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1.
Scand J Immunol ; 92(1): e12890, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32299122

RESUMO

Alloimmunization against human platelet antigen (HPA)-1a during pregnancy can cause foetal/neonatal alloimmune thrombocytopenia (FNAIT) and severe bleeding in the foetus or newborn and likely depends on several factors. HPA-1a alloimmunization is associated with DRB3*01:01, which is associated with several DR-DQ haplotypes. However, it is not known to what extent these haplotypes contribute to the prevalence of HPA-1a alloimmunization. HPA-1a-alloimmunized women, identified in a prospective study, and random donors were typed for selected DRB3, DRB4, DRB1, DQA1 and DQB1 alleles to determine allele and DR-DQ haplotype frequencies. DRB3*01:01 was carried by 94% HPA-1a-immunized women compared to 27% in the general population. In the first population, the DR3-DQ2 haplotype was overrepresented (P < .003). The prevalence of HPA-1a alloimmunization was estimated to be about twice as frequent with DR3-DQ2 compared to DR13-DQ6, together accounting for about 90% of DRB3*01:01-positive individuals. Further, we examined DQB1*02 and DRB4*01:01 alleles for their reported association with HPA-1a alloimmunization, in the context of DR-DQ haplotypes. Since ~ 80% of DQB1*02 alleles are linked to the DR3-DQ2 haplotype, the association might be coincidental. However, the DQB1*02:02-associated DR7-DQ2 haplotype was also overrepresented in alloimmunized women, suggesting a role for this allele or haplotype in HPA-1a alloimmunization. As DRB4*01:01 is predominantly associated with the DR7-DQ2 haplotype in HPA-1a-alloimmunized individuals, the reported association with FNAIT may be coincidental. Typing for DR-DQ haplotypes revealed important genetic associations with HPA-1a alloimmunization not evident from typing individual alleles, and the presence of different DRB3-associated DR-DQ haplotypes showed different prevalence of HPA-1a alloimmunization.


Assuntos
Antígenos de Plaquetas Humanas/imunologia , Predisposição Genética para Doença/genética , Antígenos HLA-DQ/genética , Cadeias HLA-DRB3/genética , Trombocitopenia Neonatal Aloimune/genética , Feminino , Frequência do Gene/genética , Técnicas de Genotipagem , Haplótipos/genética , Humanos , Recém-Nascido , Gravidez , Trombocitopenia Neonatal Aloimune/imunologia , Trombocitopenia Neonatal Aloimune/patologia
2.
Nature ; 578(7796): 600-604, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-32051586

RESUMO

Coeliac disease is a complex, polygenic inflammatory enteropathy caused by exposure to dietary gluten that occurs in a subset of genetically susceptible individuals who express either the HLA-DQ8 or HLA-DQ2 haplotypes1,2. The need to develop non-dietary treatments is now widely recognized3, but no pathophysiologically relevant gluten- and HLA-dependent preclinical model exists. Furthermore, although studies in humans have led to major advances in our understanding of the pathogenesis of coeliac disease4, the respective roles of disease-predisposing HLA molecules, and of adaptive and innate immunity in the development of tissue damage, have not been directly demonstrated. Here we describe a mouse model that reproduces the overexpression of interleukin-15 (IL-15) in the gut epithelium and lamina propria that is characteristic of active coeliac disease, expresses the predisposing HLA-DQ8 molecule, and develops villous atrophy after ingestion of gluten. Overexpression of IL-15 in both the epithelium and the lamina propria is required for the development of villous atrophy, which demonstrates the location-dependent central role of IL-15 in the pathogenesis of coeliac disease. In addition, CD4+ T cells and HLA-DQ8 have a crucial role in the licensing of cytotoxic T cells to mediate intestinal epithelial cell lysis. We also demonstrate a role for the cytokine interferon-γ (IFNγ) and the enzyme transglutaminase 2 (TG2) in tissue destruction. By reflecting the complex interaction between gluten, genetics and IL-15-driven tissue inflammation, this mouse model provides the opportunity to both increase our understanding of coeliac disease, and develop new therapeutic strategies.


Assuntos
Doença Celíaca/imunologia , Doença Celíaca/patologia , Glutens/imunologia , Antígenos HLA-DQ/imunologia , Interleucina-15/imunologia , Animais , Linfócitos T CD4-Positivos/imunologia , Feminino , Antígenos HLA-DQ/genética , Humanos , Interferon gama/imunologia , Interleucina-15/genética , Masculino , Camundongos , Camundongos Transgênicos , Proteínas dos Microfilamentos/genética , Proteínas dos Microfilamentos/metabolismo
3.
Proc Natl Acad Sci U S A ; 117(6): 3063-3073, 2020 02 11.
Artigo em Inglês | MEDLINE | ID: mdl-31974305

