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1.
Oral Health Prev Dent ; 18(3): 455-460, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32515416

RESUMO

PURPOSE: Integration of genetic information into our understanding of oral diseases has fostered the hope to intervene the disease process among genetically susceptible individuals. Oral submucous fibrosis (OSF) (mainly in the Southeast Asia region) and tobacco smoking are two of the major public health problems the world is facing today. With more and more diseases being associated with alleles of the human leukocyte antigen (HLA), the objective of the study was to explore any genetic association of OSF and smoking behaviour with specific HLA Class II DQB1*0503 and HLA DRB1*0301 alleles. MATERIALS AND METHODS: Genomic DNA was extracted from saliva of 64 patients divided into an OSF group, a tobacco smokers group and a control group. This was followed by polymerase chain reaction (PCR) with sequence-specific primer of HLA-DQB1*0503 and HLA DRB1*0301 allele, visualised under 2% agarose gel. RESULTS: A statistically significant difference was observed between the OSF group and controls in presence of HLA-DQB1*0503 allele, with 84% of the patients showing the presence. Frequency of HLA DRB1*0301 allele was also found to be significantly higher (72%) among OSF patients (p <0.001). Similar results were shown in tobacco smokers with 28% cases showing presence of HLA DRB1*0301 allele and 13 (52%) of them having DQB1*0503 allele (p <0.001). CONCLUSION: HLA-DRB1*0301 and HLA-DQB1*0503 are statistically significantly associated with susceptibility to OSF and smoking behaviour.


Assuntos
Antígenos HLA-DQ , Fibrose Oral Submucosa , Frequência do Gene , Genótipo , Cadeias HLA-DRB1 , Haplótipos , Humanos , Fumar Tabaco
2.
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
3.
4.
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
5.
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
6.
Nat Struct Mol Biol ; 27(1): 49-61, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31873306

RESUMO

The human leukocyte antigen (HLA) locus is strongly associated with T cell-mediated autoimmune disorders. HLA-DQ2.5-mediated celiac disease (CeD) is triggered by the ingestion of gluten, although the relative roles of genetic and environmental risk factors in CeD is unclear. Here we identify microbially derived mimics of gliadin epitopes and a parental bacterial protein that is naturally processed by antigen-presenting cells and activated gliadin reactive HLA-DQ2.5-restricted T cells derived from CeD patients. Crystal structures of T cell receptors in complex with HLA-DQ2.5 bound to two distinct bacterial peptides demonstrate that molecular mimicry underpins cross-reactivity toward the gliadin epitopes. Accordingly, gliadin reactive T cells involved in CeD pathogenesis cross-react with ubiquitous bacterial peptides, thereby suggesting microbial exposure as a potential environmental factor in CeD.


Assuntos
Bactérias/imunologia , Doença Celíaca/imunologia , Gliadina/imunologia , Peptídeos/imunologia , Receptores de Antígenos de Linfócitos T/imunologia , Triticum/imunologia , Bactérias/química , Doença Celíaca/microbiologia , Linhagem Celular , Células Cultivadas , Reações Cruzadas , Cristalografia por Raios X , Epitopos/imunologia , Gliadina/química , Glutens/imunologia , Antígenos HLA-DQ/química , Antígenos HLA-DQ/imunologia , Humanos , Modelos Moleculares , Mimetismo Molecular , Peptídeos/química , Receptores de Antígenos de Linfócitos T/química , Linfócitos T/imunologia , Triticum/química
7.
Immunogenetics ; 71(10): 665-667, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31673720

RESUMO

Celiac disease is a chronic inflammatory condition of the small intestine caused by aberrant adaptive immune response to gluten protein from wheat and related cereal plants. Over 90% of celiac disease patients carry the HLA-DQ2.5 allotype and HLA-DQ2.5 presents gluten peptides to gluten-reactive CD4+ T cells in celiac disease patients. A large number of HLA-DQ2.5-restricted gluten T cell epitopes have been identified over the years. These epitopes are in general proline-rich and contain at least one glutamic acid residue that is generated from glutamine in the native gluten protein by deamidation. The deamidation is mediated by the enzyme transglutaminase 2 (TG2). It has been shown that the same T cell could recognize several different HLA-DQ2.5-restricted gluten T cell epitopes due to sequence similarities. In this paper, we demonstrate that three T cell clones derived from duodenal biopsies of different celiac disease patients are able to respond to at least five different gluten T cell epitopes within the DQ2.5-glia-γ4 epitope family, including two novel epitopes.


