RESUMO
Infiltrating and tissue-resident myeloid cells are essential regulators of innate and adaptive immunity. During inflammation, and in response to microbial products, these cells can adapt to microenvironmental conditions and acquire specialized functions, including phagocytosis and the production of proinflammatory cytokines. Such myeloid plasticity is driven, in part, by epigenetic dynamics that can sustain stable phenotypes after activation, and which may lead to maladaptive cell polarization states associated with inflammation and autoimmunity. Here, we review recent reports describing epigenetic mechanisms linked to such polarization states and innate immune memory (tolerance and training) in monocyte and macrophage lineages. We discuss how these mechanisms might be targeted to develop putative immunomodulatory tools that might be used to treat a variety of immune-mediated diseases.
Assuntos
Epigênese Genética/efeitos dos fármacos , Imunidade Inata/efeitos dos fármacos , Fatores Imunológicos/uso terapêutico , Memória Imunológica/efeitos dos fármacos , Células Mieloides/efeitos dos fármacos , Animais , Epigênese Genética/genética , Epigênese Genética/imunologia , Humanos , Imunidade Inata/imunologia , Fatores Imunológicos/imunologia , Memória Imunológica/imunologia , Células Mieloides/imunologiaRESUMO
In order to develop new efficient therapies for organ transplantation, it is essential to acquire a comprehensive knowledge of the molecular mechanisms and processes, such as immune activation, chronic inflammation, and fibrosis, which lead to rejection and long-term graft loss. Recent efforts have shed some light on the epigenetic regulation associated with these processes. In this context, the bromo and extraterminal (BET) family of bromodomain proteins (BRD2, BRD3, BRD4, and BRDT) have emerged as major epigenetic players, connecting chromatin structure with gene expression changes. These proteins recognize acetylated lysines in histones and master transcription factors to recruit regulatory complex and, finally, modify the transcriptional program. Recent studies indicate that BET proteins are essential in the NF-kB-mediated inflammatory response, during the activation and differentiation of Th17-immune cells, and in profibrotic processes. Here, we review this new body of data and highlight the efficiency of BET inhibitors in several models of diseases. The promising results obtained from these preclinical models indicate that it may be time to translate these outcomes to the transplantation field, where epigenetics will be of increasing value in the coming years.
Assuntos
Epigênese Genética , Rejeição de Enxerto/prevenção & controle , Transplante de Órgãos/efeitos adversos , Fatores de Transcrição/antagonistas & inibidores , Animais , Cromatina/genética , Rejeição de Enxerto/etiologia , Rejeição de Enxerto/metabolismo , Humanos , Família Multigênica , Transdução de Sinais , Fatores de Transcrição/metabolismoRESUMO
Ankylosing spondylitis (AS) is a common, highly heritable, inflammatory arthritis for which HLA-B*27 is the major genetic risk factor, although its role in the aetiology of AS remains elusive. To better understand the genetic basis of the MHC susceptibility loci, we genotyped 7,264 MHC SNPs in 22,647 AS cases and controls of European descent. We impute SNPs, classical HLA alleles and amino-acid residues within HLA proteins, and tested these for association to AS status. Here we show that in addition to effects due to HLA-B*27 alleles, several other HLA-B alleles also affect susceptibility. After controlling for the associated haplotypes in HLA-B, we observe independent associations with variants in the HLA-A, HLA-DPB1 and HLA-DRB1 loci. We also demonstrate that the ERAP1 SNP rs30187 association is not restricted only to carriers of HLA-B*27 but also found in HLA-B*40:01 carriers independently of HLA-B*27 genotype.
Assuntos
Aminopeptidases/genética , Antígeno HLA-B27/genética , Antígeno HLA-B40/genética , Espondilite Anquilosante/etiologia , Estudos de Casos e Controles , Epistasia Genética , Predisposição Genética para Doença , Humanos , Complexo Principal de Histocompatibilidade , Antígenos de Histocompatibilidade Menor , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Engagement of the activating receptor NKG2D (natural killer group 2 member D) with its ligands (NKG2DL) major histocompatibility complex class I related-A and -B (MICA/B), UL-16 binding protein families (ULBPs 1-6) is important to ensure the innate immunity to tumor cells. However, these cells have developed strategies to downregulate NKG2DL expression and avoid immune recognition. We demonstrate that DNA methylation can contribute to the absence of NKG2DL expression during tumor progression. We analyzed the DNA methylation profiles for each NKG2DL by pyrosequencing in acute myeloid leukemia (AML), acute lymphocytic leukemia (ALL), hepatocellular carcinoma (HC), breast cancer and colon cancer cell lines. High levels of DNA methylation for NKG2DL were found in some tumor cell lines, mainly in AML cells. This hypermethylation was correlated with the absence of transcription for NKG2DL. Higher DNA methylation levels for MICA, ULBP1 and ULBP2 were observed in AML patients (n=60) compared with healthy donors (n=25). However, no DNA methylation for NKG2DL was found in colon cancer patients (n=44). Treatment with demethylating agents (5-azacytidine and 5-aza-2'-deoxycytidine) restored the expression of NKG2DL on the cell surface of AML cells, leading to an enhanced recognition by NKG2D-expressing cells. Our data suggest that NKG2DL may be aberrantly silenced by DNA methylation as a consequence of tumor development in AML patients.
