• Biomarkers
• Genetic markers
• Multiple Myeloma
• Personalized therapy
• Polymorphisms
• Treatment outcomes

• Humans
• Multiple Myeloma/drug therapy
• Multiple Myeloma/genetics
• Multiple Myeloma/etiology
• Multiple Myeloma/mortality
• Proteasome Inhibitors/therapeutic use
• Proteasome Inhibitors/pharmacology
• Treatment Outcome
• Polymorphism, Genetic
• Immunomodulating Agents/therapeutic use
• Immunomodulating Agents/pharmacology
• Biomarkers, Tumor

• Humans
• Ipilimumab/adverse effects
• Ipilimumab/therapeutic use
• CTLA-4 Antigen/genetics
• Melanoma/drug therapy
• Melanoma/genetics
• Melanoma/mortality
• Polymorphism, Single Nucleotide
• Male
• Female
• Middle Aged
• Aged
• Neoplasm Staging
• Genotype
• Adult
• Aged, 80 and over
• Antineoplastic Combined Chemotherapy Protocols/therapeutic use
• Antineoplastic Combined Chemotherapy Protocols/adverse effects
• Treatment Outcome

• Adult
• Female
• Humans
• Male
• Middle Aged
• Case-Control Studies
• CTLA-4 Antigen/genetics
• Genetic Predisposition to Disease
• Genotype
• Haplotypes
• Hepatitis A Virus Cellular Receptor 2/genetics
• Polymorphism, Single Nucleotide
• Programmed Cell Death 1 Receptor/genetics
• Tuberculosis/genetics

• Tao Yuan General Hospital, Ministry of Health and Welfare
• Ministry of Health and Welfare

• CTLA-4
• Polymorphism
• Psychiatric disorders
• Schizophrenia
• Systematic review
• mRNA expression

• Humans
• CTLA-4 Antigen/genetics
• Genetic Predisposition to Disease
• Polymorphism, Single Nucleotide
• Schizophrenia/genetics

• -318 c/t polymorphism
• ctla-4
• immunoregulatory molecule
• japanese
• urothelial cancer

• Graves’ ophthalmopathy
• bio-function
• common
• rheumatoid arthritis
• single-nucleotide polymorphisms
• systemic lupus erythematosus

• CMRPG3M0571 Chang Gung Memorial Hospital
• 110-2320-B-182A-007 Ministry of Science and Technology

• CTLA4
• biomarker
• colorectal cancer
• immune tumoral evasion
• immunotherapy

• CTLA4 polymorphisms
• bone marrow microenvironment
• cytogenetics and molecular genetics
• immune checkpoint
• multiple myeloma

Multiple sclerosis (MS) is an autoimmune neurodegenerative disorder of the central nervous system that presents heterogeneous clinical manifestations and course. It has been shown that different immune checkpoints, including Cytotoxic T-Lymphocyte Antigen 4 (CTLA-4), can be involved in the pathogenesis of MS. CTLA-4 is a critical regulator of T-cell homeostasis and self-tolerance and represents a key inhibitor of autoimmunity. In this scopingreview, we resume the current preclinical and clinical studies investigating the role of CTLA-4 in MS with different approaches. While some of these studies assessed the expression levels of CTLA-4 on T cells by comparing MS patients with healthy controls, others focused on the evaluation of the effects of common MS therapies on CTLA-4 modulation or on the study of the CTLA-4 blockade or deficiency in experimental autoimmune encephalomyelitis models. Moreover, other studies in this field aimed to discover if the CTLA-4 gene might be involved in the predisposition to MS, whereas others evaluated the effects of treatment with CTLA4-Ig in MS. Although these results are of great interest, they are often conflicting. Therefore, further studies are needed to reveal the exact mechanisms underlying the action of a crucial immune checkpoint such as CTLA-4 in MS to identify novel immunotherapeutic strategies for MS patients.

