Deletion of the Mitochondrial Membrane Protein Fam210b Is Associated with the Development of Systemic Lupus Erythematosus.

Mitochondrial dysfunction has been increasingly recognized as a trigger for systemic lupus erythematosus (SLE). Recent bioinformatics studies have suggested Fam210b as a significant candidate for the classification and therapeutic targeting of SLE. To experimentally prove the role of Fam210b in SLE, we constructed Fam210b knockout (Fam210b-/-) mice using the CRISPR-Cas9 method. We found that approximately 15.68% of Fam210b-/- mice spontaneously developed lupus-like autoimmunity, which was characterized by skin ulcerations, splenomegaly, and an increase in anti-double-stranded DNA (anti-dsDNA) IgG antibodies and anti-nuclear antibodies(ANA). Single-cell sequencing showed that Fam210b was mainly expressed in erythroid cells. Critically, the knockout of Fam210b resulted in abnormal erythrocyte differentiation and development in the spleens of mice. Concurrently, the spleens exhibited an increased number of CD71+ erythroid cells, along with elevated levels of reactive oxygen species (ROS) in the erythrocytes. The co-culture of CD71+ erythroid cells and lymphocytes resulted in lymphocyte activation and promoted dsDNA and IgG production. In summary, Fam210b knockout leads to a low probability of lupus-like symptoms in mice through the overproduction of ROS in CD71+ erythroid cells. Thus, Fam210b reduction may serve as a novel key marker that triggers the development of SLE.

Human C15orf39 Inhibits Inflammatory Response via PRMT2 in Human Microglial HMC3 Cell Line.

Microglia-mediated inflammatory response is one key cause of many central nervous system diseases, like Alzheimer's disease. We hypothesized that a novel C15orf39 (MAPK1 substrate) plays a critical role in the microglial inflammatory response. To confirm this hypothesis, we used lipopolysaccharide (LPS)-and interferon-gamma (IFN-γ)-induced human microglia HMC3 cells as a representative indicator of the microglial in vitro inflammatory response. We found that C15orf39 was down-regulated when interleukin-6 (IL-6) and tumor necrosis factor-α (TNFα) expression increased in LPS/IFN-γ-stimulated HMC3 cells. Once C15orf39 was overexpressed, IL-6 and TNFα expression were reduced in LPS/IFN-γ-stimulated HMC3 cells. In contrast, C15orf39 knockdown promoted IL-6 and TNFα expression in LPS/IFN-γ-stimulated HMC3 cells. These results suggest that C15orf39 is a suppressive factor in the microglial inflammatory response. Mechanistically, C15orf39 interacts with the cytoplasmic protein arginine methyltransferase 2 (PRMT2). Thus, we termed C15orf39 a PRMT2 interaction protein (PRMT2 IP). Furthermore, the interaction of C15orf39 and PRMT2 suppressed the activation of NF-κB signaling via the PRMT2-IκBα signaling axis, which then led to a reduction in transcription of the inflammatory factors IL6 and TNF-α. Under inflammatory conditions, NF-κBp65 was found to be activated and to suppress C15orf39 promoter activation, after which it canceled the suppressive effect of the C15orf39-PRMT2-IκBα signaling axis on IL-6 and TNFα transcriptional expression. In conclusion, our findings demonstrate that in a steady condition, the interaction of C15orf39 and PRMT2 stabilizes IκBα to inhibit IL-6 and TNFα expression by suppressing NF-κB signaling, which reversely suppresses C15orf39 transcription to enhance IL-6 and TNFα expression in the microglial inflammatory condition. Our study provides a clue as to the role of C15orf39 in microglia-mediated inflammation, suggesting the potential therapeutic efficacy of C15orf39 in some central nervous system diseases.

Mendelian randomization study on the causal effect of chickenpox on dementia.