RESUMO

The highly homologous human leukocyte antigen (HLA)-DQ2 molecules, HLA-DQ2.5 and HLA-DQ2.2, are implicated in the pathogenesis of celiac disease (CeD) by presenting gluten peptides to CD4+ T cells. However, while HLA-DQ2.5 is strongly associated with disease, HLA-DQ2.2 is not, and the molecular basis underpinning this differential disease association is unresolved. We here provide structural evidence for how the single polymorphic residue (HLA-DQ2.5-Tyr22α and HLA-DQ2.2-Phe22α) accounts for HLA-DQ2.2 additionally requiring gluten epitopes possessing a serine at the P3 position of the peptide. In marked contrast to the biased T cell receptor (TCR) usage associated with HLA-DQ2.5-mediated CeD, we demonstrate with extensive single-cell sequencing that a diverse TCR repertoire enables recognition of the immunodominant HLA-DQ2.2-glut-L1 epitope. The crystal structure of two CeD patient-derived TCR in complex with HLA-DQ2.2 and DQ2.2-glut-L1 (PFSEQEQPV) revealed a docking strategy, and associated interatomic contacts, which was notably distinct from the structures of the TCR:HLA-DQ2.5:gliadin epitope complexes. Accordingly, while the molecular surfaces of the antigen-binding clefts of HLA-DQ2.5 and HLA-DQ2.2 are very similar, differences in the nature of the peptides presented translates to differences in responding T cell repertoires and the nature of engagement of the respective antigen-presenting molecules, which ultimately is associated with differing disease penetrance.


Assuntos
Doença Celíaca , Antígenos HLA-DQ , Receptores de Antígenos de Linfócitos T , Linfócitos T CD4-Positivos/química , Linfócitos T CD4-Positivos/metabolismo , Doença Celíaca/genética , Doença Celíaca/imunologia , Doença Celíaca/metabolismo , Linhagem Celular , Cristalografia por Raios X , Epitopos de Linfócito T/química , Epitopos de Linfócito T/genética , Epitopos de Linfócito T/metabolismo , Glutens/química , Glutens/imunologia , Glutens/metabolismo , Antígenos HLA-DQ/química , Antígenos HLA-DQ/genética , Antígenos HLA-DQ/metabolismo , Humanos , Modelos Moleculares , Ligação Proteica , Receptores de Antígenos de Linfócitos T/química , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos de Linfócitos T/metabolismo
4.
J Am Soc Nephrol ; 31(2): 365-373, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31919107

RESUMO

BACKGROUND: Primary membranoproliferative GN, including complement 3 (C3) glomerulopathy, is a rare, untreatable kidney disease characterized by glomerular complement deposition. Complement gene mutations can cause familial C3 glomerulopathy, and studies have reported rare variants in complement genes in nonfamilial primary membranoproliferative GN. METHODS: We analyzed whole-genome sequence data from 165 primary membranoproliferative GN cases and 10,250 individuals without the condition (controls) as part of the National Institutes of Health Research BioResource-Rare Diseases Study. We examined copy number, rare, and common variants. RESULTS: Our analysis included 146 primary membranoproliferative GN cases and 6442 controls who were unrelated and of European ancestry. We observed no significant enrichment of rare variants in candidate genes (genes encoding components of the complement alternative pathway and other genes associated with the related disease atypical hemolytic uremic syndrome; 6.8% in cases versus 5.9% in controls) or exome-wide. However, a significant common variant locus was identified at 6p21.32 (rs35406322) (P=3.29×10-8; odds ratio [OR], 1.93; 95% confidence interval [95% CI], 1.53 to 2.44), overlapping the HLA locus. Imputation of HLA types mapped this signal to a haplotype incorporating DQA1*05:01, DQB1*02:01, and DRB1*03:01 (P=1.21×10-8; OR, 2.19; 95% CI, 1.66 to 2.89). This finding was replicated by analysis of HLA serotypes in 338 individuals with membranoproliferative GN and 15,614 individuals with nonimmune renal failure. CONCLUSIONS: We found that HLA type, but not rare complement gene variation, is associated with primary membranoproliferative GN. These findings challenge the paradigm of complement gene mutations typically causing primary membranoproliferative GN and implicate an underlying autoimmune mechanism in most cases.


Assuntos
Complemento C3/imunologia , Glomerulonefrite Membranoproliferativa/genética , Sequenciamento Completo do Genoma , Fator Nefrítico do Complemento 3/análise , Feminino , Glomerulonefrite Membranoproliferativa/etiologia , Antígenos HLA-DQ/genética , Antígenos HLA-DR/genética , Humanos , Masculino , Sorogrupo
5.
Nat Commun ; 10(1): 5247, 2019 11 20.
Artigo em Inglês | MEDLINE | ID: mdl-31748512

RESUMO

Individuals with narcolepsy suffer from abnormal sleep patterns due to loss of neurons that uniquely supply hypocretin (HCRT). Previous studies found associations of narcolepsy with the human leukocyte antigen (HLA)-DQ6 allele and T-cell receptor α (TRA) J24 gene segment and also suggested that in vitro-stimulated T cells can target HCRT. Here, we present evidence of in vivo expansion of DQ6-HCRT tetramer+/TRAJ24+/CD4+ T cells in DQ6+ individuals with and without narcolepsy. We identify related TRAJ24+ TCRαß clonotypes encoded by identical α/ß gene regions from two patients and two controls. TRAJ24-G allele+ clonotypes only expand in the two patients, whereas a TRAJ24-C allele+ clonotype expands in a control. A representative tetramer+/G-allele+ TCR shows signaling reactivity to the epitope HCRT87-97. Clonally expanded G-allele+ T cells exhibit an unconventional effector phenotype. Our analysis of in vivo expansion of HCRT-reactive TRAJ24+ cells opens an avenue for further investigation of the autoimmune contribution to narcolepsy development.


