Schizophrenia and Rheumatoid Arthritis Genetic Scenery: Potential Non-HLA Genes Involved in Both Diseases Relationship.

Background: The link between rheumatoid arthritis (RA) and schizophrenia (SZ) has long been a hot topic of deliberation among scientists from various fields. Especially when it comes to genetics, the connection between RA and SZ is still up for discussion, as can be observed in this study. The HLA genes are the most disputed in identifying a connection between the two diseases, but a more thorough investigation of other genes that may be ignored could yield something even more interesting. Thus, finding the genes responsible for this long-sought relationship will necessitate looking for them. Materials and Methods: Shared and overlapped associated genes involved between SZ and RA were extracted from four databases. The overlapping genes were examined using Database for Annotation, Visualization and Integrated Discovery (DAVID) and InnateDB to search the pertinent genes that concatenate between these two disorders. Results: A total of 91 overlapped genes were discovered, and that 13 genes, divided into two clusters, showed a similarity in function, suggesting that they may serve as an important meeting point. FCGR2A, IL18R, BTNL2, AGER, and CTLA4 are five non-HLA genes related to the immune system, which could lead to new discoveries about the connection between these two disorders. Conclusion: An in-depth investigation of these functionally comparable non-HLA genes that overlap could reveal new interesting information in both diseases. Understanding the molecular and immune-related aspects of RA and SZ may shed light on their etiology and inform future research on targeted treatment strategies.

BTN3A1 expressed in cervical cancer cells promotes Vγ9Vδ2 T cells exhaustion through upregulating transcription factors NR4A2/3 downstream of TCR signaling.

BACKGROUND: Clinical trials have shown that immunotherapy based on Vγ9Vδ2 T cells (Vδ2 T cells) is safe and well-tolerated for various cancers including cervical cancer (CC), but its overall treatment efficacy remains limited. Therefore, exploring the mechanisms underlying the suboptimal efficacy of Vδ2 T cell-based cancer immunotherapy is crucial for enabling its successful clinical translation. METHODS: Tumor samples from CC patients and CC cell line-derived xenograft (CDX) mice were analyzed using flow cytometry to examine the exhausted phenotype of tumor-infiltrating Vδ2 T cells. The interrelationship between BTN3A1 expression and Vδ2 T cells in CC, along with their correlation with patient prognosis, was analyzed using data from The Cancer Genome Atlas (TCGA) database. CC cell lines with BTN3A1 knockout (KO) and overexpression (OE) were constructed through lentivirus transduction, which were then co-cultured with expanded Vδ2 T cells, followed by detecting the function of Vδ2 T cells using flow cytometry. The pathways and transcription factors (TFs) related to BTN3A1-induced Vδ2 T cells exhaustion and the factors affecting BTN3A1 expression were identified by RNA-seq analysis, which was confirmed by flow cytometry, Western Blot, and gene manipulation. RESULTS: Tumor-infiltrating Vδ2 T cells exhibited an exhausted phenotype in both CC patients and CDX mice. BTN3A1 expressed in CC is highly enhancing exhaustion markers, while reducing the secretion of effector molecules in Vδ2 T cells. Blocking TCR or knocking down nuclear receptor subfamily 4 group A (NR4A) 2/3 can reverse BTN3A1-induced exhaustion in Vδ2 T cells. On the other hand, IFN-γ secreted by Vδ2 T cells promoted the expression of BTN3A1 and PD-L1. CONCLUSIONS: Through binding γδ TCRs, BTN3A1 expressed on tumor cells, which is induced by IFN-γ, can promote Vδ2 T cells to upregulate the expression of TFs NR4A2/3, thereby affecting their activation and expression of exhaustion-related molecules in the tumor microenvironment (TME). Therefore, targeting BTN3A1 might overcome the immunosuppressive effect of the TME on Vδ2 T cells in CC.

BTN2A1 targeting reprograms M2-like macrophages and TAMs via SYK and MAPK signaling.