Some viruses, such as varicella zoster virus, are associated with severe dementia. The present study aims to identify the causal link between chickenpox and dementia. To date, the largest publicly available genome-wide association study (GWAS) for chickenpox (710 cases and 211 856 controls from European individuals) and for dementia (5933 cases and 212 859 controls from European individuals) were used to performed this two-sample Mendelian randomization (MR) study. We found no significant pleiotropy or heterogeneity in all seven selected chickenpox genetic instrumental variants in dementia GWAS. Of seven chickenpox genetic variants, two are located in the intergenic region and five are located in intron. We found that as chickenpox genetically increased, dementia risk increased based on an inverse-variance weighted analysis (ß = 0.070, 95% confidence interval [CI] for ß: 0.014-0.126; odds ratio [OR] = 1.073, 95% CI for OR: 1.015-1.134; p = 0.014) and weighted median (ß = 0.071, 95% CI for ß: 0.002-0.141; OR = 1.074, 95% CI for OR: 1.002-1.152; p = 0.045). Reverse MR analysis showed no causal effect of dementia on chickenpox. Our analysis suggests a causal effect of genetically increased chickenpox on dementia risk. Thus, chickenpox may be a potential risk factor for dementia.

Chickenpox and multiple sclerosis: A Mendelian randomization study.

Observational studies have suggested a suspected association between varicella-zoster virus (VZV) infection and multiple sclerosis (MS), but the connection has remained unclear. The aim of the present study is to evaluate the causal relationship between chickenpox which is caused by VZV infection and MS. We performed a two-sample Mendelian randomization analysis to investigate the association of chickenpox with MS using summary statistics from genome-wide association studies (GWAS). The GWAS summary statistics data for chickenpox was from the 23andMe cohort including 107 769 cases and 15 982 controls. A large summary of statistical data from the International Multiple Sclerosis Genetics Consortium (IMSGC) was used as the outcome GWAS data set, including 14 802 MS cases and 26 703 controls. We found evidence of a significant association between genetically predicted chickenpox and risk of MS (odds ratio [OR] = 35.27, 95% confidence interval [CI] = 22.97-54.17, p = 1.46E-59). Our findings provided evidence indicating a causal effect of chickenpox on MS. Further elucidations of this association and underlying mechanisms are needed for identifying feasible interventions to promote MS prevention.

Mendelian randomization study on causal association of IL-6 signaling with pulmonary arterial hypertension.

BACKGROUND: A recent Mendelian randomization (MR) did not support an effect of the lead interleukin-6 receptor (IL-6 R) variant on risk of pulmonary arterial hypertension (PAH). Thus, we used two sets of genetic instrumental variants (IVs) and publicly available PAH genome-wide association studies (GWAS) to reassess the genetic causal link between IL-6 signaling and PAH. METHODS: Six independent IL-6 signaling and 34 independent soluble IL-6 receptor (sIL-6 R) genetic IVs from recent MR reports and PAH GWAS including 162,962 European individuals were used to perform this two-sample MR study. RESULTS: We found that as IL-6 signaling genetically increased, the risk of PAH reduced using IVW (odds ratio [OR] = 0.023, 95% confidence interval [CI]: 0.0013-0.393; p = .0093) and weighted median (OR = 0.033, 95% CI: 0.0024-0.467; p = .0116). Otherwise, as sIL-6 R genetically increased, the risk of PAH increased using IVW (OR = 1.34, 95% CI: 1.16-1.56; p = .0001), weighted median (OR = 1.36, 95% CI: 1.10-1.68; p = .005), MR-Egger (OR = 1.43, 95% CI: 1.05-1.94; p = .03), and weighted mode (OR = 1.35, 95% CI for OR: 1.12-1.63; p = .0035). CONCLUSION: Our analysis suggested the causal link between genetically increased sIL-6 R and increased risk of PAH and between genetically increased IL-6 signaling and reduced risk of PAH. Thus, higher sIL-6 R levels may be a risk factor for patients with PAH, whereas higher IL-6 signaling may be a protective factor for patients with PAH.

Mendelian randomization study on the causal effects of COVID-19 on childhood intelligence.

Although individuals with coronavirus disease 2019 (COVID-19) are known to be at increased risk for other conditions resulting from pathogenic changes (including metaplastic or anaplastic) in the lungs and other organs and organ systems, it is still unknown whether COVID-19 affects childhood intelligence. The present two-sample Mendelian randomization study aims to identify the genetic causal link between COVID-19 and childhood intelligence. Four COVID-19 genetic instrumental variants (IVs) were chosen from the largest genome-wide association studies (GWAS) for COVID-19 (hospitalized vs. population) (6406 cases and 902 088 controls of European ancestry). The largest childhood intelligence GWAS (n = 12 441 individuals of European ancestry) was used to evaluate the effect of the identified COVID-19-associated genetic IVs on childhood intelligence. We found that as the genetic susceptibility to COVID-19 increased, childhood intelligence followed a decreasing trend, according to mr_egger (ß = -0.156; p = 0.601; odds ratio [OR] = 0.856; 95% confidence interval [CI]: 0.522-1.405), simple mode (ß = -0.126; p = 0.240; OR = 0.882; 95% CI: 0.745-1.044), and weighted mode (ß = -0.121; p = 0.226; OR = 0.886; 95% CI: 0.758-1.036) analyses. This trend was further demonstrated by the weighted median (ß = -0.134; p = 0.031; OR = 0.875; 95% CI: 0.774-0.988) and the inverse variance weighted (ß = -0.152; p = 0.004; OR = 0.859; 95% CI: 0.776-0.952). Our analysis suggests a causal link between genetically increased COVID-19 and decreased childhood intelligence. Thus, COVID-19 may be a risk factor for declines in childhood intelligence.