Assuntos
Autoimunidade/imunologia , Linfócitos T CD4-Positivos/imunologia , Narcolepsia/imunologia , Orexinas/imunologia , Animais , Autoimunidade/genética , Estudos de Casos e Controles , Proliferação de Células , Cristalografia por Raios X , Drosophila , Antígenos HLA-DQ/genética , Antígenos HLA-DQ/imunologia , Humanos , Região de Junção de Imunoglobulinas/genética , Narcolepsia/genética , Tolerância Periférica , Fenótipo , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia
6.
Hum Immunol ; 80(12): 966-975, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31604581

RESUMO

BACKGROUND: HLA mismatching is a well known risk factor for worst outcomes in kidney transplantation. METHODS: In the present study, HLA antigen and eplet mismatches were determined in 151 living donor-recipient pairs transplanted between 2007 and 2014 and rejection episodes and graft survival were evaluated. RESULTS: We found that high HLA-II eplet mismatch load (EpMM ≥ 13, versus low EpMM ≤ 5), was an independent predictor of AMR (adjusted HR = 14.839; P = 0.011), while HLA-II AgMM was not. We also showed that HLA-II EpMM load was a significant better predictor of AMR than AgMM (c-statistic = 0.064; P = 0.023). After discriminating HLA-II into HLA-DR and HLA-DQ loci we demonstrated that high versus low eplet mismatch load for HLA-DR (T3 ≥ 6 versus T = 0-1, p = 0.013) and HLA-DQ (T3 ≥ 7 versus T = 0-1, p = 0.009) are independent predictors for AMR. HLA-II EpMM increased discrimination performance of the classical HLA-II AgMM risk model (IDI, 0.061, 95%CI: 0.005-0.195) for AMR. Compared with AgMM, HLA-II eplet model adequately reclassified 13 of 17 patients (76.5%) with AMR and 92 of 134 patients (68.7%) without AMR (cfNRI, 0.785, 95%CI: 0.300-1.426). CONCLUSIONS: Our study evidences that eplet-based matching is a refinement of the classical HLA antigen mismatch analysis in LDKT and is a potential biomarker for personalized assessment of alloimmune risk.


Assuntos
Rejeição de Enxerto/genética , Antígenos HLA-DQ/genética , Antígenos HLA-DR/genética , Isoanticorpos/metabolismo , Transplante de Rim , Doença Aguda , Idoso , Idoso de 80 Anos ou mais , Seguimentos , Rejeição de Enxerto/diagnóstico , Antígenos HLA-DQ/imunologia , Antígenos HLA-DR/imunologia , Histocompatibilidade/genética , Teste de Histocompatibilidade , Humanos , Imunidade Humoral , Doadores Vivos , Pessoa de Meia-Idade , Medicina de Precisão , Prognóstico , Risco
7.
mSphere ; 4(5)2019 10 09.
Artigo em Inglês | MEDLINE | ID: mdl-31597722

RESUMO

Nonmenstrual toxic shock syndrome (nmTSS), linked to TSST-1-producing CC30 Staphylococcus aureus, is the leading manifestation of toxic shock syndrome (TSS). Due to case rarity and a lack of tractable animal models, TSS pathogenesis is poorly understood. We developed an S. aureus abscess model in HLA class II transgenic mice to investigate pathogenesis and treatment. TSST-1 sensitivity was established using murine spleen cell proliferation assays and cytokine assays following TSST-1 injection in vivo HLA-DQ8 mice were infected subcutaneously with a tst-positive CC30 methicillin-sensitive S. aureus clinical TSS-associated isolate. Mice received intraperitoneal flucloxacillin, clindamycin, flucloxacillin and clindamycin, or a control reagent. Abscess size, bacterial counts, TSST-1 expression, and TSST-1 bioactivity were measured in tissues. Antibiotic effects were compared with the effects of control reagent. Purified TSST-1 expanded HLA-DQ8 T-cell Vß subsets 3 and 13 in vitro and instigated cytokine release in vivo, confirming TSST-1 sensitivity. TSST-1 was detected in abscesses (0 to 8.0 µg/ml) and draining lymph nodes (0 to 0.2 µg/ml) of infected mice. Interleukin 6 (IL-6), gamma interferon (IFN-γ), KC (CXCL1), and MCP-1 were consistent markers of inflammation during infection. Clindamycin-containing antibiotic regimens reduced abscess size and TSST-1 production. Infection led to detectable TSST-1 in soft tissues, and TSST-1 was detected in draining lymph nodes, events which may be pivotal to TSS pathogenesis. The reduction in TSST-1 production and lesion size after a single dose of clindamycin underscores a potential role for adjunctive clindamycin at the start of treatment of patients suspected of having TSS to alter disease progression.IMPORTANCE Staphylococcal toxic shock syndrome (TSS) is a life-threatening illness causing fever, rash, and shock, attributed to toxins produced by the bacterium Staphylococcus aureus, mainly toxic shock syndrome toxin 1 (TSST-1). TSS was in the past commonly linked with menstruation and high-absorbency tampons; now, TSS is more frequently triggered by other staphylococcal infections, particularly of skin and soft tissue. Investigating the progress and treatment of TSS in patients is challenging, as TSS is rare; animal models do not mimic TSS adequately, as toxins interact best with human immune cells. We developed a new model of staphylococcal soft tissue infection in mice producing human immune cell proteins, rendering them TSST-1 sensitive, to investigate TSS. The significance of our research was that TSST-1 was found in soft tissues and immune organs of mice and that early treatment of mice with the antibiotic clindamycin altered TSST-1 production. Therefore, the early treatment of patients suspected of having TSS with clindamycin may influence their response to treatment.