• Animals
• Autoimmunity/genetics
• CTLA-4 Antigen/genetics
• Encephalomyelitis, Autoimmune, Experimental/genetics
• Encephalomyelitis, Autoimmune, Experimental/pathology
• Humans
• Multiple Sclerosis/drug therapy
• Multiple Sclerosis/genetics
• T-Lymphocytes

Type 1 diabetes (T1D) is an autoimmune disease that develops in the interplay between genetic and environmental factors. A majority of individuals who develop T1D have a HLA make up, that accounts for 50% of the genetic risk of disease. Besides these HLA haplotypes and the insulin region that importantly contribute to the heritable component, genome-wide association studies have identified many polymorphisms in over 60 non-HLA gene regions that also contribute to T1D susceptibility.

Combining the risk genes in a score (T1D-GRS), significantly improved the prediction of disease progression in autoantibody positive individuals. Many of these minor-risk SNPs are associated with immune genes but how they influence the gene and protein expression and whether they cause functional changes on a cellular level remains a subject of investigation. A positive correlation between the genetic risk and the intensity of the peripheral autoimmune response was demonstrated both for HLA and non-HLA genetic risk variants. We also observed epigenetic and genetic modulation of several of these T1D susceptibility genes in dendritic cells (DCs) treated with vitamin D3 and dexamethasone to acquire tolerogenic properties as compared to immune activating DCs (mDC) illustrating the interaction between genes and environment that collectively determines risk for T1D. A notion that targeting such genes for therapeutic modulation could be compatible with correction of the impaired immune response, inspired us to review the current knowledge on the immune-related minor risk genes, their expression and function in immune cells, and how they may contribute to activation of autoreactive T cells, Treg function or β-cell apoptosis, thus contributing to development of the autoimmune disease.

• Tregs
• immunoregulation
• risk gene variants
• tolerogenic dendritic cells
• type 1 diabetes
• vitamin D

• Antibody-mediated rejection
• Single-nucleotide polymorphism
• Tailored immunosuppression

Milk samples from 10,641 dairy cattle were screened by a mass spectrometry method for extreme concentrations of the A or B isoforms of the whey protein, β-lactoglobulin (BLG), to identify causative genetic variation driving changes in BLG concentration.

A cohort of cows, from a single sire family, was identified that produced milk containing a low concentration of the BLG B protein isoform. A genome-wide association study (GWAS) of BLG B protein isoform concentration in milk from AB heterozygous cows, detected a group of highly significant single nucleotide polymorphisms (SNPs) within or close to the BLG gene. Among these was a synonymous G/A variation at position + 78 bp in exon 1 of the BLG gene (chr11:103256256G > A). The effect of the A allele of this SNP (which we named B’) on BLG expression was evaluated in a luciferase reporter assay in transfected CHO-K1 and MCF-7 cells. In both cell types, the presence of the B’ allele in a plasmid containing the bovine BLG gene from -922 to + 898 bp (relative to the transcription initiation site) resulted in a 60% relative reduction in mRNA expression, compared to the plasmid containing the wild-type B sequence allele. Examination of a mammary RNAseq dataset (n = 391) identified 14 heterozygous carriers of the B’ allele which were homozygous for the BLG B protein isoform (BB’). The level of expression of the BLG B’ allele was 41.9 ± 1.0% of that of the wild-type BLG B allele. Milk samples from three cows, homozygous for the A allele at chr11:103,256,256 (B’B’), were analysed (HPLC) and showed BLG concentrations of 1.04, 1.26 and 1.83 g/L relative to a mean of 4.84 g/L in milk from 16 herd contemporaries of mixed (A and B) BLG genotypes. The mechanism by which B’ downregulates milk BLG concentration remains to be determined.

High-throughput screening and identification of outliers, enabled the discovery of a synonymous G > A mutation in exon 1 of the B allele of the BLG gene (B’), which reduced the milk concentration of β-lactoglobulin B protein isoform, by more than 50%. Milk from cows carrying the B’ allele is expected to have improved processing characteristics, particularly for cheese-making.

The online version contains supplementary material available at 10.1186/s12711-022-00711-z.

