An autoimmune disease variant of IgG1 modulates B cell activation and differentiation

Chen, Xiangjun; Sun, Xiaolin; Yang, Wei; Yang, Bing; Zhao, Xiaozhen; Chen, Shuting; He, Lili; Chen, Hui; Yang, Changmei; Xiao, Le; Guo, Jianping; He, Jing; Zhang, Fuping; Zheng, Fang; Hu, Zhibin; Yang, Zhiyong; Lou, Jizhong; Zheng, Wenjie; Qi, Hai; Xu, Chenqi; Zhang, Hong; Shan, Hongying; Zhou, Xu‐jie; Wang, Qingwen; Shi, Yi; Lai, Luhua; Li, Zhanguo; Liu, Wanli

doi:10.1126/science.aap9310

Cited by 34 publications

(28 citation statements)

References 28 publications

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“…3–5 These autoantibodies may play an important role in the pathogenesis of SLE. 6–9 Identifying new autoantibodies will benefit our understanding of SLE diagnosis and therapy.…”

Section: Introductionmentioning

confidence: 99%

Antibodies against carbamylated vimentin exist in systemic lupus erythematosus and correlate with disease activity

Jia

Liu

et al. 2020

Lupus

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Objectives Antibodies against carbamylated protein (anti-CarP) were found to be a promising marker to evaluate joint damage and disease activity in patients with rheumatoid arthritis (RA). However, whether anti-CarP antibodies were present in systemic lupus erythematosus (SLE) remained ambiguous. We have therefore undertaken this study to assess the levels of serum anti-CarP antibodies and to evaluate their clinical value in SLE. Methods Serum levels of antibodies against carbamylated-vimentin (anti-Carp) were measured by enzyme immunosorbent assay in 100 patients with SLE, 76 with RA, 17 with primary Sjögren syndrome (pSS), and 68 healthy controls. Data analyses between anti-Carp antibodies and other laboratory measures were performed using SPSS 24 software for Windows. Results The levels of serum anti-CarP antibodies in patients with SLE were significantly higher than those in healthy controls. In addition, anti-CarP antibodies were present in SLE patients lacking the disease-specific antibodies, including anti-Smith–negative patients (24.4%, 21/86), anti-dsDNA–negative patients (29.3%, 12/41), anti-nucleosome–negative patients (21.4%, 9/42), and antiribosomal P protein antibody–negative patients (23.7%, 18/76). There were significant differences between the anti-CarP–positive and anti-CarP–negative SLE patients in clinical and laboratory features, such as age, erythrocyte sedimentation rate (ESR), C-reactive protein, rheumatoid factor, third-generation cyclic citrullinated peptide (CCP3), anticardiolipin, D-dipolymer, complement 3, immunoglobulin G (IgG), red blood cell count (RBC) and hemoglobin. After adjusting for age and disease duration, the high levels of anti-CarP antibodies were still correlated with low RBC, hemoglobin and high ESR, IgG and CCP3. Active SLE patients demonstrated higher anti-CarP IgG than inactive patients. Moreover, the levels of anti-CarP were significantly higher in SLE patients with arthralgia and/or arthritis than in those without joint involvement. Conclusions Anti-CarP antibodies were present in SLE patients and associated with the disease severity. These might provide a potential supplement to other specific autoantibodies for diagnosis of SLE and serve as a promising marker for measuring joint damage in the disease.

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“…3–5 These autoantibodies may play an important role in the pathogenesis of SLE. 6–9 Identifying new autoantibodies will benefit our understanding of SLE diagnosis and therapy.…”

Section: Introductionmentioning

confidence: 99%

Antibodies against carbamylated vimentin exist in systemic lupus erythematosus and correlate with disease activity

Jia

Liu

et al. 2020

Lupus

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“…Pristane-induced lupus-like animal model was used to reflect the disease of SLE in this study, as the accelerated cells death and the presentation of apoptotic debris as autoantigen are considered as the mainly mechanisms of this model [36]. Bm12- induced cGVHD model was another lupus-like autoimmunine model [37] and was also utilized in the current study to identify the effect of SMS1 on SLE-like autoimmunity. In bm12-induced lupus-like model, cognate recognition of the MHC II in recipient B cells by donor CD4 + T cells results in extensive activation of host B cells and production of auto-Abs from recipient B-lymphocytes [38].…”