Gm40600 promotes CD4+ T-cell responses by interacting with Ahnak.

It is important to characterize novel proteins involved in T- and B-cell responses. Our previous study demonstrated that a novel protein, Mus musculus Gm40600, reduced the proliferation of Mus musculus plasmablast (PB)-like SP 2/0 cells and B-cell responses induced in vitro by LPS. In the present study, we revealed that Gm40600 directly promoted CD4+ T-cell responses to indirectly up-regulate B-cell responses. Importantly, we found that CD4+ T-cell responses, including T-cell activation and differentiation and cytokine production, were increased in Gm40600 transgenic (Tg) mice and were reduced in Gm40600 knockout (KO) mice. Finally, we demonstrated that Gm40600 promoted the Ahnak-mediated calcium signalling pathway by interacting with Ahnak to maintain a cytoplasmic lateral location of Ahnak in CD4+ T cells. Collectively, our data suggest that Gm40600 promotes CD4+ T-cell activation to up-regulate the B-cell response via interacting with Ahnak to promote the calcium signalling pathway. The results suggest that targeting Gm40600 may be a means to control CD4+ T-cell-related diseases.

Increased mTOR cancels out the effect of reduced Xbp-1 on antibody secretion in IL-1α-deficient B cells.

IL-1α in vitro promotes immunoglobulin secretion by inducing proliferation of mature B cells, whereas IL-1α deficiency has no effect on in vivo antibody production. However, the reason IL-1α deficiency does not reduce in vivo antibody production is still unclear. In this study, we found that similar as in vivo data, IL-1α deficiency did not affect antibody production in in vitro LPS-stimulated B cells. Surprisingly, LPS-stimulated IL-1α-/- B cells reduced a key antibody production-related transcription factor X-box binding protein 1 (Xbp-1) expression. Furthermore, we found that IL-1α deficiency up-regulated mTOR expression, which bypassed Xbp-1 for immunoglobulin secretion. Finally, we showed that Xbp-1 suppressed mTOR expression, whereas mTOR suppressed the activation of Xbp-1 promoter via JunB. Together, these data suggest that IL-1a deficiency reduced Xbp-1 and up-regulated mTOR. This may explain why IL-1α deficiency has no effect on antibody production.

CD19 regulates ADAM28-mediated Notch2 cleavage to control the differentiation of marginal zone precursors to MZ B cells.

As the first line of defence, marginal zone (MZ) B cells play principal roles in clearing blood-borne pathogens during infection and are over-primed in autoimmune diseases. However, the basic mechanisms underlying MZ B-cell development are still unclear. We found here that CD19 deficiency blocked the differentiation of marginal zone precursors (MZP) to MZ B cells, whereas CD19 expression in CD19-deficient MZP rescues MZ B-cell generation. Furthermore, CD19 regulates Notch2 cleavage by up-regulating ADAM28 expression in MZP. Finally, we found that CD19 suppressed Foxo1 expression to promote ADAM28 expression in MZP. These results suggest that CD19 controls the differentiation of MZP to MZ B cells by regulating ADAM28-mediated Notch2 cleavage. Thus, we demonstrated the basic mechanisms underlying the differentiation of MZP to MZ B cells.

Foxd3 suppresses interleukin-10 expression in B cells.