• Alopecia areata
• CTLA-4
• Gene polymorphisms
• Meta-analysis

• Antibiotic resistance
• Bloodstream infection
• Escherichia coli
• Mortality

• CTLA-4
• clinical outcome
• epithelial ovarian cancer
• genetic susceptibility
• polymorphism

Genetic association studies on alopecia areata (AA) performed in various populations have shown heterogeneous results. The aim of the current review was to synthesize the results of said studies to estimate the impact of FAS, FASL, PTPN22, CTLA4 and IL2RA gene polymorphisms on AA susceptibility.

A systematic literature search was conducted in the Medline, Web of Science, Scopus, EMBASE and LILACS databases. Studies published up to June 2020 were included. The results available in the grey literature including the Open Grey and Google Scholar databases were also used. The texts of potentially related studies were screened by individual reviewers. Evidence of publication bias was assessed using the Newcastle-Ottawa scale and the quality of evidence was assessed using the GRADE system. The quantitative synthesis was performed using the fixed effect model.

Out of 1784 articles, we identified 18 relevant articles for the qualitative synthesis and 16 for the quantitative synthesis. In a study of rs2476601 polymorphism of PTPN22 gene, including 1292 cases and 1832 controls, a correlation was found with the risk of developing AA in the allelic model (OR1.49 [95% C:1.13–1.95]), the heterozygous codominant (OR1.44 [95% CI:1:19–1.76]) and dominant model (OR1.43 [95% CI:1.18–1.73]). No association was found between the presence of FASL, PTPN22, CTLA and IL2RA gene polymorphisms with AA susceptibility.

The results suggest that the T allele of the single nucleoid polymorphism (SNP) rs2476601 in PTPN22 gene is a risk factor for developing alopecia areata. However, more robust studies defining the ethnic background of the population of origin are required, so that the risk identified in the present study can be validated. Additionally, a greater number of studies is necessary to evaluate the role of the FAS, FASL, PTPN22, CTLA4 and IL2RA genetic variants, given the heterogenous results found in the literature.

Dysregulation of T cells mediated immune responses is a hallmark in the development of systemic lupus erythematosus (SLE). Recent genome wide association study (GWAS) revealed the genetic contribution of variants located in the cytotoxic T lymphocyte-associated protein-4 (CTLA4)-inducible T cell co-stimulator (ICOS) intergenic region to SLE susceptibility. Our aim is to find a functional variant in this region.

The genetic association results in the CTLA4-ICOS region from previous GWAS were adopted to select the potential variant which was further replicated in two independent cohorts (Henan cohort 2053 SLE patients and 1845 healthy controls, Beijing cohort 2303 SLE patients and 19,262 healthy). In order to explore the functional significance in SLE, bioinformatics with validation experiments (including electrophoretic mobility shift assay and luciferase reporter assay) and mRNA expression analysis were also performed.

A variant located in the CTLA4-ICOS intergenic region, rs17268364, was associated with susceptibility to SLE patients in Chinese populations (risk allele, p_meta = 7.02×10⁻¹¹, OR 1.19, 95%CI 1.13–1.26). The bioinformatics suggested that rs17268364 might affect the expression of CTLA4, not ICOS. The rs17268364 risk G allele containing sequence reduced the expression of the reporter gene by binding transcriptional repressor Ewing sarcoma breakpoint region 1 (EWSR1). Following genotype-mRNA expression, the analysis also showed the risk allele of rs17268364 was associated with low CTLA4 expression in lupus nephritis (LN) patients. Healthy individuals carrying rs17268364 risk G allele was significantly correlated with higher levels of IFN-α signature including increased lymphocyte antigen 6E (LY6E) (p=0.031), interferon-stimulated gene 15 (ISG15) (p=0.038), interferon regulatory factor 9 (IRF9) (p=0.028), and interferon regulatory factor 5 (IRF5) (p=0.040) mRNA expression.

The present study confirmed the functional role of rs17268364 in the CTLA4-ICOS intergenic region that increased SLE susceptibility in the Chinese population.

The online version contains supplementary material available at 10.1186/s13075-021-02664-y.