Section: Discussionmentioning

confidence: 99%

Sphingomyelin synthase 1 enhances BCR signaling to promote lupus-like autoimmune response

Wang

Ming

et al. 2019

EBioMedicine

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Background Sphingomyelin synthase 1 (SMS1) has been reported to participate in hepatitis and atherosclerosis. However, its role in autoimmune response is not clear. This study investigates the possible involvement of SMS1 in B-cell activation and lupus-like autoimmunity. Methods SMS1 knockout lupus-like animal model and SLE patient samples were utilized. B-cell activation and associated signal transduction were detected by flow cytometry, confocal analysis and western blotting. The SMS1 expression in B cells was measured by real-time qPCR. Findings SMS1 deficiency suppressed B-cell activation in culture, which was restored by exogenous SM supplementation. The BCR-mediated early signal transduction including the colocalization of BCR with F-actin or pY/pBtk, and the phosphorylation of intracellular Fyn and Syk were impaired in SMS1 knockout B cells. Furthermore, SMS1 knockout mice showed reduced production and deposition of autoantibodies, accompanied by less severe kidney pathological changes after pristane induction. SMS1 deficiency also displayed lower autoantibody titers and 24 h urine protein excretion in bm12-induced lupus, which were associated with reduced B-cell activation. Adoptively transferred wide-type B cells partially recovered B-cell activation and autoantibody production in SMS1 deficient bm12-induced lupus mice. Moreover, the SMS1 mRNA level in B cells of SLE patients was increased and positively correlated with the serum anti-dsDNA level, IgG and globulin titers. Interpretation These data suggest that SMS1 is involved in lupus-like autoimmunity via regulating BCR signal transduction and B cell activation. (Word count for the abstract: 230).

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“…Similarly, SNP associations have been reported in IGHG3 * 18 (S176Y SNP:rs201430154) to increase the risk of inhibiting components of protein replacement therapies in hemophilia (69). The importance of considering non-allotypic allelic variation is further highlighted by the discovery of a SNP in the cytoplasmic tail of IgG1 which is prevalent in cases of systemic lupus erythematosus (57). This variant has major implications for the humoral response upon infection or vaccination, and in autoimmune disorders, by enhancing IgG1 expression.…”

Section: Implications Of Constant Domain Diversity In Diseasementioning

confidence: 92%

“…Immunoglobulin allotypes and haplotypes have long been associated with susceptibility to infections and diseases including breast cancer (56), autoimmunity (57,58), malaria (39,59), herpes (16,60,61), and hepatitis C (62,63). More recently, studies have even linked constant domain diversity to longevity observed in certain populations (64).…”

Section: Implications Of Constant Domain Diversity In Diseasementioning

confidence: 99%

Beyond Allotypes: The Influence of Allelic Diversity in Antibody Constant Domains

Warrender

Kelton

2020

Front. Immunol.

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Polymorphic diversity in antibody constant domains has long been defined by allotypic motifs that cross react with the sera of other individuals. Improvements in sequencing technologies have led to the discovery of a large number of new allelic sequences that underlie this diversity. Many of the point mutations lie outside traditional allotypic motifs suggesting they do not elicit immunogenic responses. As antibodies play an important role in immune defense and biotechnology, understanding how this newly resolved diversity influences the function of antibodies is important. This review investigates the current known diversity of antibody alleles at a protein level for each antibody isotype as well as the kappa and lambda light chains. We focus on evidence emerging for how these mutations perturb antibody interactions with antigens and Fc receptors that are critical for function, as well as the influence this might have on the use of antibodies as therapeutics and reagents.

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An autoimmune disease variant of IgG1 modulates B cell activation and differentiation

Cited by 34 publications

References 28 publications

Antibodies against carbamylated vimentin exist in systemic lupus erythematosus and correlate with disease activity

Antibodies against carbamylated vimentin exist in systemic lupus erythematosus and correlate with disease activity

Sphingomyelin synthase 1 enhances BCR signaling to promote lupus-like autoimmune response

Beyond Allotypes: The Influence of Allelic Diversity in Antibody Constant Domains

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