Interleukin-10-positive (IL-10+ ) regulatory B (Breg) cells play an important role in restraining excessive inflammatory responses by secreting IL-10. However, it is still unclear what key transcription factors determine Breg cell differentiation. Hence, we explore what transcription factor plays a key role in the expression of IL-10, a pivotal cytokine in Breg cells. We used two types of web-based prediction software to predict transcription factors binding the IL-10 promoter and found that IL-10 promoter had many binding sites for Foxd3. Chromatin immunoprecipitation PCR assay demonstrated that Foxd3 directly binds the predicted binding sites around the start codon upstream by -1400 bp. Further, we found that Foxd3 suppressed the activation of IL-10 promoter by using an IL-10 promoter report system. Finally, knocking out Foxd3 effectively promotes Breg cell production by up-regulating IL-10 expression. Conversely, up-regulated Foxd3 expression was negatively associated with IL-10+ Breg cells in lupus-prone MRL/lpr mice. Hence, our data suggest that Foxd3 suppresses the production of IL-10+ Breg cells by directly binding the IL-10 promoter. This study demonstrates the mechanism for Breg cell production and its application to the treatment of autoimmune diseases by regulating Foxd3 expression.

Mendelian randomization study on causal association of FAM210B with drug-induced lupus.

OBJECTIVE: Due to the complexity of drug-induced lupus (DIL) pathogenesis, more susceptibility factors need to be discovered. FAM210B is a new mitochondrial protein whose function has not been fully elucidated. This study will explore whether there is a correlation between FAM210B and the risk of DIL. METHODS: At first, we extracted three FAM210B genetic variants from the GTEx database (n = 948), and extracted their corresponding genome-wide association study (GWAS) summary statistics from DIL (101 DIL cases and 218691 controls). Then, we performed a Mendelian randomization (MR) study to evaluate the causal association of the expression of FAM210B with DIL using inverse-variance weighted (IVW), the weighted median, MR-Egger, and MR-PRESSO test. RESULTS: We successfully extracted three FAM210B single-nucleotide polymorphisms (SNPs) (rs116032784, rs34361943 and rs33923703) from the GTEx_Analysis_v8_eQTL data that can reduce FAM210B expression. The results of the MR analysis showed that genetically reduced expression of FAM210B was significantly associated with increased risk of DIL in European ancestry based on the IVW method (ß = 1.037, p = 0.001, odds ratio [OR] = 2.821, 95% confidence interval [CI]:1.495-5.322). CONCLUSION: MR analysis showed a causal relationship between FAM210B expression and the risk of DIL disease. Our results suggested that FAM210B may be a marker that can mark susceptibility of DIL in the future. It provides evidence for the study of DIL, but its specific mechanism of action in DIL needs to be further studied. Key Points •This is the first MR analysis to examine the association between FAM210B and DIL. •The findings of this study suggested that reduced FAM210B expression is associated with the increased risk of DIL. •FAM210B may be a marker that can mark susceptibility of DIL in the future.

Mendelian Randomization Study on the Putative Causal Effects of Omega-3 Fatty Acids on Low Back Pain.

Previous observational studies have suggested an important role of omega-3 in low back pain. In the present study, we used a two-sample Mendelian randomization (MR) study to identify the putative causal link between omega-3 and low back pain. A broadly used genome-wide association study (GWAS) (n = 8,866 individuals from European ancestry) was used to select plasma omega-3 genetic instrumental variables (IVs). A previously reported GWAS (4,863 cases and 74,589 controls from European ancestry) for low back pain were used to assess the effect of plasma omega-3 levels on low back pain. MR-egger_intercept, MR-PRESSO, MR_egger, and inverse variance weighted (IVW) in Cochran's Q-test were used to determine the pleiotropy and heterogeneity, respectively. MR-egger, weighted median, IVW, and weighted mode were used to perform MR analysis. Finally, the effect of a single nucleotide polymorphism (SNP) was used to test the SNP bias. We did not find a significant pleiotropy or heterogeneity of all six selected plasma omega-3 genetic IVs in low back pain GWAS. Expectedly, we found that as plasma omega-3 levels genetically increased, the risk of low back pain had a decreased trend using MR-egger (Beta = -0.593, p = 0.228; OR = 0.553) and weighted mode (Beta = -0.251, p = 0.281; OR = 0.778). This reduced trend was further proven by weighted median (Beta = -0.436, p = 0.025; OR = 0.646) and IVW (Beta = -0.366, p = 0.049; OR = 0.694). Our analysis suggested a putative causal link between genetically increased plasma omega-3 levels and the reduced risk of low back pain in European ancestries. Thus, the supplementation of omega-3 may be important for the prevention and treatment of low back pain.