• CTLA4-ICOS
• Immune checkpoint
• Single nucleotide polymorphisms
• Systemic lupus erythematosus
• rs17268364

• Polymorphism, Single Nucleotide
• Humans
• Quantitative Trait Loci
• Genome-Wide Association Study/methods
• CTLA-4 Antigen/genetics
• High-Throughput Nucleotide Sequencing/methods

• P50 AR070588 NIAMS NIH HHS
• R01 MH095797 NIMH NIH HHS
• R01 MH106910 NIMH NIH HHS
• National Institute of Mental Health

Recent epidemiological studies have found an alarming trend of increased cancer incidence in adults younger than 50 years of age and projected a substantial rise in cancer incidence over the next 10 years in this age group. This trend was exemplified in the incidence of non-cardia gastric cancer and its disproportionate impact on non-Hispanic white females under the age of 50. The trend is concurrent with the increasing incidence of autoimmune diseases in industrialized countries, suggesting a causal link between the two. While autoimmunity has been suspected to be a risk factor for some cancers, the exact mechanisms underlying the connection between autoimmunity and cancer remain unclear and are often controversial. The link has been attributed to several mediators such as immune suppression, infection, diet, environment, or, perhaps most plausibly, chronic inflammation because of its well-recognized role in tumorigenesis. In that regard, autoimmune conditions are common causes of chronic inflammation and may trigger repetitive cycles of antigen-specific cell damage, tissue regeneration, and wound healing. Illustrating the connection between autoimmune diseases and cancer are patients who have an increased risk of cancer development associated with genetically predisposed insufficiency of cytotoxic T lymphocyte-associated protein 4 (CTLA4), a prototypical immune checkpoint against autoimmunity and one of the main targets of cancer immune therapy. The tumorigenic process triggered by CTLA4 insufficiency has been shown in a mouse model to be dependent on the type 2 cytokines interleukin-4 (IL4) and interleukin-13 (IL13). In this type 2 inflammatory milieu, crosstalk with type 2 immune cells may initiate epigenetic reprogramming of epithelial cells, leading to a metaplastic differentiation and eventually malignant transformation even in the absence of classical oncogenic mutations. Those findings complement a large body of evidence for type 1, type 3, or other inflammatory mediators in inflammatory tumorigenesis. This review addresses the potential of autoimmunity as a causal factor for tumorigenesis, the underlying inflammatory mechanisms that may vary depending on host-environment variations, and implications to cancer prevention and immunotherapy.

• autoimmunity
• cancer
• chronic inflammation
• interleukin-13
• interleukin-4
• metaplasia
• tumorigenesis
• type 2 immunity

• Banff classification
• allograft rejection
• cytotoxic T-lymphocyte associated protein 4
• kidney transplantation
• polymorphism

• Alleles
• Allografts
• B7-2 Antigen/genetics
• CD28 Antigens/genetics
• CTLA-4 Antigen/genetics
• Gene Frequency
• Genotype
• Graft Rejection/genetics
• Graft Rejection/immunology
• Humans
• Kidney Transplantation/methods
• Linkage Disequilibrium
• Lymphocyte Activation/genetics
• Lymphocyte Activation/immunology
• Multivariate Analysis
• Polymorphism, Single Nucleotide
• Retrospective Studies
• Risk Factors
• T-Lymphocytes/immunology
• T-Lymphocytes/metabolism

• CTLA4
• gene expression
• polymorphism
• real-time PCR
• rs231775
• vitiligo

• Adult
• CTLA-4 Antigen/genetics
• Case-Control Studies
• Female
• Gene Expression
• Gene Frequency
• Genetic Association Studies
• Genetic Predisposition to Disease
• Humans
• Male
• Middle Aged
• Polymorphism, Single Nucleotide
• Vitiligo/etiology
• Vitiligo/genetics
• White People/genetics
• Young Adult

• MED-2018-3-9-F-7906 The Deanship of Scientific Research, Northern Border University, Arar, KSA