Assuntos
Antibacterianos/uso terapêutico , Toxinas Bacterianas/genética , Enterotoxinas/genética , Choque Séptico/microbiologia , Infecções dos Tecidos Moles/microbiologia , Infecções Estafilocócicas/tratamento farmacológico , Superantígenos/genética , Animais , Citocinas , Modelos Animais de Doenças , Feminino , Antígenos HLA-DQ/genética , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Choque Séptico/tratamento farmacológico , Infecções dos Tecidos Moles/tratamento farmacológico , Infecções Estafilocócicas/microbiologia , Staphylococcus aureus/efeitos dos fármacos , Staphylococcus aureus/patogenicidade
8.
Pediatrics ; 144(4)2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31492765

RESUMO

BACKGROUND AND OBJECTIVES: Celiac disease (CeD) is associated with psychopathology in children. It is unknown whether this association is present in children with celiac disease autoimmunity (CDA) identified by screening. We examined the associations between subclinical CDA and emotional and behavioral problems in children without previous CeD diagnosis. METHODS: In a population-based cohort study of 3715 children (median age: 6 years), blood titers of tissue transglutaminase autoantibodies were analyzed. CDA was defined as a measurement of tissue transglutaminase autoantibodies ≥7 U/mL (n = 51). Children with previous CeD diagnosis or children on a gluten-free diet, were excluded. The Child Behavior Checklist (CBCL) was filled in by parents and was used to assess behavioral and emotional problems of children at a median age of 5.9 years. Multiple linear regression models were applied to evaluate the cross-sectional associations between CDA and CBCL scores. Sensitivity analyses were done in a subgroup of children who were seropositive carrying the HLA antigen risk alleles for CeD. RESULTS: In basic models, CDA was not associated with emotional and behavioral problems on the CBCL scales. After adjustment for confounders, CDA was significantly associated with anxiety problems (ß = .29; 95% confidence interval 0.02 to 0.55; P = .02). After exclusion of children who did not carry the HLA-DQ2 and/or HLA-DQ8 risk alleles (n = 4), CDA was additionally associated with oppositional defiant problems (ß = .35; 95% confidence interval 0.02 to 0.69). Associations were not explained by gastrointestinal complaints. CONCLUSIONS: Our results reveal that CDA, especially combined with the HLA-DQ2 and HLA-DQ8 risk alleles, is associated with anxiety problems and oppositional defiant problems. Further research should be used to establish whether behavioral problems are a reflection of subclinical CeD.


Assuntos
Ansiedade/imunologia , Transtornos de Deficit da Atenção e do Comportamento Disruptivo/imunologia , Doenças Autoimunes/psicologia , Doença Celíaca/imunologia , Doença Celíaca/psicologia , Autoanticorpos/sangue , Doenças Autoimunes/sangue , Doenças Autoimunes/genética , Doença Celíaca/sangue , Doença Celíaca/diagnóstico , Lista de Checagem , Criança , Pré-Escolar , Intervalos de Confiança , Feminino , Proteínas de Ligação ao GTP/imunologia , Antígenos HLA-DQ/sangue , Antígenos HLA-DQ/genética , Humanos , Lactente , Modelos Lineares , Masculino , Comportamento Problema/psicologia , Estudos Prospectivos , Sensibilidade e Especificidade , Fatores Sexuais , Transglutaminases/imunologia
9.
Curr Pharm Biotechnol ; 20(14): 1181-1193, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31456516

RESUMO

Celiac Disease (CD) is a complex autoimmune enteropathy of the small intestine that commonly occurs in genetically predisposed individuals due to intake of gluten and related proteins. Gluten consumption, duration of breast-feeding, various infections, especially frequent intestinal infections, vaccinations and use of antibiotics can be linked to CD. It is predicted that it affects 1% of the global population and its incidence rate is increasing. Most of the people with the HLA-DQ2 or HLADQ8 are at a higher risk of developing this disease. The link between infections and autoimmune diseases has been very much considered in recent years. In several studies, we explained that pathogenic and non-pathogenic microorganisms might have multiple roles in initiation, exacerbation, and development of Irritable Bowel Syndrome (IBS) and Inflammatory Bowel Disease (IBD). In various studies, the relationship between infections caused by viruses, such as Epstein-Barr Virus (EBV), Rotavirus, Hepatitis C (HCV), Hepatitis B virus (HBV), Cytomegalovirus (CMV), and Influenza virus, and parasites including Giardia spp. and Toxoplasma gondii with CD has been raised. However, increasing evidence proposes that some of these microorganisms, especially helminths, can also have protective and even therapeutic roles in the CD process. Therefore, in order to determine the role of microorganisms in the process of this disease, we attempted to summarize the evidence suggesting the role of viral and parasitic agents in pathogenesis of CD.