Tumor-associated macrophages (TAMs), often adopting an immunosuppressive M2-like phenotype, correlate with unfavorable cancer outcomes. Our investigation unveiled elevated expression of the butyrophilin (BTN)2A1 in M2-like TAMs across diverse cancer types. We developed anti-BTN2A1 monoclonal antibodies (mAbs), and notably, one clone demonstrated a robust inhibitory effect on M2-like macrophage differentiation, inducing a shift toward an M1-like phenotype both in vitro and ex vivo in TAMs from patients with cancer. Macrophages treated with this anti-BTN2A1 mAb exhibited enhanced support for T cell proliferation and interferon-gamma (IFNγ) secretion. Mechanistically, BTN2A1 engagement induced spleen tyrosine kinase (SYK) recruitment, leading to sequential SYK and extracellular signal-regulated kinase (ERK) phosphorylation. Inhibition of SYK or ERK phosphorylation abolished M2 reprogramming upon BTN2A1 engagement. Our findings, derived from an analysis of macrophages from healthy donors and human tumors, underscore the pivotal role of BTN2A1 in immunosuppressive macrophage differentiation and function, offering potential applications in cancer immunotherapy.

Overcoming limitations for antibody-based therapies targeting γδ T (Vg9Vd2) cells.

Therapeutic strategies targeting non-adaptive immune cells are currently in clinical development. γδT cells are a small subtype of T cells (1-10% of total T cells) that mediate their effector function without the necessity of the antigen presenting machinery, and also share functional properties with innate cells. Among the different γδT subtypes, antibodies against Vγ9Vδ2T have reported signs of clinical efficacy in early clinical studies. In this review we describe the biology of this subtype of non-conventional T cells and provide insights into the mechanism of action of novel antibodies that activate these cells. We will focus on antibodies targeting the BTN3A ligand and bi-specific γδT cell engagers. We will review in detail the advantages of these strategies including the potential for overcoming mechanisms of resistance to check point inhibitors, or the much more adequate safety profile compared with agents activating classical T cells. Limitations identified during the first studies in humans and strategies to overcome them will be revised and discussed. Finally, clinical options for future clinical development will be suggested.

A Ménage à trois: NLRC5, immunity, and metabolism.

The nucleotide-binding and oligomerization domain-like receptors (NLRs) NLR family CARD domain-containing protein 5 (NLRC5) and Class II Major Histocompatibility Complex Transactivator (CIITA) are transcriptional regulators of major histocompatibility complex (MHC) class I and class II genes, respectively. MHC molecules are central players in our immune system, allowing the detection of hazardous 'non-self' antigens and, thus, the recognition and elimination of infected or transformed cells from the organism. Recently, CIITA and NLRC5 have emerged as regulators of selected genes of the butyrophilin (BTN) family that interestingly are located in the extended MHC locus. BTNs are transmembrane proteins exhibiting structural similarities to B7 family co-modulatory molecules. The family member BTN2A2, which indeed contributes to the control of T cell activation, was found to be transcriptionally regulated by CIITA. NLRC5 emerged instead as an important regulator of the BTN3A1, BTN3A2, and BTN3A3 genes. Together with BTN2A1, BTN3As regulate non-conventional Vγ9Vδ2 T cell responses triggered by selected metabolites of microbial origin or accumulating in hematologic cancer cells. Even if endogenous metabolites conform to the canonical definition of 'self', metabolically abnormal cells can represent a danger for the organism and should be recognized and controlled by immune system cells. Collectively, new data on the role of NLRC5 in the expression of BTN3As link the mechanisms regulating canonical 'non-self' presentation and those marking cells with abnormal metabolic configurations for immune recognition, an evolutionary parallel that we discuss in this perspective review.

Vγ9Vδ2 T cells recognize butyrophilin 2A1 and 3A1 heteromers.

Butyrophilin (BTN) molecules are emerging as key regulators of T cell immunity; however, how they trigger cell-mediated responses is poorly understood. Here, the crystal structure of a gamma-delta T cell antigen receptor (γδTCR) in complex with BTN2A1 revealed that BTN2A1 engages the side of the γδTCR, leaving the apical TCR surface bioavailable. We reveal that a second γδTCR ligand co-engages γδTCR via binding to this accessible apical surface in a BTN3A1-dependent manner. BTN2A1 and BTN3A1 also directly interact with each other in cis, and structural analysis revealed formation of W-shaped heteromeric multimers. This BTN2A1-BTN3A1 interaction involved the same epitopes that BTN2A1 and BTN3A1 each use to mediate the γδTCR interaction; indeed, locking BTN2A1 and BTN3A1 together abrogated their interaction with γδTCR, supporting a model wherein the two γδTCR ligand-binding sites depend on accessibility to cryptic BTN epitopes. Our findings reveal a new paradigm in immune activation, whereby γδTCRs sense dual epitopes on BTN complexes.