Mendelian Randomization Study on Causal Association of Pyroglutamine with COVID-19.

BACKGROUND: Glutamine family amino acids such as glutamate, pyroglutamate, and glutamine have been shown to play important roles in COVID-19. However, it is still unclear about the role of pyroglutamate in COVID-19. Thus, we use a two-sample Mendelian randomization (MR) study to identify the genetic causal link between blood pyroglutamine levels and COVID-19 risk. METHODS: Pyroglutamine genetic instrumental variables (IVs) were chosen from the largest pyroglutamine-associated genome-wide association studies (GWAS). The largest COVID-19 GWAS dataset was employed to evaluate the causal link between blood pyroglutamine levels and COVID-19 risk using two-sample MR analysis. RESULTS: We found no significant pleiotropy or heterogeneity of pyroglutamine-associated genetic IVs in COVID-19 GWAS. Interestingly, we found that as pyroglutamine genetically increased, the risk of COVID-19 decreased using inverse variance weighted (IVW) (Beta = - 0.644, p = 0.003; OR = 0.525, 95% CI [0.346-0.798]) and weighted median (Beta = - 0.609, p = 0.013; OR = 0.544, 95% CI [0.337-0.878]). CONCLUSION: Our analysis suggests a causal link between genetically increased pyroglutamine and reduced risk of COVID-19. Thus, pyroglutamine may be a protective factor for patients with COVID-19.

Single-cell atlas of splenocytes reveals a critical role of a novel plasma cell‒specific marker Hspa13 in antibody class-switching recombination and somatic hypermutation.

Our previous study had shown that member 13 (Hspa13) of heat shock protein family A (Hsp70) promotes plasma cell (PC) production and antibody secretion. To further explore Hspa13 expression and function, we combined single-cell RNA-sequencing and antigen receptor lineage (BCR) analysis to characterize sheep red cell‒primed splenocytes. The single-cell transcriptional profiles revealed that Hspa13 is specifically and highly expressed in PCs. These results suggest that Hspa13 is a novel PC-specific marker. In terms of its function, we found that the CD19cre-mediated conditional knock-out (cKO) of Hspa13 reduced the expression of Ebi3 and IL-10 in PCs. Ebi3 and IL-10 are important factors in IL-4‒secreting type 2 helper T cell (Th2) activation and differentiation. As expected, we found that the Hspa13 cKO reduced IL‒4-expressing follicular helper T (Tfh2) cells. Finally, the single-cell antigen receptor analysis demonstrated that the Hspa13 cKO reduced the Aicda-mediated antibody class-switching recombination (CSR) and somatic hypermutation (SHM) in germinal centers (GCs) B cells. Altogether, the single-cell atlas of splenocytes revealed a critical indirect role for the novel PC-specific marker Hspa13 in CSR and SHM in GC B cells by promoting Ebi3 and IL-10 expression in PCs to induce IL-4-expressing Tfh2 cells. Further exploration of Hspa13 expression and function will provide valuable clues for how to use Hspa13 in the treatment of autoimmune diseases.

Mendelian randomization study on the causal effects of omega-3 fatty acids on rheumatoid arthritis.

OBJECTIVES: To resolve the ongoing debate on the role of plasma omega-3 fatty acids in rheumatoid arthritis (RA), we attempted to identify the association between omega-3 intake and the risk of RA. METHODS: We analyzed data from the largest genome-wide association study (GWAS) for omega-3 fatty acids (N = 114,999 of European ancestry) and RA (14,361 cases and 43,923 controls of European ancestry). Mendelian randomization-egger_intercept, MR-PRESSO, and Cochran's Q test were used to determine pleiotropy and heterogeneity. Egger, weighted median, inverse variance weighted (IVW), simple mode, and weighted mode were used to evaluate the causal association of plasma omega-3 levels on RA. RESULTS: We found no significant pleiotropy, heterogeneity, and bias among the omega-3 genetic instrumental variables (IVs) in RA GWAS datasets. MR analysis demonstrated that as omega-3 levels genetically increased, the risk of MS increased using MR-egger (Beta = 0.137, p = 0.037; OR = 1.146, 95% CI: [1.014, 1.296]), weighted median (Beta = 0.162, p = 0.001; OR = 1.176, 95% CI: [1.070, 1.292]), IVW (Beta = 0.102, p = 0.025; OR = 1.108, 95% CI: [1.013, 1.211]), simple mode (Beta = 0.219, p = 0.149; OR = 1.245, 95% CI: [0.931, 1.665]), and weighted mode (Beta = 0.146, p = 0.006; OR = 1.157, 95% CI: [1.051, 1.274]). CONCLUSIONS: Our analysis suggested a causal association between genetically increased plasma omega-3 levels and the increased risk of RA in populations with European ancestry. Thus, to reduce the risk of RA, those of European descent should reduce omega-3 intake. Key Points • No significant pleiotropy or heterogeneity among the omega-3 genetic IVs in RA GWAS datasets. • Genetically increased plasma omega-3 levels enhanced the risk of RA in European lineages.