Several studies have demonstrated that the genetic polymorphisms in the genes encoding immune regulatory molecules, namely cytotoxic T-lymphocyte-associated protein 4 (CTLA4) and CD28, play a fundamental role in susceptibility to rheumatoid arthritis (RA). Several disperse population studies have resulted in conflicting outcomes regarding the genetic polymorphisms in these genes and RA risk. This systematic review and meta-analysis study was performed to reach a conclusive understanding of the role of single-nucleotide polymorphisms (SNPs) of CTLA4-rs231775, CTLA4-rs5742909, and CD28-rs1980422 in susceptibility to RA. Databases (ISI Web of Science, MEDLINE/PubMed, and Scopus) were searched to find the case–control studies surveying the association of CTLA4 gene rs231775, CTLA4 gene rs5742909, and CD28 gene rs1980422 polymorphisms and RA susceptibility in different population until August 2020. Association comparison between the polymorphisms and RA proneness was assessed using pooled odds ratio (OR) and their corresponding 95% confidence interval. This study was conducted on 16 population studies, comprising 1078 RA patients and 1118 healthy controls for CTLA4-rs231775, 2193 RA patients and 2580 healthy controls for CTLA4-rs5742909, and 807 RA patients and 732 healthy controls for CD28-rs1980422. Analysis indicated that G-allele, GG and GA genotypes, and dominant model for rs231775, recessive model for rs5742909, and C-allele, CC and CT genotypes, and recessive model for rs1980422 were significantly associated with increased RA risk. This meta-analysis showed that genetic polymorphisms of both immune inhibitory and activating genes, including CTLA4-rs231775, CTLA4-rs5742909, and CD28-rs1980422 polymorphisms, may increase susceptibility to RA.

• CD28
• CTLA4
• meta-analysis
• polymorphism
• rheumatoid arthritis

• Iran
• biomarker
• genotyping
• single nucleotide polymorphisms
• thyroid cancer

• T lymphocyte
• immune checkpoints
• immunosuppression
• myeloid cell
• sepsis

• Gene Expression Regulation/immunology
• Humans
• Immune Checkpoint Proteins/immunology
• Immune Tolerance
• Leukocytes/immunology
• Leukocytes/pathology
• Sepsis/immunology
• Sepsis/pathology
• Sepsis/therapy

• R01 AI151210 NIAID NIH HHS
• T32 GM108554 NIGMS NIH HHS
• R01 GM104306 NIGMS NIH HHS
• T32 GM007347 NIGMS NIH HHS
• T32 GM152284 NIGMS NIH HHS
• K08 GM123345 NIGMS NIH HHS
• R01 GM119197 NIGMS NIH HHS

• BTLA
• CTLA-4
• LAG-3
• PD-1/PD-L1
• TIM-3
• cancer risk
• immune checkpoint molecules
• polymorphisms

• Animals
• Biomarkers, Tumor/genetics
• Clinical Decision-Making
• Genetic Predisposition to Disease
• Heredity
• Humans
• Immune Checkpoint Inhibitors/therapeutic use
• Immune Checkpoint Proteins/genetics
• Neoplasms/drug therapy
• Neoplasms/genetics
• Neoplasms/immunology
• Neoplasms/pathology
• Pedigree
• Phenotype
• Polymorphism, Single Nucleotide
• Precision Medicine
• Risk Assessment
• Risk Factors

• cytotoxic t lymphocyte antigen 4
• head and neck cancer
• susceptibility
• systematic review

• Humans
• Asian People
• China
• CTLA-4 Antigen/genetics
• Genetic Predisposition to Disease
• Head and Neck Neoplasms/genetics
• Polymorphism, Genetic
• Systematic Reviews as Topic
• Meta-Analysis as Topic