Synthesis and evaluation of (E)-4-hydroxy-3-methyl-but-2-enyl diphosphate analogs as competitive partial agonists of butyrophilin 3A1.

Phosphoantigens (pAgs) induce conformational changes after binding to the intracellular region of BTN3A1 which result in its clustering with BTN2A1, forming an activating ligand for the Vγ9Vδ2 T cell receptor. Here, we designed a small panel of bulky analogs of the prototypical pAg (E)-4-hydroxy-3-methyl-but-2-enyl diphosphate (HMBPP) that contain an aromatic ring attached to the C-3 position in place of methyl group. These compounds bind with high affinity to BTN3A1 but fail to fully support its interaction with BTN2A1 and only partially trigger T cell activation relative to HMBPP. Furthermore, they can compete with HMBPP for cellular binding to BTN3A1 and reduce the cellular response to HMBPP, a classic partial agonist phenotype. Trifluoromethyl analog 6e was the weakest agonist but the strongest inhibitor of HMBPP ELISA response. Our study provides a rationale for the mode of action of pAg-induced γδ T cell activation and provides insights into other naturally occurring BTN proteins and their respective ligands.

High expression of BTN3A1 is associated with clinical and immunological characteristics and predicts a poor prognosis in advanced human gliomas.

Introduction: Gliomas represent the most prevalent and aggressive tumors within the central nervous system. Despite the current standard treatments, the median survival time for glioblastoma patients remains dismal, hovering around 14 months. While attempts have been made to inhibit the PD-1/PD-L1 and CTLA-4/CD80-CD86 axes through immunotherapy, the outcomes have yet to demonstrate significant efficacy. The immune checkpoint Butyrophilin 3A1 (BTN3A1) can either be involved in advantageous or detrimental function depending on the cancer type. Methods: In our study, we utilized a Moroccan cohort to delve into the role of BTN3A1 in gliomas. A transcriptomic analysis was conducted on 34 patients, which was then corroborated through a protein analysis in 27 patients and validated using the TCGA database (n = 667). Results: Our results revealed an elevated expression of BTN3A1 in glioblastoma (grade 4), as evidenced in both the TCGA database and our cohort of Moroccan glioma patients. Within the TCGA cohort, BTN3A1 expression was notably higher in patients with wild-type IDH. We observed a positive correlation between BTN3A1 expression and immune infiltration of B cells, CD8+ T cells, naive CD4+ T cells, and M2 macrophages. Patients exhibiting increased BTN3A1 expression also presented elevated levels of TGF-ß, IL-10, and TIM-3 compared to those with reduced BTN3A1 expression. Notably, patients with high BTN3A1 expression were associated with a poorer prognosis than their counterparts with lower expression. Conclussion: Our findings suggest that BTN3A1 might promote the establishment of an immunosuppressive microenvironment. Consequently, targeting BTN3A1 could offer novel therapeutic avenues for the management of advanced gliomas.

From immunomodulation to therapeutic prospects: Unveiling the biology of butyrophilins in cancer.

Butyrophilin (BTN) proteins are a type of membrane protein that belongs to the Ig superfamily. They exhibit a high degree of structural similarity to molecules in the B7 family. They fulfill a complex function in regulating immune responses, including immunomodulatory roles, as they influence γδ T cells. The biology of BTN molecules indicates that they are capable of inhibiting the immune system's ability to detect antigens within tumors. A dynamic association between BTN molecules and cellular surfaces is also recognized in specific contexts, influencing their biology. Notably, the dynamism of BTN3A1 is associated with the immunosuppression of T cells or the activation of Vγ9Vδ2 T cells. Cancer immunotherapy relies heavily on T cells to modulate immune function within the intricate interaction of the tumor microenvironment (TME). A significant interaction between the TME and antitumor immunity involves the presence of BTN, which should be taken into account when developing immunotherapy. This review explores potential therapeutic applications of BTN molecules, based on the current understanding of their biology.

Milk Fat Globule Proteins Are Relevant Bovine Milk Allergens in Patients with α­Gal Syndrome.