The E3 ubiquitin ligase Itch is required for B-cell development.

The E3 ubiquitin ligase Itch interacts with Foxo1 and targets it for ubiquitination and degradation during follicular helper T-cell differentiation, whereas the transcription factor Foxo1 plays a critical role in B-cell development. Thus, we proposed that Itch mediates B-cell differentiation. Unexpectedly, we found that Itch deficiency downregulated Foxo1 expression in B cells. Itch cKO (conditional knock out in B cells) mice had fewer pro-B cells in the bone marrow, more small resting IgM-IgD-B cells in the periphery, and lower B-cell numbers in the lymph nodes through decreased Foxo1-mediated IL-7Rα, RAG, and CD62L expression, respectively. Importantly, Itch deficiency reduced Foxo1 mRNA expression by up-regulating JunB-mediated miR-182. Finally, Foxo1 negatively regulated JunB expression by up-regulating Itch. Thus, we have identified a novel regulatory axis between Itch and Foxo1 in B cells, suggesting that Itch is essential for B-cell development.

Anti­IL­39 (IL­23p19/Ebi3) polyclonal antibodies ameliorate autoimmune symptoms in lupus­like mice.

The interleukin (IL)­12 family cytokines have been examined as therapeutic targets in the treatment of several autoimmune diseases. Our previous study showed that a novel IL­12 family cytokine, IL­39 (IL­23p19/Ebi3) mediates inflammation in lupus­like mice. In the present study, the effect of anti­mouse IL­39 polyclonal antibodies on autoimmune symptoms in lupus­like mice was investigated. Rabbit anti­mouse IL­39 polyclonal antibodies were produced by immunization with recombinant mouse IL­39, and purified using protein A chromatography. These antibodies were subsequently used to treat lupus­like mice. Flow cytometry, captured images, ELISA and H&E staining were used to determine the effect of anti­IL­39 polyclonal antibodies on inflammatory cells, autoantibody titers, proteinuria, infiltrating inflammatory cells and the structure of the glomerular region. The anti­IL­39 polyclonal antibodies effectively reduced the numbers of inflammatory cells, splenomegaly, autoantibody titers, proteinuria, infiltrating inflammatory cells, and restored the structure of the glomerular region in MRL/lpr mice. Taken together, these results suggested that anti­IL­39 polyclonal antibodies ameliorated autoimmune symptoms in lupus­like mice. Therefore, IL­39 may be used as a possible target for the treatment of systemic lupus erythematosus.

B cells regulate thymic CD8+T cell differentiation in lupus-prone mice.

Previous studies have shown that under normal physiological conditions thymic B cells play a critical function in T cell negative selection. We tested the effect of thymic B cells on thymic T-cell differentiation in autoimmune diseases including systemic lupus erythematosus (SLE). We found that thymic B cells and CD8- CD4+ and CD4-CD8+T cells increased, whereas CD4+CD8+T cells decreased in lupus-prone mice. Once B cells were reduced, the change was reversed. Furthermore, we found that B cells blocked thymic immature single positive (ISP) CD4-CD8+CD3lo/-RORγt- T cells progression into CD4+CD8+T cells. Interestingly, we found a novel population of thymic immature T cells (CD4-CD8+CD3loRORγt+) that were induced into mature CD4-CD8+CD3+RORγt+T cells by B cells in lupus-prone mice. Importantly, we found that IgG, produced by thymic B cells, played a critical role in the differentiation of thymic CD8+ISP and mature RORγt+CD8+ T cells in lupus-prone mice. In conclusion, B cells blocked the differentiation from thymic CD8+ISP and induced the differentiation of a novel immature CD4-CD8+CD3loRORγt+T cells into mature RORγt+CD8+ T cells by secreting IgG antibody in lupus-prone mice.