RESUMO
Hypodermis is the predominant site of Staphylococcus aureus infections that cause cellulitis. Given the importance of macrophages in tissue remodeling, we examined the hypodermal macrophages (HDMs) and their impact on host susceptibility to infection. Bulk and single-cell transcriptomics uncovered HDM subsets with CCR2-dichotomy. HDM homeostasis required the fibroblast-derived growth factor CSF1, ablation of which abrogated HDMs from the hypodermal adventitia. Loss of CCR2- HDMs resulted in accumulation of the extracellular matrix component, hyaluronic acid (HA). HDM-mediated HA clearance required sensing by the HA receptor, LYVE-1. Cell-autonomous IGF1 was required for accessibility of AP-1 transcription factor motifs that controlled LYVE-1 expression. Remarkably, loss of HDMs or IGF1 limited Staphylococcus aureus expansion via HA and conferred protection against cellulitis. Our findings reveal a function for macrophages in the regulation of HA with an impact on infection outcomes, which may be harnessed to limit the establishment of infection in the hypodermal niche.
Assuntos
Infecções Estafilocócicas , Staphylococcus aureus , Humanos , Staphylococcus aureus/fisiologia , Celulite (Flegmão)/metabolismo , Macrófagos/metabolismo , Matriz ExtracelularRESUMO
Hair follicles (HFs) function as hubs for stem cells, immune cells, and commensal microbes, which must be tightly regulated during homeostasis and transient inflammation. Here we found that transmembrane endopeptidase ADAM10 expression in upper HFs was crucial for regulating the skin microbiota and protecting HFs and their stem cell niche from inflammatory destruction. Ablation of the ADAM10-Notch signaling axis impaired the innate epithelial barrier and enabled Corynebacterium species to predominate the microbiome. Dysbiosis triggered group 2 innate lymphoid cell-mediated inflammation in an interleukin-7 (IL-7) receptor-, S1P receptor 1-, and CCR6-dependent manner, leading to pyroptotic cell death of HFs and irreversible alopecia. Double-stranded RNA-induced ablation models indicated that the ADAM10-Notch signaling axis bolsters epithelial innate immunity by promoting ß-defensin-6 expression downstream of type I interferon responses. Thus, ADAM10-Notch signaling axis-mediated regulation of host-microbial symbiosis crucially protects HFs from inflammatory destruction, which has implications for strategies to sustain tissue integrity during chronic inflammation.
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Proteína ADAM10/imunologia , Secretases da Proteína Precursora do Amiloide/imunologia , Disbiose/imunologia , Folículo Piloso/patologia , Linfócitos/imunologia , Proteínas de Membrana/imunologia , Receptores Notch/imunologia , Pele/microbiologia , Alopecia/imunologia , Alopecia/patologia , Animais , Corynebacterium , Disbiose/patologia , Feminino , Folículo Piloso/imunologia , Imunidade Inata , Inflamação/imunologia , Inflamação/metabolismo , Inflamação/patologia , Camundongos , Transdução de Sinais/imunologia , Pele/imunologia , Pele/patologiaRESUMO
BACKGROUND: TCF3 is a transcription factor contributing to early lymphocyte differentiation. Germline monoallelic dominant negative and biallelic loss-of-function (LOF) null TCF3 mutations cause a fully penetrant severe immunodeficiency. We identified 8 individuals from 7 unrelated families with monoallelic LOF TCF3 variants presenting with immunodeficiency with incomplete clinical penetrance. OBJECTIVE: We sought to define TCF3 haploinsufficiency (HI) biology and its association with immunodeficiency. METHODS: Patient clinical data and blood samples were analyzed. Flow cytometry, Western blot analysis, plasmablast differentiation, immunoglobulin secretion, and transcriptional activity studies were conducted on individuals carrying TCF3 variants. Mice with a heterozygous Tcf3 deletion were analyzed for lymphocyte development and phenotyping. RESULTS: Individuals carrying monoallelic LOF TCF3 variants showed B-cell defects (eg, reduced total, class-switched memory, and/or plasmablasts) and reduced serum immunoglobulin levels; most but not all presented with recurrent but nonsevere infections. These TCF3 LOF variants were either not transcribed or translated, resulting in reduced wild-type TCF3 protein expression, strongly suggesting HI pathophysiology for the disease. Targeted RNA sequencing analysis of T-cell blasts from TCF3-null, dominant negative, or HI individuals clustered away from healthy donors, implying that 2 WT copies of TCF3 are needed to sustain a tightly regulated TCF3 gene-dosage effect. Murine TCF3 HI resulted in a reduction of circulating B cells but overall normal humoral immune responses. CONCLUSION: Monoallelic LOF TCF3 mutations cause a gene-dosage-dependent reduction in wild-type protein expression, B-cell defects, and a dysregulated transcriptome, resulting in immunodeficiency. Tcf3+/- mice partially recapitulate the human phenotype, underscoring the differences between TCF3 in humans and mice.