Assuntos
Doença Celíaca/imunologia , Epitopos de Linfócito T/imunologia , Glutens/imunologia , Antígenos HLA-DQ/imunologia , Fragmentos de Peptídeos/imunologia , Linfócitos T/imunologia , Humanos
8.
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
9.
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
10.
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
11.
Proc Natl Acad Sci U S A ; 116(39): 19600-19608, 2019 09 24.
Artigo em Inglês | MEDLINE | ID: mdl-31501349

RESUMO

HLA class II genes provide the strongest genetic contribution to rheumatoid arthritis (RA). HLA-DRB1 alleles encoding the sequence DERAA are RA-protective. Paradoxically, RA risk is increased in women with DERAA+ children born prior to onset. We developed a sensitive qPCR assay specific for DERAA, and found 53% of DERAA-/- women with RA had microchimerism (Mc; pregnancy-derived allogeneic cells) carrying DERAA (DERAA-Mc) vs. 6% of healthy women. DERAA-Mc quantities correlated with an RA-risk genetic background including DERAA-binding HLA-DQ alleles, early RA onset, and aspects of RA severity. CD4+ T cells showed stronger response against DERAA+ vs. DERAA- allogeneic cell lines in vitro, in line with an immunogenic role of allogeneic DERAA. Results indicate a model where DERAA-Mc activates DERAA-directed T cells that are naturally present in DERAA-/- individuals and can have cross-reactivity against joint antigens. Moreover, we provide an explanation for the enigmatic observation that the same HLA sequence differentially affects RA risk through Mendelian inheritance vs. microchimeric cell acquisition.


Assuntos
Artrite Reumatoide/imunologia , Antígenos HLA-DQ/imunologia , Cadeias HLA-DRB1/genética , Adulto , Alelos , Células Alógenas , Quimerismo , Reações Cruzadas , Epitopos/genética , Feminino , Predisposição Genética para Doença , Cadeias HLA-DRB1/metabolismo , Humanos , Linfócitos T/imunologia
12.
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
14.
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
15.
Med Hypotheses ; 130: 109267, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31383332

RESUMO

Presentation of many unwanted epitopes within tetanus toxoid vaccine to lymphocyte clones may lead to production of many unwanted antibodies. Moreover an ideal vaccine must cover all individuals in a population that is dependent to the kinds of human leukocyte antigen alleles. Concerning these issues, our study was aimed to in silico design of a multi-epitope tetanus vaccine (METV) in order to improve population coverage and protectivity of tetanus vaccine as well as reduction of complications. Concerning these issues, a novel rational filtration was implemented to design a novel METV using immunoinformatics and surface epitope mapping approaches. Prediction of epitopes for tetanus toxin was performed in the candidate country in which the frequency had been gathered from almost all geographical distributions. The most strong binder epitopes for major histocompatibility complex class II were selected and among them the surface epitopes of native toxin were selected. The population coverage of the selected epitopes was estimated. The final candidate epitopes had highly population coverage. Molecular docking was performed to prediction of binding affinity of our candidate epitopes to the HLA-DRB1 alleles. At first, 680 strong binder epitopes were predicted. Among them 11 epitopes were selected. Finally, 4 epitopes had the most population coverage and suggested as a tetra-epitope tetanus vaccine. 99.41% of inessential strong binders were deleted using our tree steps filtration. HLA-DP had the most roles in epitope presentation. Molecular docking analysis proved the strong binding affinity of candidate epitopes to the HLA-DRB1 alleles. In conclusion, we theoretically reduced 99.41% of unwanted antibodies using our novel filtration strategies. Our tetra-epitope tetanus vaccine showed 100% population coverage in the candidate country. Furthermore, it was demonstrated that HLA-DP and HLA-DQ had more potential in epitope presentation in comparison to HLA-DRB1.


Assuntos
Mapeamento de Epitopos/métodos , Antígenos HLA/imunologia , Toxoide Tetânico/química , Alelos , Alergia e Imunologia/instrumentação , Biologia Computacional , Desenho de Fármacos , Epitopos , Antígenos HLA-DP/imunologia , Antígenos HLA-DQ/imunologia , Cadeias HLA-DRB1/imunologia , Humanos , Conformação Molecular , Simulação de Acoplamento Molecular
16.
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
17.
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
18.
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
20.
Cell ; 177(6): 1583-1599.e16, 2019 05 30.
Artigo em Inglês | MEDLINE | ID: mdl-31150624

RESUMO

T and B cells are the two known lineages of adaptive immune cells. Here, we describe a previously unknown lymphocyte that is a dual expresser (DE) of TCR and BCR and key lineage markers of both B and T cells. In type 1 diabetes (T1D), DEs are predominated by one clonotype that encodes a potent CD4 T cell autoantigen in its antigen binding site. Molecular dynamics simulations revealed that this peptide has an optimal binding register for diabetogenic HLA-DQ8. In concordance, a synthetic version of the peptide forms stable DQ8 complexes and potently stimulates autoreactive CD4 T cells from T1D patients, but not healthy controls. Moreover, mAbs bearing this clonotype are autoreactive against CD4 T cells and inhibit insulin tetramer binding to CD4 T cells. Thus, compartmentalization of adaptive immune cells into T and B cells is not absolute, and violators of this paradigm are likely key drivers of autoimmune diseases.


Assuntos
Linfócitos B/imunologia , Linfócitos T CD4-Positivos/imunologia , Diabetes Mellitus Tipo 1/imunologia , Adolescente , Adulto , Autoantígenos/imunologia , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/metabolismo , Epitopos/imunologia , Feminino , Células HEK293 , Antígenos HLA-DQ/imunologia , Antígenos HLA-DQ/ultraestrutura , Humanos , Ativação Linfocitária/imunologia , Linfócitos/imunologia , Linfócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Simulação de Dinâmica Molecular , Peptídeos , Ligação Proteica/imunologia
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