Alpha-gal syndrome (AGS) is a mammalian meat allergy associated with tick bites and specific IgE to the oligosaccharide galactose-α-1,3-galactose (α-gal). Recent studies have shown that 10-20% of AGS patients also react to the dairy proteins. Considering the already described role of the meat lipid fraction in AGS manifestations, the aim of this work has been to investigate whether the milk fat globule proteins (MFGPs) could be involved in AGS. The MFGPs are extracted and their recognition by the IgE of AGS patients is proved through immunoblotting experiments. The identification of the immunoreactive proteins by LC-HRMS analysis allows to demonstrate for the first time that butyrophillin, lactadherin, and xanthine oxidase (XO) are α-gal glycosylated. The role of xanthine oxidase seems to be prevalent since it is highly recognized by both the anti-α-gal antibody and AGS patient sera. The results obtained in this study provide novel insights in the characterization of α-Gal carrying glycoproteins in bovine milk, supporting the possibility that milk, especially in its whole form, may give reactions in AGS patients. Although additional factors are probably associated with the clinical manifestations, the avoidance of milk and milk products should be considered in individuals with AGS showing symptoms related to milk consumption.

Dissecting the shared genetic landscape of anxiety, depression, and schizophrenia.

BACKGROUND: Numerous studies highlight the genetic underpinnings of mental disorders comorbidity, particularly in anxiety, depression, and schizophrenia. However, their shared genetic loci are not well understood. Our study employs Mendelian randomization (MR) and colocalization analyses, alongside multi-omics data, to uncover potential genetic targets for these conditions, thereby informing therapeutic and drug development strategies. METHODS: We utilized the Consortium for Linkage Disequilibrium Score Regression (LDSC) and Mendelian Randomization (MR) analysis to investigate genetic correlations among anxiety, depression, and schizophrenia. Utilizing GTEx V8 eQTL and deCODE Genetics pQTL data, we performed a three-step summary-data-based Mendelian randomization (SMR) and protein-protein interaction analysis. This helped assess causal and comorbid loci for these disorders and determine if identified loci share coincidental variations with psychiatric diseases. Additionally, phenome-wide association studies, drug prediction, and molecular docking validated potential drug targets. RESULTS: We found genetic correlations between anxiety, depression, and schizophrenia, and under a meta-analysis of MR from multiple databases, the causal relationships among these disorders are supported. Based on this, three-step SMR and colocalization analyses identified ITIH3 and CCS as being related to the risk of developing depression, while CTSS and DNPH1 are related to the onset of schizophrenia. BTN3A1, PSMB4, and TIMP4 were identified as comorbidity loci for both disorders. Molecules that could not be determined through colocalization analysis were also presented. Drug prediction and molecular docking showed that some drugs and proteins have good binding affinity and available structural data. CONCLUSIONS: Our study indicates genetic correlations and shared risk loci between anxiety, depression, and schizophrenia. These findings offer insights into the underlying mechanisms of their comorbidities and aid in drug development.

Vγ9Vδ2 T-cells Are Potent Inhibitors of SARS-CoV-2 Replication and Represent Effector Phenotypes in Patients With COVID-19.

Vγ9Vδ2 T cells play a key role in the innate immune response to viral infections through butyrophilin 3A (BTN3A). Here, we report blood Vγ9Vδ2 T cells decreased in clinically mild COVID-19 compared to healthy volunteers, and this was maintained up to 28 days and in the recovery period. Terminally differentiated Vγ9Vδ2 T cells tended to be enriched on the day of diagnosis, 28 days after, and during the recovery period. These cells showed cytotoxic and inflammatory activities following anti-BTN3A activation. BTN3A upregulation and Vγ9Vδ2 T-cell infiltration were observed in a lung biopsy from a fatal SARS-CoV-2 infection. In vitro, SARS-CoV-2 infection increased BTN3A expression in macrophages and lung cells that enhanced the anti-SARS-CoV-2 Vγ9Vδ2 T-cell cytotoxicity and interferon-γ and tumor necrosis factor-α. Increasing concentrations of anti-BTN3A lead to viral replication inhibition. Altogether, we report Vγ9Vδ2 T cells are important in the immune response against SARS-CoV-2 infection and activation by anti-BTN3A antibody may enhance their response. Clinical Trials Registration. NCT04816760.

Ex vivo expansion and activation of Vγ9Vδ2 T cells by CELMoDs in combination with zoledronic acid.