Assuntos
Doenças Autoimunes/imunologia , Doença Celíaca/imunologia , Parasitos , Vírus , Animais , Doenças Autoimunes/parasitologia , Doenças Autoimunes/virologia , Doença Celíaca/parasitologia , Doença Celíaca/virologia , Glutens/efeitos adversos , Antígenos HLA-DQ/genética , Humanos , Parasitos/imunologia , Vírus/imunologia
10.
BMC Med ; 17(1): 165, 2019 08 23.
Artigo em Inglês | MEDLINE | ID: mdl-31438962

RESUMO

BACKGROUND: The objective of this cross-sectional study was to explore the relationship of detectable C-peptide secretion in type 1 diabetes to clinical features and to the genetic architecture of diabetes. METHODS: C-peptide was measured in an untimed serum sample in the SDRNT1BIO cohort of 6076 Scottish people with clinically diagnosed type 1 diabetes or latent autoimmune diabetes of adulthood. Risk scores at loci previously associated with type 1 and type 2 diabetes were calculated from publicly available summary statistics. RESULTS: Prevalence of detectable C-peptide varied from 19% in those with onset before age 15 and duration greater than 15 years to 92% in those with onset after age 35 and duration less than 5 years. Twenty-nine percent of variance in C-peptide levels was accounted for by associations with male gender, late age at onset and short duration. The SNP heritability of residual C-peptide secretion adjusted for gender, age at onset and duration was estimated as 26%. Genotypic risk score for type 1 diabetes was inversely associated with detectable C-peptide secretion: the most strongly associated loci were the HLA and INS gene regions. A risk score for type 1 diabetes based on the HLA DR3 and DQ8-DR4 serotypes was strongly associated with early age at onset and inversely associated with C-peptide persistence. For C-peptide but not age at onset, there were strong associations with risk scores for type 1 and type 2 diabetes that were based on SNPs in the HLA region but not accounted for by HLA serotype. CONCLUSIONS: Persistence of C-peptide secretion varies widely in people clinically diagnosed as type 1 diabetes. C-peptide persistence is influenced by variants in the HLA region that are different from those determining risk of early-onset type 1 diabetes. Known risk loci for diabetes account for only a small proportion of the genetic effects on C-peptide persistence.


Assuntos
Peptídeo C/sangue , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/genética , Adolescente , Adulto , Idade de Início , Estudos Transversais , Progressão da Doença , Feminino , Genótipo , Antígenos HLA-DQ/genética , Humanos , Masculino , Fatores de Risco , Adulto Jovem
11.
Sci Adv ; 5(8): eaaw9336, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31457096

RESUMO

Human leukocyte antigen (HLA)-DQ8 transdimer (HLA-DQA1*0501/DQB1*0302) confers exceptionally high risk in autoimmune diabetes. However, little is known about HLA-DQ8 transdimer-restricted CD4 T cell recognition, an event crucial for triggering HLA-DQ8 transdimer-specific anti-islet immunity. Here, we report a high degree of epitope overlap and T cell promiscuity between susceptible HLA-DQ8 and HLA-DQ8 transdimer. Despite preservation of putative residues for T cell receptor (TCR) contact, stronger disease-associated responses to cross-reactive, immunodominant islet epitopes are elicited by HLA-DQ8 transdimer. Mutagenesis at the α chain of HLA-DQ8 transdimer in complex with the disease-relevant GAD65250-266 peptide and in silico analysis reveal the DQ α52 residue located within the N-terminal edge of the peptide-binding cleft for the enhanced T cell reactivity, altering avidity and biophysical affinity between TCR and HLA-peptide complexes. Accordingly, a structurally promiscuous but nondegenerate TCR-HLA-peptide interface is pivotal for HLA-DQ8 transdimer-mediated autoimmune diabetes.


Assuntos
Autoantígenos/imunologia , Reações Cruzadas/imunologia , Antígenos HLA-DQ/imunologia , Ilhotas Pancreáticas/imunologia , Linfócitos T/imunologia , Linfócitos T/metabolismo , Alelos , Sequência de Aminoácidos , Diabetes Mellitus Tipo 1/etiologia , Diabetes Mellitus Tipo 1/metabolismo , Epitopos/química , Epitopos/imunologia , Antígenos HLA-DQ/química , Antígenos HLA-DQ/genética , Humanos , Modelos Moleculares , Multimerização Proteica , Relação Estrutura-Atividade , Especificidade do Receptor de Antígeno de Linfócitos T
13.
Am J Gastroenterol ; 114(10): 1587-1592, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31274511

RESUMO

Celiac disease is a common inflammatory disease triggered by dietary gluten in genetically susceptible individuals. The strongest and best-characterized genetic susceptibilities in celiac disease are class II human leukocyte antigen (HLA) genes known as HLA-DQ2 and DQ8. HLA genetic testing is available through a number of commercial and academic laboratories and is used in the evaluation of celiac disease and to identify at-risk family members. Importantly, HLA genetic testing has a high negative predictive value for celiac disease, but a low positive predictive value. Therefore, for a practicing clinician, it is important to understand when to order HLA genetic testing, what test to order, and how to interpret the result. This review provides a practical primer on HLA genetics in celiac disease.