Assuntos
Fatores de Transcrição Hélice-Alça-Hélice Básicos , Haploinsuficiência , Síndromes de Imunodeficiência , Animais , Humanos , Camundongos , Linfócitos B , Fatores de Transcrição Hélice-Alça-Hélice Básicos/genética , Imunoglobulinas/genética , Síndromes de Imunodeficiência/genética , Linfócitos TRESUMO
IKAROS is a transcription factor forming homo- and heterodimers and regulating lymphocyte development and function. Germline mutations affecting the IKAROS N-terminal DNA binding domain, acting in a haploinsufficient or dominant-negative manner, cause immunodeficiency. Herein, we describe 4 germline heterozygous IKAROS variants affecting its C-terminal dimerization domain, via haploinsufficiency, in 4 unrelated families. Index patients presented with hematologic disease consisting of cytopenias (thrombocytopenia, anemia, neutropenia)/Evans syndrome and malignancies (T-cell acute lymphoblastic leukemia, Burkitt lymphoma). These dimerization defective mutants disrupt homo- and heterodimerization in a complete or partial manner, but they do not affect the wild-type allele function. Moreover, they alter key mechanisms of IKAROS gene regulation, including sumoylation, protein stability, and the recruitment of the nucleosome remodeling and deacetylase complex; none affected in N-terminal DNA binding defects. These C-terminal dimerization mutations are largely associated with hematologic disorders, display dimerization haploinsufficiency and incomplete clinical penetrance, and differ from previously reported allelic variants in their mechanism of action. Dimerization mutants contribute to the growing spectrum of IKAROS-associated diseases displaying a genotype-phenotype correlation.
Assuntos
Células Germinativas/metabolismo , Haploinsuficiência/genética , Neoplasias Hematológicas/patologia , Fator de Transcrição Ikaros/metabolismo , Multimerização Proteica , Adolescente , Adulto , Idoso , Sequência de Aminoácidos , Sequência de Bases , Centrômero/metabolismo , Segregação de Cromossomos/genética , DNA/metabolismo , Feminino , Regulação da Expressão Gênica , Heterocromatina/metabolismo , Histona Desacetilase 1/metabolismo , Humanos , Fator de Transcrição Ikaros/química , Fator de Transcrição Ikaros/genética , Masculino , Pessoa de Meia-Idade , Proteínas Mutantes/metabolismo , Mutação/genética , Linhagem , Ligação Proteica , Processamento de Proteína Pós-Traducional , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Sumoilação , Transcrição GênicaRESUMO
BACKGROUND: CARD9 deficiency is an autosomal recessive primary immunodeficiency underlying increased susceptibility to fungal infection primarily presenting as invasive CNS Candida and/or cutaneous/invasive dermatophyte infections. More recently, a rare heterozygous dominant negative CARD9 variant c.1434 + 1G > C was reported to be protective from inflammatory bowel disease. OBJECTIVE: We studied two siblings carrying homozygous CARD9 variants (c.1434 + 1G > C) and born to heterozygous asymptomatic parents. One sibling was asymptomatic and the other presented with candida esophagitis, upper respiratory infections, hypogammaglobulinemia, and low class-switched memory B cells. METHODS AND RESULTS: The CARD9 c.1434 + 1G > C variant generated two mutant transcripts confirmed by mRNA and protein expression: an out-of-frame c.1358-1434 deletion/ ~ 55 kDa protein (CARD9Δex.11) and an in-frame c.1417-1434 deletion/ ~ 61 kDa protein (CARD9Δ18 nt.). Neither transcript was able to form a complete/functional CBM complex, which includes TRIM62. Based on the index patient's CVID-like phenotype, CARD9 expression was tested and detected in lymphocytes and monocytes from humans and mice. The functional impact of different CARD9 mutations and gene dosage conditions was evaluated in heterozygous and homozygous c.1434 + 1 G > C members of the index family, and in WT (two WT alleles), haploinsufficiency (one WT, one null allele), and null (two null alleles) individuals. CARD9 gene dosage impacted lymphocyte and monocyte functions including cytokine generation, MAPK activation, T-helper commitment, transcription, plasmablast differentiation, and immunoglobulin production in a differential manner. CONCLUSIONS: CARD9 exon 11 integrity is critical to CBM complex function. CARD9 is expressed and affects particular T and B cell functions in a gene dosage-dependent manner, which in turn may contribute to the phenotype of CARD9 deficiency.