Assuntos
Proteínas Ligadas por GPI/metabolismo , Leucemia Mieloide Aguda/imunologia , Subfamília K de Receptores Semelhantes a Lectina de Células NK/metabolismo , Evasão Tumoral , Linhagem Celular Tumoral , Metilação de DNA , Proteínas Ligadas por GPI/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Humanos , Ligantes , Subfamília K de Receptores Semelhantes a Lectina de Células NK/imunologiaRESUMO
The aim of this study was to analyse the association of specific killer cell immunoglobulin-like receptors (KIR) genes and haplotypes with susceptibility to ankylosing spondylitis (AS) and its different clinical manifestations in a Spanish population. The presence or absence of all KIR genes was studied for their association with AS. A total of 176 patients with AS and 435 healthy control subjects were selected for this study based on clinical criteria. The commercial KIR-sequence-specific oligonucleotides (SSO) typing kit was used to investigate KIR typing. Frequencies of KIR2DS1 and KIR3DS1 genes were increased significantly in patients compared with healthy controls [52·8 versus 38·2%, PBonf < 0·01, odds ratio (OR) = 1·81 (1·28-2·59); 51·7 versus 37·5%, PBonf < 0·01, OR = 1·79 (1·25-2·54)]. Moreover, the frequency of activating genotypes in the AS patient group was significantly higher than in the healthy control group (P < 0·05). KIR2DS1 and KIR3DS1, in addition to human leucocyte antigen (HLA)-B27, may play an important role in the pathogenesis of AS. However, we show that the contribution of the KIR genes to AS susceptibility extends beyond the association with individual KIRs, with an imbalance between activating and inhibitory KIR genes seeming to influence the susceptibility to AS.
Assuntos
Frequência do Gene , Predisposição Genética para Doença , Genótipo , Receptores KIR3DS1/genética , Receptores KIR/genética , Espondilite Anquilosante/genética , Feminino , Técnicas de Genotipagem , Antígeno HLA-B27/genética , Antígeno HLA-B27/imunologia , Humanos , Masculino , Receptores KIR/imunologia , Receptores KIR3DS1/imunologia , Espondilite Anquilosante/imunologia , Espondilite Anquilosante/patologiaRESUMO
Cytomegalovirus (CMV) infection exerts an enormous effect on human immunity, as it is associated with an immune-impaired response, a variety of chronic diseases, and overall survival in elderly individuals. Levels of anti-CMV antibodies may be associated with the differentiation degree of T cell subsets. Titers are significantly higher in the elderly and positively correlated with specific CD4(+) T cell responses to CMV. In the elderly, antibody titers are associated with the degree of differentiation and the T cell receptor excision circle (TREC) content in CD4(+) T cells, with other features of the immune risk profile, and with a reduced ability to respond to immunization in vivo. Associations may be absent in young subjects because their anti-CMV antibody titers are lower than those of the elderly. However, comparing young and elderly individuals with similar antibody levels reveals differences in their highly differentiated and naïve T cells. These are more marked in individuals with high titers. In parallel with the increase in anti-CMV antibodies, the elderly experience a significant reduction in absolute counts of naïve CD4(+) T cells, which may be a strategy to compensate for the expansion of differentiated cells and to avoid an increase in total T cells. In summary, our results show that titers of anti-CMV antibodies, and not only CMV seropositivity, are related to differentiation status and immunocompetence in the elderly, making this as an important prognostic marker of the status of immune system function.
Assuntos
Anticorpos Antivirais/sangue , Infecções por Citomegalovirus/imunologia , Citomegalovirus/imunologia , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Diferenciação Celular , Infecções por Citomegalovirus/virologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Linfócitos T/imunologiaRESUMO
Ankylosing spondylitis (AS) is a chronic inflammatory rheumatic disease that primarily involves the axial skeleton and the sacroiliac joint, but may also affect peripheral joints and entheses. AS susceptibility is clearly attributable to genetic factors and the link between human leukocyte antigen (HLA)-B27 and AS is the strongest association between an HLA class I molecule and a disease. However, there is evidence for the involvement of other, non-B27 factors within the major histocompatibility complex (MHC) in AS susceptibility. MHC class I is clearly the most significant genetic region for the disease, although most of the genetic association of this region is driven by HLA-B27. Moreover, several studies have investigated the MHC class II region and its association with AS. This review summarizes the current findings concerning the MHC genetics of the disease, focusing in particular on the associations of HLA with AS found in different ethnic populations throughout the world, and the possible mechanisms underlying them.
Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe I/genética , Espondilite Anquilosante/genética , Espondilite Anquilosante/imunologia , Frequência do Gene/genética , Antígenos de Histocompatibilidade Classe I/imunologia , Antígenos de Histocompatibilidade Classe II/imunologia , HumanosAssuntos
Antígeno HLA-B14/genética , Antígeno HLA-B27/genética , Grupos Populacionais , Espondilite Anquilosante/genética , África Subsaariana , Burkina Faso , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Teste de Histocompatibilidade , Humanos , Polimorfismo Genético , Espondilite Anquilosante/epidemiologia , Espondilite Anquilosante/imunologia , Togo , ZâmbiaRESUMO
Killer immunoglobulin-like receptors (KIRs) are related to the activation and inhibition of NK cells and may play an important role in the innate response against infection with viruses such as hepatitis C virus (HCV). We examined whether the different combinations of KIRs with their HLA class I ligands influenced the response to combined treatment (pegylated alpha interferon and ribavirin) of patients infected by HCV. A total of 186 consecutive patients diagnosed with chronic HCV infection were analyzed. Seventy-seven patients exhibited HCV RNA levels at 6 months posttreatment and were called nonresponders (NR), while 109 cleared viral RNA and were named sustained viral responders (SVR). Patients were typed for HLA-B, HLA-Cw, KIR genes, and HCV genotype. In our study, the frequency of the KIR2DL2 allele was significantly increased in NR (P < 0.001; odds ratio [OR] = 1.95), as was the frequency of the KIR2DL2/KIR2DL2 genotype (P < 0.005; OR = 2.52). In contrast, the frequencies of the KIR2DL3 genotype (P < 0.001) and KIR2DL3/KIR2DL3 genotype (P < 0.05; OR = 0.54) were significantly increased in the SVR. Different combinations of KIR2DL2 and KIR2DL3 alleles with their ligands were analyzed. The frequency of the KIR2DL2/KIR2DL2-HLA-C1C2 genotype was significantly increased in the NR (P < 0.01; OR = 3.15). Additionally, we found a higher frequency of the KIR2DL3/KIR2DL3-HLA-C1C1 genotype in the SVR group (P < 0.05; OR = 0.33). These results were not affected by the HCV genotype. In conclusion, patients who carried the KIR2DL2/KIR2DL2-HLA-C1C2 genotype were less prone to respond to treatment. However, the KIR2DL3/KIR2DL3-HLA-C1C1 genotype clearly correlated with a satisfactory response to treatment, defined by the clearance of HCV RNA.
Assuntos
Hepatite C Crônica/tratamento farmacológico , Hepatite C Crônica/imunologia , Receptores KIR/genética , Adulto , Antivirais/uso terapêutico , Quimioterapia Combinada , Feminino , Genótipo , Antígenos HLA/genética , Hepacivirus/genética , Humanos , Interferon-alfa/uso terapêutico , Masculino , Pessoa de Meia-Idade , Farmacogenética/métodos , RNA Viral/sangue , Receptores KIR2DL2 , Receptores KIR2DL3 , Ribavirina/uso terapêutico , Resultado do Tratamento , Carga Viral/efeitos dos fármacosRESUMO
HLA-B27 confers susceptibility to ankylosing spondylitis but AS disease mechanisms remain unknown. We determined here the effect of polymorphism and tapasin dependence on the expression, intracellular maturation and homodimer formation among HLA-B27 subtypes. We found that B*2709 with a histidine at position 116 was strongly associated with the transporter associated with antigen processing complex, correlated with lower, non-conformational expression on the cell surface, delayed maturation rate and minimal conformational and non-conformational homodimer formation. In contrast, B*2705 showed a low dependence for transporter associated with antigen processing, faster intracellular maturation and increased levels of homodimeric forms. The absence of tapasin significantly influenced the rate of intracellular maturation of B*2709, showing faster transport out of the endoplasmic reticulum, but similar to that of B*2705. All B27 subtypes examined were unable to express conformational homodimeric forms in the absence of tapasin. This study suggests that HLA-B27 polymorphism drives the tapasin dependency, rates of intracellular maturation and expressions of homodimers.