Assuntos
Doença Celíaca/diagnóstico , Testes Genéticos/normas , Antígenos HLA-DQ/genética , Guias de Prática Clínica como Assunto , Biomarcadores/sangue , Biópsia , Doença Celíaca/sangue , Doença Celíaca/genética , Doença Celíaca/imunologia , Duodeno/imunologia , Duodeno/metabolismo , Duodeno/patologia , Gastroenterologia/normas , Predisposição Genética para Doença , Glutens/imunologia , Glutens/metabolismo , Antígenos HLA-DQ/imunologia , Humanos , Absorção Intestinal/genética , Absorção Intestinal/imunologia , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/patologia , Valor Preditivo dos Testes
14.
Nutrients ; 11(6)2019 May 29.
Artigo em Inglês | MEDLINE | ID: mdl-31146428

RESUMO

BACKGROUND: Non-Celiac Wheat Sensitivity (NCWS) is still a largely undefined condition, due to the lack of a diagnostic marker. Few data are available about the nutritional characteristics of NCWS patients at diagnosis. AIMS: To evaluate the proportion of NCWS patients who were underweight, normal weight, overweight, or obese at diagnosis, and to search for possible correlations between their Body Mass Index (BMI) and other NCWS-related disease characteristics. PATIENTS AND METHODS: The clinical charts of 145 NCWS patients (125 F, 20 M, mean age 37.1 ± 11.4 years), diagnosed between January 2012 and March 2018, were reviewed. As a comparison, 84 celiac disease (CD) patients (73 F, 11 M, mean age 39.8 ± 13.9 years) were evaluated. All NCWS diagnoses were based on a double-blind placebo-controlled wheat challenge (DBPCWC) method. RESULTS: BMI distribution was similar in the NCWS (6.2% underweight and 15.2% obese subjects) and CD patients (6% underweight and 7.1% obese subjects). Underweight NCWS subjects were significantly younger and had a shorter clinical history than the overweight or obese ones. Unlike the other NCWS patients, none of them had a DQ2 and/or DQ8 haplotype. Overweight and obese NCWS patients were more frequently suffering from associated autoimmune diseases than the other BMI categories (P = 0.05). Compared to the CD controls, NCWS patients showed a higher frequency of Irritable Bowel Syndrome (IBS)-like (P = 0.01) and extraintestinal symptoms (P = 0.03) and a longer clinical history (P = 0.04), whereas weight loss was more frequent in CD (P = 0.02). CONCLUSIONS: NCWS patients showed a BMI distribution similar to CD patients. However, NCWS was found to be a heterogenous condition that regards BMI, and clinical characteristics differed between the underweight and overweight/obese patients.


Assuntos
Índice de Massa Corporal , Sobrepeso/fisiopatologia , Magreza/fisiopatologia , Hipersensibilidade a Trigo/fisiopatologia , Adulto , Autoimunidade , Feminino , Antígenos HLA-DQ/genética , Antígenos HLA-DQ/imunologia , Haplótipos , Humanos , Masculino , Pessoa de Meia-Idade , Sobrepeso/diagnóstico , Sobrepeso/imunologia , Prognóstico , Estudos Retrospectivos , Magreza/diagnóstico , Magreza/imunologia , Hipersensibilidade a Trigo/diagnóstico , Hipersensibilidade a Trigo/imunologia
15.
Indian J Gastroenterol ; 38(3): 203-210, 2019 06.
Artigo em Inglês | MEDLINE | ID: mdl-31183842

RESUMO

BACKGROUND: Celiac disease (CD) is a lifelong condition with significant morbidity and requires an accurate diagnosis. Guidelines for pediatric CD were revised by the European and British Societies of Paediatric Gastroenterology Hepatology and Nutrition in 2012 and 2013, respectively. New recommendations introduced non-biopsy pathway (NBP) of diagnosis for a selective group of symptomatic children whose anti-tissue transglutaminase (anti-tTG) antibody titer is greater than ten times upper limit of normal. A clear understanding of the guidelines amongst consultant pediatricians will ensure all children with suspected CD receive a prompt and secure diagnosis. The aim of this study was to establish the interpretation and implementation of the revised guideline for CD amongst consultant general pediatricians in Southwest England (SWE) during the study period. METHODS: Telephone/email survey was conducted amongst consultant general pediatricians (n ≈ 140) working in 12 secondary care hospitals across SWE. The survey included eight questions incorporating three main themes: understanding of diagnostic pathway particularly for non-biopsy diagnosis, awareness of laboratory tests involved, and variations in practice in relation to the revised guidelines. RESULTS: Responses were available from 101/140 (72%). One hundred respondents were aware of the revised guidelines for diagnosing CD. However, only 17 respondents stated all the criteria of the guideline required for diagnosis by NBP, with further 17 seeking immediate advice from a specialist. Forty-four listed both the criteria for HLA-DQ2/DQ8 testing applicable to pediatricians. Forty-nine out of 100 pediatricians would commence gluten-free diet only after all the results were available. Thirty-three pediatricians also considered asymptomatic children with high anti-tTG titer eligible for diagnosis of CD by NBP. CONCLUSIONS: There is a need for improved understanding of revised CD guidelines amongst consultant general pediatricians especially while using the NBP and requesting HLA-DQ2/DQ8 testing.