Assuntos
Candidíase Mucocutânea Crônica , Alelos , Animais , Proteínas Adaptadoras de Sinalização CARD/genética , Dosagem de Genes , Homozigoto , Humanos , Camundongos , FenótipoRESUMO
BACKGROUND/OBJECTIVE: This study was done to examine the role of CD40 ligand (CD40L) in children with Kawasaki disease (KD). There is paucity of literature on this aspect of KD. METHODS: This was a case-control study of patients with KD diagnosed at the Allergy Immunology Unit, Postgraduate Institute of Medical Education and Research, Chandigarh, India. CD40L expression on activated CD3+ T cells was measured using flow cytometry, and soluble CD40L (sCD40L) was measured using enzyme-linked immunosorbent assay. RESULTS: We included 14 children with KD, 14 healthy controls, and 12 febrile controls for the purpose of this study. Mean percentage CD40L expression was higher in patients with KD (before administration of intravenous immunoglobulin [IVIg]) as compared with normal and febrile controls. This difference was statistically significant when compared with normal control (p = 0.00; confidence interval [CI], 8.92-20.30), but was not statistically significant when compared with febrile controls (p = 0.138; CI, -3.50 to 22.08). CD40L expression decreased after giving IVIg, but the difference was not statistically significant (p = 0.073; CI, -1.04 to 19.73). Mean sCD40L values increased significantly after giving IVIg (when repeated after a median period of 11 days; p = 0.001; CI, -0.77 to -0.29). There was no statistically significant difference between mean sCD40L in patients with KD (before giving IVIg) as compared with normal and febrile controls (p = 0.42; CI, -1.11 to -0.51 and p = 0.641; CI, -0.37 to 0.57, respectively). CONCLUSIONS: CD40L may have important role in the pathogenesis of KD. However, these results need to be validated in larger multicenter studies.
Assuntos
Ligante de CD40 , Síndrome de Linfonodos Mucocutâneos , Estudos de Casos e Controles , Criança , Humanos , Índia/epidemiologia , Síndrome de Linfonodos Mucocutâneos/diagnóstico , Síndrome de Linfonodos Mucocutâneos/tratamento farmacológico , Linfócitos TRESUMO
The noncanonical NF-κB pathway is implicated in diverse biological and immunological processes. Monoallelic C-terminus loss-of-function and gain-of-function mutations of NFKB2 have been recently identified as a cause of immunodeficiency manifesting with common variable immunodeficiency (CVID) or combined immunodeficiency (CID) phenotypes. Herein we report a family carrying a heterozygous nonsense mutation in NFKB2 (c.809G > A, p.W270*). This variant is associated with increased mRNA decay and no mutant NFKB2 protein expression, leading to NFKB2 haploinsufficiency. Our findings demonstrate that bona fide NFKB2 haploinsufficiency, likely caused by mutant mRNA decay and protein instability leading to the transcription and expression of only the wild-type allele, is associated with clinical immunodeficiency, although with incomplete clinical penetrance. Abnormal B cell development, hypogammaglobulinemia, poor antibody response, and abnormal noncanonical (but normal canonical) NF-κB pathway signaling are the immunologic hallmarks of this disease. This adds a third allelic variant to the pathophysiology of NFKB2-mediated immunodeficiency disorders.
