by multi-disciplinary techniques, which was initiated by the clinical genetic studies of SLE susceptible loci, followed by large-scale multi-center epidemiological analyses. The conclusions from clinical studies were then validated by genetically modified mice models, followed by mechanistic studies that were supported by advanced optical imaging techniques, conventional biochemical and molecular dynamics simulation approaches. This joint study potentiated the understanding of the function and pathogenesis of SLE susceptible loci, providing a new target for SLE therapy. This joint study may also set up an example for the investigations of complex diseases including SLE.