Assuntos
Doença Celíaca/diagnóstico , Gastroenterologia , Conhecimentos, Atitudes e Prática em Saúde , Pediatria , Padrões de Prática Médica , Autoanticorpos/sangue , Doença Celíaca/dietoterapia , Dieta Livre de Glúten , Inglaterra , Proteínas de Ligação ao GTP/imunologia , Testes Genéticos , Antígenos HLA-DQ/genética , Haplótipos , Humanos , Guias de Prática Clínica como Assunto , Inquéritos e Questionários , Transglutaminases/imunologia
16.
Genet Test Mol Biomarkers ; 23(6): 418-422, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31066583

RESUMO

Aim: Celiac disease (CD) is strongly associated with HLA-DQ2.2, HLA-DQ2.5, and HLA-DQ8. Up to 99.7% of all CD patients are positive for either one or two of these genetic markers, demonstrating a high negative predictive value. This has led to the development of diagnostic kits that, instead of providing a full HLA-DQ typing, detect only these three HLA-DQ types. Our aim was to compare three different kits for their performance, utilization, and costs. Because 0.4-3.6% of all CD patients test positive for HLA-DQ7 and negative for the aforementioned types, information provided by the kits regarding DQ7 alpha and beta chains was evaluated as well. Materials and Methods: Fifty DNA samples previously typed with the SSCP method were analyzed using three commercial kits. Results and Discussion: All kits report hetero- or homozygosity for HLA-DQ2.5. The XeliGen kit directly detects HLA-DQ7, but is relatively expensive. The MLPA kit is the least expensive in terms of reagents and may indirectly detect HLA-DQ7. The CeliaSCAN kit is easy to use and provides indirect information about HLA-DQ7.5. Conclusion: All kits correctly identify the CD risk genes. The resources of the laboratory and the intended use should determine the preference for any of the HLA-DQ typing kits herein described.


Assuntos
Doença Celíaca/diagnóstico , Antígenos HLA-DQ/genética , Teste de Histocompatibilidade/métodos , Alelos , Doença Celíaca/genética , Feminino , Frequência do Gene/genética , Marcadores Genéticos , Predisposição Genética para Doença/genética , Testes Genéticos/métodos , Genótipo , Humanos , Masculino , Kit de Reagentes para Diagnóstico , Fatores de Risco
17.
Mol Immunol ; 112: 40-50, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31078115

RESUMO

The classical HLA class I genes (HLA Ia) were extensively studied because of their implication in clinical fields and anthropology. Less is known about worldwide genetic diversity and linkage disequilibrium for non-classical HLA class I genes (HLA Ib) and HLA pseudogenes. Notably, HLA-H, which is deleted in a fraction of the population, remains scarcely explored. The aims of this study were 1/ to get further insight into HLA-H genetic diversity and into how this variability potentially affects its expression and 2/ to define HLA Ib worldwide allelic diversity and linkage. Exome sequence data from the 1000 Genomes Project were used to define second field HLA-A, -E, -F, -G and -H typing using PolyPheMe software. Allelic and two-loci haplotype frequencies were estimated using Gene[Rate] software both at worldwide and continental levels. Eleven novel HLA-H alleles identified in exome data were validated by NGS performed on 25 genomic DNA samples from the same cohort. Phylogenetic analysis and frequency distribution of HLA-H alleles revealed three clades, each predominantly represented in Admixed American, European and East Asian populations, African populations and South Asian populations. Among these eleven novel alleles, two potentially encode complete transmembrane HLA proteins. We confirm the high LD between HLA-H and -A, and between HLA-H and -G, and show the three genes have distinct worldwide allelic distribution. Conversely, HLA-E and HLA-F both showed little LD, displayed restricted allelic diversity and practically no difference in their distribution across the planet. Our work thus reveals an unexpectedly high HLA-H genetic diversity, with alleles highly represented in Asia possibly encoding a functional HLA protein. Functional implication of these results remains to be explored, both in physiological and pathological contexts.


Assuntos
Variação Genética/genética , Antígenos HLA-DQ/genética , Haplótipos/genética , Proteína da Hemocromatose/genética , Alelos , Ásia , Grupo com Ancestrais do Continente Asiático/genética , Frequência do Gene/genética , Genes MHC Classe I/genética , Humanos , Desequilíbrio de Ligação/genética , Filogenia
18.
DNA Cell Biol ; 38(7): 708-717, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31081687

RESUMO

microRNAs (miRNAs) are a novel class of single-stranded RNAs with a key role in the regulation of gene expression. miRNA main mechanism of action involves interaction with the mRNA transcribed from the genes, leading to the target mRNA silencing and degradation. Indeed, it is easy to conceive that a defective miRNA-based mRNA regulation may compromise normal cell function and cause genetic diseases. A wide spectrum of studies has focused on the identification and introduction of regulatory diseases-specific miRNAs for the past decade. Overexpression or downregulation of several miRNAs can potentially stimulate or inhibit pathways related to the pathogenesis of celiac disease (CD). CD is a chronic inflammatory disease characterized by small intestinal mucosal injury and nutrient malabsorption in genetically susceptible individuals after the dietary ingestion of gluten. The disease is characterized by villous atrophy, intraepithelial lymphocyte infiltration, and chronic inflammation and activation of lamina propria T cells. The common genetic background in CD is the presence of heterodimeric human leukocyte antigen class II molecules DQ2 or DQ8 that account for ∼40% of the genetic predisposition in this disease. In fact, by minute identification of these miRNAs and related targets and mechanisms, specific therapeutics can be developed to suppress these pathophysiological pathways through the enhancement or inhibition of miRNAs. This development can open a new prospect for personalized medicine.