Assuntos
Agamaglobulinemia/diagnóstico , Agamaglobulinemia/genética , Estudos de Associação Genética , Predisposição Genética para Doença , Haploinsuficiência , Mutação , Subunidade p52 de NF-kappa B/genética , Adolescente , Adulto , Alelos , Feminino , Estudos de Associação Genética/métodos , Genótipo , Humanos , Imunofenotipagem , Linfócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Sequenciamento do Exoma , Adulto JovemRESUMO
Due to typesetting mistake, the caption of Figure 2 was mistakenly replaced with the caption of Figure 3.
RESUMO
X-linked hyper IgM Syndrome (XLHIGM), the most frequent form of the Hyper IgM syndromes is a primary immune deficiency resulting from a mutation in the CD40 ligand gene (CD40LG). We analyzed the clinical and laboratory features of ten patients with XLHIGM, who were diagnosed at a tertiary care hospital in North India. Most common infections were sinopulmonary infections (80%) and diarrhea (50%). Sclerosing cholangitis and necrotising fasciitis were noted in one patient each. Three novel mutations in CD40LG (c.429_429 delA, p. G144DfsX5; c.500â¯Gâ¯>â¯A, p.G167E and c.156â¯Gâ¯>â¯C, p.K52â¯N) were detected. In addition, we found one missense mutation, two splice site mutations and two large deletions, which have been previously reported. Four (4) patients had expired at the time of analysis. We report the first series of XLHIGM from North India where we have documented unique features such as pulmonary alveolar proteinosis and infections with Mycobacterium sp.
Assuntos
Ligante de CD40/genética , Diarreia/genética , Síndrome de Imunodeficiência com Hiper-IgM Tipo 1/genética , Mutação/genética , Infecções por Mycobacterium/genética , Mycobacterium/fisiologia , Proteinose Alveolar Pulmonar/genética , Infecções Respiratórias/genética , Células Cultivadas , Criança , Pré-Escolar , Citometria de Fluxo , Humanos , Síndrome de Imunodeficiência com Hiper-IgM Tipo 1/fisiopatologia , Índia , Lactente , Masculino , FenótipoAssuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Doença Granulomatosa Crônica/diagnóstico , Doença Granulomatosa Crônica/genética , Mutação , NADPH Oxidase 2/genética , Cariótipo Anormal , Biomarcadores , Análise Mutacional de DNA , Citometria de Fluxo , Genes Ligados ao Cromossomo X , Humanos , Lactente , Masculino , Linhagem , Fenótipo , Tomografia Computadorizada por Raios XRESUMO
BACKGROUND: Hyper IgE syndrome (HIES) is a rare primary immunodeficiency disorder characterized by the triad of elevated IgE and eosinophilia, eczema and recurrent skin and pulmonary infections. Mutation in the STAT3 gene accounts for majority of the autosomal dominant and sporadic forms of HIES. OBJECTIVE: To report clinical and molecular analyses of patients with Hyper IgE syndrome from a single tertiary care center in India. METHODS: Four patients with suspected HIES were studied. Flowcytometry for T(H)17 cell numbers and phosphoSTAT3, and STAT3 gene sequencing were performed. RESULTS: T(H)17 cells were significantly reduced. Mutations were found in the DNA-binding domain in three and a mutation in the transactivation domain in one patient. One of the mutations detected was a novel mutation (g54792 c.1018A> C p.K340Q) in the DNA binding domain. Mycobacterial infection, which is usually not commonly associated with HIES was found in two of our cases, one with a cutaneous abscess in the shoulder, and the other with BCG site reactivation. CONCLUSIONS: A novel mutation in the STAT3 is reported. Mycobacterial infections can be seen in the spectrum of HIES related infections.