In this meta-analysis, we systematically investigated the correlation between single nucleotide polymorphisms (SNPs) and pancreatic cancer (PC) risk. We searched PubMed, Network Science, EMBASE, Cochrane Library, China National Knowledge Infrastructure (CNKI), China Science and Technology Periodical Database (VIP), and Wanfang databases up to January 2020 for studies on PC risk-associated SNPs. We identified 45 case-control studies (36,360 PC patients and 54,752 non-cancer individuals) relating to investigations of 27 genes and 54 SNPs for this meta-analysis. Direct meta-analysis followed by network meta-analysis and Thakkinstian algorithm analysis showed that homozygous genetic models for CTLA-4 rs231775 (OR =0.326; 95% CI: 0.218-0.488) and VDR rs2228570 (OR = 1.976; 95% CI: 1.496-2.611) and additive gene model for TP53 rs9895829 (OR = 1.231; 95% CI: 1.143-1.326) were significantly associated with PC risk. TP53 rs9895829 was the most optimal SNP for diagnosing PC susceptibility with a false positive report probability < 0.2 at a stringent prior probability value of 0.00001. This systematic review and meta-analysis suggest that TP53 rs9895829, VDR rs2228570, and CTLA-4 rs231775 are significantly associated with PC risk. We also demonstrate that TP53 rs9895829 is a potential diagnostic biomarker for estimating PC risk.

• FPRP
• network meta-analysis
• pancreatic cancer
• single nucleotide polymorphisms

• Cancer treatment
• Graves’ disease
• Immune checkpoint inhibitors
• Immune-related adverse events
• Thyroid eye disease

Pemphigus is a group of autoimmune bullous skin diseases that result in significant morbidity. As for other multifactorial autoimmune disorders, environmental factors may trigger the disease in genetically susceptible individuals. The goals of this review are to summarize the state of knowledge about the genetic variation that may affect the susceptibility and pathogenesis of pemphigus vulgaris and pemphigus foliaceus – both the endemic and the sporadic forms –, to compare and discuss the possible meaning of the associations reported, and to propose recommendations for new research initiatives. Understanding how genetic variants translate into pathogenic mechanisms and phenotypes remains a mystery for most of the polymorphisms that contribute to disease susceptibility. However, genetic studies provide a strong foundation for further developments in this field by generating testable hypotheses. Currently, results still have limited influence on disease prevention and prognosis, drug development, and clinical practice, although the perspectives for future applications for the benefit of patients are encouraging. Recommendations for the continued advancement of our understanding as to the impact of genetic variation on pemphigus include these partially overlapping goals: (1) Querying the functional effect of genetic variants on the regulation of gene expression through their impact on the nucleotide sequence of cis regulatory DNA elements such as promoters and enhancers, the splicing of RNA, the structure of regulatory RNAs and proteins, binding of these regulatory molecules to regulatory DNA elements, and alteration of epigenetic marks; (2) identifying key cell types and cell states that are implicated in pemphigus pathogenesis and explore their functional genomes; (3) integrating structural and functional genomics data; (4) performing disease-progression longitudinal studies to disclose the causal relationships between genetic and epigenetic variation and intermediate disease phenotypes; (5) understanding the influence of genetic and epigenetic variation in the response to treatment and the severity of the disease; (6) exploring gene-gene and genotype-environment interactions; (7) developing improved pemphigus-prone and non-prone animal models that are appropriate for research about the mechanisms that link genotypes to pemphigus. Achieving these goals will demand larger samples of patients and controls and multisite collaborations.

CTLA-4 and CD28 belong to co-stimulation molecules, the abnormal expression of which can regulate the T cell activation and then affect the degree of immune response. Moreover, blood transfusion reaction (TR) is a kind of immune reaction. Consequently, the hypothesis of this study was that the TR still occurred after transfusing leukoreduced blood components as a result of the sensitivity of immune system, and a small number of immune stimulations were enough to induce an immune response in patients. There were 38 cases and 36 healthy controls included in this study. The selected CD28 gene were sequenced to search single nucleotide polymorphism (SNPs), and the correlation between TR and these SNPs was analyzed. According to our data, only the rs3181097 (promoter, −1059) of CD28 gene polymorphism was associated with TR. The p value of rs3181097 under the co-dominant model was 0.031. GG was used as a reference genotype, the p value of GG vs. AG was 0.010 (OR: 0.210, 95% CI: 0.062–0.712), and GG vs. AG + AA was 0.028 (OR: 0.292, 95% CI: 0.095–0.901). In addition to CTLA-4, CD28 gene was also a crucial SNP in TR, because there was a signification for the haplotype with G_rs3181097 (p = 0.015). Consequently, we suggested that the TR was related to CD28 by regulating the degree of immune response.