Assuntos
Doença Celíaca/genética , MicroRNAs/genética , Biomarcadores/metabolismo , Doença Celíaca/metabolismo , Doença Celíaca/patologia , Glutens/metabolismo , Antígenos HLA-DQ/genética , Antígenos HLA-DQ/metabolismo , Humanos , MicroRNAs/metabolismo
19.
Indian J Gastroenterol ; 38(2): 178-182, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-31025255

RESUMO

Celiac disease (CeD) occurs only in individuals who are able to express human leukocyte antigens (HLA) DQ2 or DQ8, and these are expressed in nearly a third of healthy people in the West. As the disease is very uncommon in Tamil Nadu, we evaluated the possibility that the relevant genes are infrequent in this population. Four hundred healthy adults without any gastrointestinal abnormalities were recruited from Vellore district of Tamil Nadu. Genomic DNA was extracted from venous blood and amplified by PCR using the allele-specific primers for the following alleles-DQA1*0201, 0301, and 0501 and DQB1*02, 0201, and 0302, which determine the CeD risk haplotypes. Among the 400 healthy adults, the presence of DQ2.5 (DQB1*0201-DQA1*0501) and DQ2.2 (DQB1*02-DQA1*0201) haplotypes was found in 8.25% and 14.25%, respectively. DQ8 (DQB1*0302-DQA1*0301) haplotype was identified in only 3% of healthy individuals. Overall, approximately a quarter of healthy adults in Tamil Nadu had the potential CeD risk haplotypes of HLA DQ2.5, DQ2.2, and DQ8.


Assuntos
Doença Celíaca/genética , Frequência do Gene/genética , Antígenos HLA-DQ/genética , Haplótipos/genética , Adolescente , Adulto , Idoso , Feminino , Predisposição Genética para Doença/genética , Genética Populacional , Humanos , Índia , Masculino , Pessoa de Meia-Idade , Risco , Adulto Jovem
20.
Nat Commun ; 10(1): 1198, 2019 03 13.
Artigo em Inglês | MEDLINE | ID: mdl-30867416

RESUMO

Microbe-host interactions are generally homeostatic, but when dysfunctional, they can incite food sensitivities and chronic diseases. Celiac disease (CeD) is a food sensitivity characterized by a breakdown of oral tolerance to gluten proteins in genetically predisposed individuals, although the underlying mechanisms are incompletely understood. Here we show that duodenal biopsies from patients with active CeD have increased proteolytic activity against gluten substrates that correlates with increased Proteobacteria abundance, including Pseudomonas. Using Pseudomonas aeruginosa producing elastase as a model, we show gluten-independent, PAR-2 mediated upregulation of inflammatory pathways in C57BL/6 mice without villus blunting. In mice expressing CeD risk genes, P. aeruginosa elastase synergizes with gluten to induce more severe inflammation that is associated with moderate villus blunting. These results demonstrate that proteases expressed by opportunistic pathogens impact host immune responses that are relevant to the development of food sensitivities, independently of the trigger antigen.


Assuntos
Proteínas de Bactérias/metabolismo , Doença Celíaca/imunologia , Proteínas na Dieta/imunologia , Interações entre Hospedeiro e Microrganismos/imunologia , Metaloendopeptidases/metabolismo , Receptor PAR-2/imunologia , Adulto , Idoso , Animais , Antígenos/imunologia , Antígenos/metabolismo , Proteínas de Bactérias/genética , Biópsia , Estudos de Casos e Controles , Doença Celíaca/diagnóstico por imagem , Doença Celíaca/microbiologia , Doença Celíaca/patologia , Estudos de Coortes , Colonoscopia , Proteínas na Dieta/metabolismo , Modelos Animais de Doenças , Duodeno/imunologia , Duodeno/metabolismo , Duodeno/microbiologia , Duodeno/patologia , Feminino , Microbioma Gastrointestinal/imunologia , Vida Livre de Germes , Glutens/imunologia , Glutens/metabolismo , Antígenos HLA-DQ/genética , Antígenos HLA-DQ/imunologia , Antígenos HLA-DQ/metabolismo , Humanos , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiologia , Mucosa Intestinal/patologia , Masculino , Metaloendopeptidases/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos NOD , Camundongos Transgênicos , Pessoa de Meia-Idade , Proteólise , Pseudomonas aeruginosa/imunologia , Pseudomonas aeruginosa/metabolismo , Receptor PAR-2/metabolismo , Regulação para Cima , Adulto Jovem
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