Assuntos
Síndrome de Job/genética , Fator de Transcrição STAT3/genética , Adulto , Pré-Escolar , Análise Mutacional de DNA , Citometria de Fluxo , Humanos , Índia , Lactente , Síndrome de Job/imunologia , Masculino , Mutação , Linhagem , Células Th17/imunologiaRESUMO
BACKGROUND & OBJECTIVES: Gamma H2AX, a marker of DNA double stranded breaks (DSB) has been found to be over expressed in various tumours. The objective of the present work was to study the expression of γH2AX in infiltrating ductal carcinoma (IDC) and fibroadenoma (FA) cases and to associate the expression in IDC with cytomorphological features and DNA ploidy. METHODS: The expression of γH2AX was studied in fine needle aspirates of 16 cases of IDC and 15 FA cases. The expression in IDC was correlated with the cytological grade, apoptotic (AI) and mitotic indices (MI) and ploidy status. RESULTS: A high γH2AX expression was noted in IDC as compared to FA. Amongst the IDC cases the γH2AX was found to be significantly over expressed in DNA diploid IDC cases as compared to the aneuploid ones. INTERPRETATION & CONCLUSIONS: The study suggests a role of γH2AX in breast carcinogenesis which needs to be explored further. Moreover, the γH2AX expression together with ploidy status may serve as a means of assigning the patients of IDC to a better prognostic category irrespective of the cytomorphogical parameters.
Assuntos
Neoplasias da Mama/genética , Carcinoma Ductal/genética , Fibroadenoma/genética , Histonas/biossíntese , Adulto , Biomarcadores Tumorais/genética , Neoplasias da Mama/patologia , Carcinogênese/genética , Carcinoma Ductal/patologia , Feminino , Fibroadenoma/patologia , Regulação Neoplásica da Expressão Gênica , Histonas/genética , Humanos , PrognósticoRESUMO
BACKGROUND: Psoriasis is associated with significant morbidity and impaired quality of life. Identification of the host genes that influence disease susceptibility and can potentially guide future, targeted therapy is the need of the hour. AIMS: The aim of the study was to investigate the associations of macrophage migration inhibitory factor (MIF) gene polymorphisms, that is, a 5-8-CATT tetra nucleotide repeats at -794 (-794*CATT5-8) and a single-nucleotide polymorphism at -173 (-173*G/C) with the risk of chronic plaque psoriasis and to observe the correlation, if any, of disease determinants with genetic functional variants and circulating MIF levels. METHODS: Five hundred and seventeen individuals (265 psoriasis patients and 252 controls) were genotyped for MIF gene polymorphisms. Data were analyzed with respect to disease susceptibility, serum MIF levels, disease severity, age at onset, disease duration and presence of comorbidities. RESULTS: The presence of co-morbidities was more frequently noted in patients with late onset disease (P = 0.01). No statistically significant differences were observed either in genotype (P = 0.680) or allele frequency (P = 0.69) with respect to distribution of MIF-173*G/C polymorphism between patients and controls. The frequencies of genotypes -794*CATT 5/7 and 7/7 were significantly lower in patients (P = 0.027* and 0.038*, respectively). CATT*5/MIF-173*C haplotype occurred at a higher frequency in patients (odds ratio 3.03, 95% confidence intervals 1.09-8.47, P = 0.02). The mean serum MIF levels were significantly higher in patients as compared to controls (P < 0.001). The presence of either extended MIF -794*CATT repeats or C allele did not reveal any significant association with serum MIF levels or age at onset. Analysis of effect of various disease determinants revealed no significant association with genetic variants and serum MIF levels. LIMITATIONS: The lesional expression of MIF could not be studied. CONCLUSION: Our results showed that CATT*5/MIF-173*C haplotype is associated with increased susceptibility to psoriasis vulgaris.