As multiple myeloma (MM) progresses, immune effector cells decrease in number and function and become exhausted. This remains an insurmountable clinical issue that must be addressed by development of novel modalities to revitalize anti-MM immunity. Human Vγ9Vδ2 T (Vδ2+ γδ T) cells serve as the first line of defense against pathogens as well as tumors and can be expanded ex vivo from peripheral blood mononuclear cells (PBMCs) upon treatment with amino-bisphosphonates in combination with IL-2. Here, we demonstrated that next-generation immunomodulators called cereblon E3 ligase modulators (CELMoDs), as well as lenalidomide and pomalidomide, expanded Th1-like Vδ2+ γδ T cells from PBMCs in the presence of zoledronic acid (ZA). However, the expansion of Th1-like Vδ2+ γδ T cells by these immunomodulatory drugs was abolished under IL-2 blockade, although IL-2 production was induced in PBMCs. BTN3A1 triggers phosphoantigen presentation to γδ T-cell receptors and is required for γδ T-cell expansion and activation. ZA but not these immunomodulatory drugs upregulated BTN3A1 in monocytes. These results suggest that immunomodulatory drugs and ZA have cooperative roles in expansion of Th1-like Vδ2+ γδ T cells, and provide the important knowledge for clinical application of human Vδ2+ γδ T cells as effector cells.

BTN1A1 is a novel immune checkpoint mutually exclusive to PD-L1.

BACKGROUND: While Programmed cell death protein 1 (PD-1)/programmed cell death-ligand 1 (PD-L1) blockade is a potent antitumor treatment strategy, it is effective in only limited subsets of patients with cancer, emphasizing the need for the identification of additional immune checkpoints. Butyrophilin 1A1 (BTN1A1) has been reported to exhibit potential immunoregulatory activity, but its ability to function as an immune checkpoint remains to be systematically assessed, and the mechanisms underlying such activity have yet to be characterized. METHODS: BTN1A1 expression was evaluated in primary tumor tissue samples, and its ability to suppress T-cell activation and T cell-dependent tumor clearance was examined. The relationship between BTN1A1 and PD-L1 expression was further characterized, followed by the development of a BTN1A1-specific antibody that was administered to tumor-bearing mice to test the amenability of this target to immune checkpoint inhibition. RESULTS: BTN1A1 was confirmed to suppress T-cell activation in vitro and in vivo. Robust BTN1A1 expression was detected in a range of solid tumor tissue samples, and BTN1A1 expression was mutually exclusive with that of PD-L1 as a consequence of its inhibition of Janus-activated kinase/signal transducer and activator of transcription signaling-induced PD-L1 upregulation. Antibody-mediated BTN1A1 blockade suppressed tumor growth and enhanced immune cell infiltration in syngeneic tumor-bearing mice. CONCLUSION: Together, these results confirm that the potential of BTN1A1 is a bona fide immune checkpoint and a viable immunotherapeutic target for the treatment of individuals with anti-PD-1/PD-L1 refractory or resistant disease, opening new avenues to improving survival outcomes for patients with a range of cancers.

Unsynchronized butyrophilin molecules dictate cancer cell evasion of Vγ9Vδ2 T-cell killing.

Vγ9Vδ2 T cells are specialized effector cells that have gained prominence as immunotherapy agents due to their ability to target and kill cells with altered pyrophosphate metabolites. In our effort to understand how cancer cells evade the cell-killing activity of Vγ9Vδ2 T cells, we performed a comprehensive genome-scale CRISPR screening of cancer cells. We found that four molecules belonging to the butyrophilin (BTN) family, specifically BTN2A1, BTN3A1, BTN3A2, and BTN3A3, are critically important and play unique, nonoverlapping roles in facilitating the destruction of cancer cells by primary Vγ9Vδ2 T cells. The coordinated function of these BTN molecules was driven by synchronized gene expression, which was regulated by IFN-γ signaling and the RFX complex. Additionally, an enzyme called QPCTL was shown to play a key role in modifying the N-terminal glutamine of these BTN proteins and was found to be a crucial factor in Vγ9Vδ2 T cell killing of cancer cells. Through our research, we offer a detailed overview of the functional genomic mechanisms that underlie how cancer cells escape Vγ9Vδ2 T cells. Moreover, our findings shed light on the importance of the harmonized expression and function of gene family members in modulating T-cell activity.

The B7:CD28 family and friends: Unraveling coinhibitory interactions.