• CD28
• gene polymorphism
• transfusion reaction (TR)

• CTLA-4
• CTLA4 polymorphism
• Clinical disease
• Hepatitis B virus
• Hepatocellular carcinoma

The pathogenesis of basal cell carcinoma (BCC) is multifactorial and not fully elucidated. Previous studies showed that behaviour of the tumour may be influenced by the immune system and identified CD4⁺CD25⁺FoxP3⁺ regulatory T cells (T_regs) as dominant immune cells in BCC microenvironment. The function and development of Tregs is regulated by FOXP3, encoding transcription factor Forkhead box P3. FOXP3 regulates transcription of many genes, including up-regulation of cytotoxic lymphocyte-associated antigen-4 gene (CTLA-4). Expressed on Tregs, CTLA-4 interacts with antigen-presenting cells to inhibit T-cell activation.

To investigate the role of two polymorphisms (rs3761548 and rs2232365) of FOXP3 and CTLA-4 polymorphism (rs5742909) in BCC patients from northern Poland.

We analysed 280 unrelated patients with BCC of mean age 70.93 ±11.53 (70.54 ±12.55 women, 71.38 ±10.26 men) and 200 healthy, unrelated age- and sex-matched volunteers.

The differences in the occurrence of BCC between genotypes and alleles of the analysed polymorphisms were not statistically significant. In the studied group, the presence of the CC genotype in CTLA-4 rs5742909 polymorphism was statistically more frequent in patients with multiple BCCs.

It seems that the analysed FOXP3 and CTLA-4 polymorphisms do not influence the BCC susceptibility. CTLA-4 rs5742909 polymorphism may influence the susceptibility to multiple BCCs.

• FOXP3, CTLA-4
• basal cell carcinoma
• gene polymorphism

• cytotoxic T lymphocyte-associated protein 4
• oesophageal squamous cell carcinoma
• prognosis
• risk factor
• single nucleotide polymorphism

Leukocytes and cytokines in blood units have been known to be involved in febrile non-hemolytic transfusion reaction (FNHTR), and these adverse reactions still occur while using pre-storage leukoreduced blood products. Blood transfusion is similar to transplantation because both implant allogeneic cells or organs into the recipient. CTLA4 gene polymorphism was found to be associated with graft-versus-host disease in hematopoietic stem cell transplantation. We performed a prospective cohort study at a major tertiary care center to investigate the correlation of CTLA4 gene polymorphism and transfusion reactions. Selected CTLA4 gene SNPs were genotyped and compared between patients with transfusion-associated adverse reactions (TAARs) and healthy controls. Nineteen patients and 20 healthy subjects were enrolled. There were 4 SNPs showing differences in allele frequency between patients and controls, and the frequency of “A” allele of rs4553808, “G” allele of rs62182595, “G” allele of rs16840252, and “C” allele of rs5742909 were significantly higher in patients than in controls. Moreover, these alleles also showed significantly higher risk of TAARs (OR = 2.357, 95%CI: 1.584–3.508, p = 0.02; OR = 2.357, 95%CI: 1.584–3.508, p = 0.02; OR = 2.462, 95%CI: 1.619–3.742, p = 0.008; OR = 2.357, 95%CI: 1.584–3.508, p = 0.02; OR = 2.357, 95%CI: 1.584–3.508, p = 0.02, respectively). The present study demonstrated the correlation of CTLA4 gene polymorphism and transfusion reaction, and alleles of 4 CTLA4 SNPs with an increased risk of TAARs were found. It is important to explore the potential immune regulatory mechanism affected by SNPs of costimulatory molecules, and it could predict transfusion reaction occurrence and guide preventive actions.