Assuntos
Fatores Inibidores da Migração de Macrófagos , Psoríase , Humanos , Polimorfismo de Nucleotídeo Único/genética , Haplótipos , Estudos Transversais , Fatores Inibidores da Migração de Macrófagos/genética , Qualidade de Vida , Predisposição Genética para Doença/genética , Regiões Promotoras Genéticas , Estudos de Casos e Controles , Gravidade do Paciente , Psoríase/diagnóstico , Psoríase/epidemiologia , Psoríase/genéticaRESUMO
The IL-2 receptor α chain (IL-2Rα/CD25) is constitutively expressed on double-negative (DN2/DN3 thymocytes and regulatory T cells (Tregs) but induced by IL-2 on T and natural killer (NK) cells, with Il2ra expression regulated by a STAT5-dependent super-enhancer. We investigated CD25 regulation and function using a series of mice with deletions spanning STAT5-binding elements. Deleting the upstream super-enhancer region mainly affected constitutive CD25 expression on DN2/DN3 thymocytes and Tregs, with these mice developing autoimmune alopecia, whereas deleting an intronic region decreased IL-2-induced CD25 on peripheral T and NK cells. Thus, distinct super-enhancer elements preferentially control constitutive versus inducible expression in a cell type-specific manner. The mediator-1 coactivator colocalized with specific STAT5-binding sites. Moreover, both upstream and intronic regions had extensive chromatin interactions, and deletion of either region altered the super-enhancer structure in mature T cells. These results demonstrate differential functions for distinct super-enhancer elements, thereby indicating previously unknown ways to manipulate CD25 expression in a cell type-specific fashion.
Assuntos
Interleucina-2 , Fator de Transcrição STAT5 , Animais , Camundongos , Elementos Facilitadores Genéticos/genética , Interleucina-2/genética , Interleucina-2/farmacologia , Subunidade alfa de Receptor de Interleucina-2/genética , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Receptores de Interleucina-2 , Fator de Transcrição STAT5/genética , Fator de Transcrição STAT5/metabolismoAssuntos
Tirosina Quinase da Agamaglobulinemia , Agamaglobulinemia , Artrite , Doenças Genéticas Ligadas ao Cromossomo X , Tirosina Quinase da Agamaglobulinemia/genética , Agamaglobulinemia/genética , Artrite/genética , Criança , Doenças Genéticas Ligadas ao Cromossomo X/genética , Humanos , Masculino , MutaçãoAssuntos
Aspergilose/complicações , Doença Granulomatosa Crônica/complicações , Hipertensão/complicações , Deficiência de IgA/complicações , Pneumonia/complicações , Artéria Pulmonar/fisiopatologia , Aspergilose/diagnóstico por imagem , Criança , Doença Granulomatosa Crônica/diagnóstico por imagem , Humanos , Hipertensão/diagnóstico por imagem , Deficiência de IgA/diagnóstico por imagem , Masculino , Pneumonia/diagnóstico por imagem , Artéria Pulmonar/diagnóstico por imagem , RadiografiaRESUMO
Skin is our body's outermost physical barrier and an immunological interface enriched with various immune and non-immune cells. However, efficient generation of single-cell suspensions for flow cytometry analysis can be challenging. Here, we provide protocols to obtain epidermal and whole skin cell suspensions as well as gating strategies to identify mouse keratinocytes and skin immune cell subsets via flow cytometry. For complete details on the use and execution of this protocol, please refer to Sakamoto et al. (2021).