Immune responses must be tightly regulated to ensure both optimal protective immunity and tolerance. Costimulatory pathways within the B7:CD28 family provide essential signals for optimal T cell activation and clonal expansion. They provide crucial inhibitory signals that maintain immune homeostasis, control resolution of inflammation, regulate host defense, and promote tolerance to prevent autoimmunity. Tumors and chronic pathogens can exploit these pathways to evade eradication by the immune system. Advances in understanding B7:CD28 pathways have ushered in a new era of immunotherapy with effective drugs to treat cancer, autoimmune diseases, infectious diseases, and transplant rejection. Here, we discuss current understanding of the mechanisms underlying the coinhibitory functions of CTLA-4, PD-1, PD-L1:B7-1 and PD-L2:RGMb interactions and less studied B7 family members, including HHLA2, VISTA, BTNL2, and BTN3A1, as well as their overlapping and unique roles in regulating immune responses, and the therapeutic potential of these insights.

N-terminal ectodomain of BTNL2 inhibits T cell activation via a non-canonical interaction with its putative receptor that results in a delayed progression of DSS-induced ulcerative colitis.

Butyrophilin-like 2 (BTNL2) is a T cell inhibitory molecule that interacts with unknown binding partners to modulate the immune response in a number of inflammatory and autoimmune diseases. In this study, we found that the inhibitory effects of BTNL2 on T cell activation and effector functions can be executed by its N-terminal IgV domain (BTNL2 IgV1) alone. Structure-guided mutation of key residues on BTNL2 IgV1 based on known receptor-ligand interfaces involving immunoglobulin superfamily members revealed that BTNL2 uses a non-canonical binding interface with its putative receptor. A high avidity BTNL2 IgV1 probe revealed that in an inducible model of ulcerative colitis, severe colitis was accompanied by a selective enrichment of BTNL2-receptor expressing effector-memory CD4+ and CD8+ T cells in the Peyer's patches. Intraperitoneal administration of BTNL2 IgV1 resulted in a significant delay in the progression of DSS-induced colitis and also showed reduced activation of the BTNL2-receptor-expressing T cells in the Peyer's patches. Thus, this study demonstrates that the BTNL2-receptor-expressing T cells in the Peyer's patches participate in the disease pathogenesis and can serve as a novel therapeutic target in ulcerative colitis, which can be modulated by BTNL2 IgV1.

Synergistic effects of BTN3A1, SHP2, CD274, and STAT3 gene polymorphisms on the risk of systemic lupus erythematosus: a multifactorial dimensional reduction analysis.

OBJECTIVE: Systemic lupus erythematosus is a complex autoimmune disorder, and evidence supports the significance of genetic polymorphisms in SLE genetic susceptibility. The aim of this study was to assess the effects of BTN3A1 (butyrophilin 3A1), SHP2 (Src homology-2 containing protein tyrosine phosphatase), CD274 (programmed cell death 1 ligand 1), and STAT3 (signal transducer-activator of transcription 3) gene interactions on SLE risk. MATERIALS AND METHODS: Two hundred and ninety patients diagnosed with SLE and 370 healthy controls were recruited. A multifactor dimensionality reduction (MDR) approach was used to determine the epistasis among single nucleotide polymorphisms (SNPs) on the BTN3A1 (rs742090), SHP2 (rs58116261), CD174 (rs702275), and STAT3 (rs8078731) genes. The best risk prediction model was identified in terms of precision and cross-validation consistency. RESULTS: Allele A and genotype AA were negatively related to genetic susceptibility of SLE for BTN3A1 rs742090 (OR = 0.788 (0.625-0.993), P = 0.044; OR = 0.604 (0.372-0.981), P = 0.040). For STAT3 rs8078731, allele A and genotype AA were positively related to the risk of SLE (OR = 1.307 (1.032-1.654), P = 0.026; OR = 1.752 (1.020-3.010), P = 0.041). MDR analysis revealed the most significant interaction between BTN3A1 rs742090 and SHP2 rs58116261. The best risk prediction model was a combination of BTN3A1 rs742090, SHP2 rs58116261, and STAT3 rs8078731 (accuracy = 0.5866, consistency = 10/10, OR = 1.9870 (1.5964-2.4731), P = 0.001). CONCLUSION: These data indicate that risk prediction models formed by gene interactions (BTN3A1, SHP2, STAT3) can identify susceptible populations of SLE. Key Points • BTN3A1 rs742090 polymorphism was a protective factor for systemic lupus erythematosus, while STAT3 rs8078731 polymorphism was a risk factor. • There was a strong synergistic effect of BTN3A1 rs742090 and SHP2 rs58116261, and interaction among BTN3A1 rs742090, SHP2 rs58116261, and STAT3 rs8078731 constructed the best model to show association with SLE risk.