• CTLA4
• gene polymorphism
• leukoreduction
• transfusion reaction

• Cytotoxic T-lymphocyte-associated antigen-4
• Glomerulonephritides, kidney function

• Adult
• Aged
• Antigens, CD/metabolism
• CTLA-4 Antigen/blood
• CTLA-4 Antigen/genetics
• CTLA-4 Antigen/metabolism
• Female
• Gene Expression Regulation
• Glomerulonephritis/immunology
• Glomerulonephritis/physiopathology
• Humans
• Immunoglobulins/blood
• Kidney/physiopathology
• Lymphocyte Activation
• Lymphocyte Count
• Lymphocyte Subsets/immunology
• Lymphocyte Subsets/metabolism
• Male
• Middle Aged
• ROC Curve
• Young Adult

• UMO-2016/23/B/NZ6/02844 Narodowe Centrum Nauki
• DS460 Uniwersytet Medyczny w Lublinie

The development of inhibitors against infused factor VIII represents the most severe complication of substitution therapy in hemophilia A (HA) patients. Data on risk factors for inhibitor formation in Iraqi Kurdish patients with HA are unavailable. This study aimed to evaluate the impact of two single nucleotide polymorphisms (SNPs) in an immune regulatory gene in the emergence of inhibitors.

We focused on 126 patients with either severe or mild/moderate HA presenting with and without inhibitors. We analyzed the frequency of two polymorphisms in the cytotoxic T lymphocyte-associated protein-4 gene (CTLA-4; CTLA-4-318C > T and CTLA-4 + 49A > G). Genotyping was performed using restriction fragment length polymorphism–PCR and direct sequencing.

We found no significant correlation between the CTLA-4-318 C > T T allele and inhibitor development among patients with severe or mild/moderate HA. However, a significantly high inhibitor risk was detected for the CTLA-4 + 49 A > G G allele (odds ratio [OR] = 3.1, 95% confidence interval [CI] = 1.383–7.024) and (OR = 4, 95% CI = 1.719–9.437) among patients with severe and mild/moderate HA, respectively.

We conclude that the CTLA-4 +49 A > G SNP plays a substantial role as a potential risk determinant for inhibitor formation in Iraqi Kurdish patients with HA.

• CTLA4
• Hemophilia A
• immune regulatory gene
• inhibitors
• risk factors
• single nucleotide polymorphism

• Cytotoxic T lymphocyte associated antigen-4
• Myasthenia gravis
• Polymorphism
• Severity
• Susceptibility

Immune checkpoint molecules, like CTLA-4, TIM-3, PD-1, are negative regulators of immune responses to avoid immune injury. Checkpoint regulators are thought to actively participate in the immune defense of infections, prevention of autoimmunity, transplantation, and tumor immune evasion. Maternal-fetal immunotolerance represents a real immunological challenge for the immune system of the mother: beside acceptance of the semiallogeneic fetus, the maternal immune system has to be prepared for immune defense mostly against infections. In this particular situation, the role of immune checkpoint molecules could be of special interest. In this review, we describe current knowledge on the role of immune checkpoint molecules in reproductive immunology.

• CTLA-4
• PD-1
• TIM-3
• immune checkpoint molecule
• immunotolerance
• pregnancy
• reproductive immunology

• Focal segmental glomerulosclerosis
• Minimal change disease
• Nephrotic syndrome
• Single nucleotide polymorphisms
• sCTLA4

• Alleles
• Biomarkers
• CTLA-4 Antigen/genetics
• Comorbidity
• Female
• Genotype
• Humans
• Kaplan-Meier Estimate
• Male
• Prognosis
• Proportional Hazards Models
• Sepsis/diagnosis
• Sepsis/genetics
• Sepsis/mortality
• Severity of Illness Index
• Survival Analysis
• Time Factors
• White People/genetics

• Volkswagen Foundation

• CD152
• CTLA-4
• Follicular thyroid carcinoma
• Papillary thyroid carcinoma
• Polymorphism
• Single-nucleotide
• rs231775
• rs5742909

• Adult
• Alleles
• CTLA-4 Antigen/genetics
• Case-Control Studies
• Cross-Sectional Studies
• Female
• Gene Frequency
• Genetic Predisposition to Disease
• Genotype
• Humans
• Male
• Middle Aged
• Polymorphism, Single Nucleotide
• Thyroid Neoplasms/genetics

• 91-01-01-5545 Shiraz University of Medical Sciences
• ICR-100-502 Shiraz Institute for Cancer Research, Shiraz University of Medical Sciences