Assuntos
Queratinócitos , Pele , Animais , Citometria de Fluxo/métodos , Camundongos , SuspensõesRESUMO
Background: Hyper-IgE syndrome (HIES) caused by loss-of-function (LOF) mutations in STAT3 gene (STAT3 LOF HIES) is associated with dental and facial abnormalities in addition to immunological defects. The role of STAT3 in the pathogenesis of the dental/facial features is, however, poorly elucidated. Objectives: Since mechanism of cellular resorption of mineralized tissues such as bone and teeth are similar, we attempted to study the expression of genes involved in bone homeostasis in STAT3 LOF HIES. Methods: Peripheral blood mononuclear cells from healthy controls (HCs), STAT3 LOF HIES patients, STAT3-/- PC-3 cells and STAT3+/+ LNCaP cells were stimulated with IL-6 and quantitative PCR array was performed to study the relative mRNA expression of 43 pre-selected genes. PCR array finding were further evaluated after stattic induced STAT3 inhibition. Results: Osteopontin (OPN) gene was seen to be significantly upregulated after IL-6 stimulation in HC (mean fold change 18.6, p = 0.01) compared with HIES subjects. Inhibition of STAT3 signaling by stattic followed by IL-6 stimulation abrogated the OPN response in HCs suggesting that IL-6-induced STAT3 signaling regulates OPN expression. Bioinformatics analysis predicted the presence of STAT3 response element TTCCAAGAA at position -2005 of the OPN gene. Conclusion: Regulation of OPN gene through IL-6-mediated STAT3 activation and its significant dysregulation in STAT3 LOF HIES subjects could make OPN a plausible candidate involved in the pathogenesis of dental/facial manifestations in HIES.
Assuntos
Regulação da Expressão Gênica , Síndrome de Job/genética , Mutação com Perda de Função , Osteopontina/genética , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Transcrição Gênica , Adolescente , Adulto , Sítios de Ligação , Linhagem Celular Tumoral , Pré-Escolar , Biologia Computacional/métodos , Elementos Facilitadores Genéticos , Perfilação da Expressão Gênica , Humanos , Interleucina-6/metabolismo , Síndrome de Job/diagnóstico , Síndrome de Job/imunologia , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Masculino , Fenótipo , Fosforilação , Estudos Prospectivos , Ligação Proteica , Elementos de Resposta , Proteína 3 Supressora da Sinalização de Citocinas/genéticaRESUMO
Background: Psoriasis is associated with significant morbidity and impaired quality of life. Identification of the host genes that influence disease susceptibility and can potentially guide future, targeted therapy is the need of the hour. Aims: The aim of the study was to investigate the associations of macrophage migration inhibitory factor (MIF) gene polymorphisms, that is, a 5–8-CATT tetra nucleotide repeats at -794 (-794*CATT5–8) and a single-nucleotide polymorphism at -173 (-173*G/C) with the risk of chronic plaque psoriasis and to observe the correlation, if any, of disease determinants with genetic functional variants and circulating MIF levels. Methods: Five hundred and seventeen individuals (265 psoriasis patients and 252 controls) were genotyped for MIF gene polymorphisms. Data were analyzed with respect to disease susceptibility, serum MIF levels, disease severity, age at onset, disease duration and presence of comorbidities. Results: The presence of co-morbidities was more frequently noted in patients with late onset disease (P = 0.01). No statistically significant differences were observed either in genotype (P = 0.680) or allele frequency (P = 0.69) with respect to distribution of MIF-173*G/C polymorphism between patients and controls. The frequencies of genotypes -794*CATT 5/7 and 7/7 were significantly lower in patients (P = 0.027* and 0.038*, respectively). CATT*5/MIF-173*C haplotype occurred at a higher frequency in patients (odds ratio 3.03, 95% confidence intervals 1.09–8.47, P = 0.02). The mean serum MIF levels were significantly higher in patients as compared to controls (P < 0.001). The presence of either extended MIF -794*CATT repeats or C allele did not reveal any significant association with serum MIF levels or age at onset. Analysis of effect of various disease determinants revealed no significant association with genetic variants and serum MIF levels. Limitations: The lesional expression of MIF could not be studied. Conclusion: Our results showed that CATT*5/MIF-173*C haplotype is associated with increased susceptibility to psoriasis vulgaris.