Assuntos
Dimerização , Antígeno HLA-B27/genética , Antígeno HLA-B27/metabolismo , Proteínas de Membrana Transportadoras/metabolismo , Células Cultivadas , Antígeno HLA-B27/química , Humanos , Polimorfismo Genético , Ligação Proteica/genética , Conformação Proteica , Dobramento de Proteína , Multimerização Proteica/genética , Transporte Proteico/genética , Espondiloartropatias/genética , Espondiloartropatias/metabolismoRESUMO
NKG2D is one of the best characterized activating receptors on Natural Killer (NK) and CD8+ T cells. This receptor recognizes several different ligands (MICA/MICB and ULBPs) induced by cellular stress and infection. In addition to the role described in cancer surveillance, recent data highlight the importance of NKG2D and its ligands in organ transplantation. Allografts show evidence of MICA and MICB expression in both acute and chronic rejection. The presence of anti-MICA antibodies has been correlated with incidence of graft rejection. Furthermore, NKG2D-ligand engagement activates NK cells, which provides T-cell costimulation, and enhances antigen specific CTL-mediated cytotoxicity. Activated NK cells may function as a bridge between innate and adaptive immunity associated with transplantation. Activated NK cells in response to IL-15 can also trigger organ rejection through NKG2D and affect the maturation of both donor and recipient antigen presenting cells (APCs) and ultimately the T-cell allogeneic response. Regulatory T cells, which modulate T-cell responses in organ transplantation and infections, were reduced in numbers by NK cells exposed to intracellular pathogens, possibly via interaction with one NK2GD receptor. Blockage of NKG2D-NKG2D-L interactions provides a novel pathway for development of inhibitors. These studies have important clinical and therapeutic implications in solid organ transplantation.
Assuntos
Subfamília K de Receptores Semelhantes a Lectina de Células NK/fisiologia , Transplante de Órgãos , Rejeição de Enxerto/imunologia , Humanos , Ligantes , Receptores Imunológicos/antagonistas & inibidoresRESUMO
Objetivos: describir la frecuencia y características clínico-analíticasde la pancreatitis aguda (PA) recidivante con enteropatíapor gluten (EG) asociada.Pacientes y métodos: estudiamos de forma prospectiva loscasos de pancreatitis agudas ingresados en nuestro Servicio duranteel año 2006. Registramos un total de 185 pacientes. A lasformas recurrentes que fueron 40 en total (22%), les aplicamos unprotocolo clínico-analítico consistente en la determinación demarcadores serológicos, genéticos y biopsias duodenales, paradescartar una EG asociada.Resultados: un total de 34 pacientes (18%) cumplían criteriosclínico-biológicos de EG asociada (grupo 1) y se compararon conel resto de las PA no-EG (n = 161) (grupo 2). La edad media en laEG fue de 54 ± 25 años, ligeramente inferior al grupo 2, (61 ±14) (NS). Existía un ligero predominio de mujeres (50%) en el grupo1, respecto al grupo 2 (38,5%) (NS). Siete pacientes del grupo1 (20%) presentaron una PA grave, frente a 27 (17%) en el grupo2 (NS). La presencia de colelitiasis en el grupo 1, fue de 6 casos(18%), significativamente inferior a la del grupo 2, de 72 casos(45%) (p < 0,05). Cuatro pacientes con EG desarrollaron seudoquistes(12%) frente a 13 (8%) en el grupo 2 (NS).La transglutaminasa tisular (TGt) estaba elevada únicamente en3 casos (9%). Nueve pacientes (34%) fueron DQ2 (+) y 4 (12%)DQ8 (+), siendo el resto (54%), negativos para ambos marcadores.Existía una duodenitis difusa desde el punto de vista endoscópicoen 32 pacientes (95%). Las biopsias duodenales, mostraronatrofia vellositaria (Marsh 3) en 2 casos (6%); infiltración inflamatoriade la submucosa (Marsh 2) en 10 casos (29,4%); aumento delos linfocitos intraepiteliales (Marsh 1) en 8 casos (23,5%) y mucosanormal (Marsh 0) en 14 casos (41,2%). La respuesta a la DSGal año, fue excelente en 30 pacientes (88%).Conclusiones: la PA recidivante con EG, constituye una asociaciónrelativamente frecuente, indistinguible desde el punto devista clínico y evolutivo del resto de PA, excepto por una menorpresencia de colelitiasis (p < 0,05)
Objectives: to describe the frequency and the clinical and laboratorycharacteristics of relapsing acute pancreatitis (AP) associatedwith gluten enteropathy (GE).Patients and methods: we prospectively examined all acutepancreatitis cases admitted to our Department in 2006. Werecorded a total of 185 patients. With recurring forms, 40 (22%)in all, we used a clinical-lab protocol including serologic and geneticmarkers, and duodenal biopsy to rule out GE.Results: a total of 34 patients (18%) met clinical-biological criteriafor GE (group 1), and were compared to the remaining non-GE AP cases (n = 161) (group 2). Mean age in the GE group was54 ± 25 years, slightly younger than group 2 (61 ± 14) (NS).There was a mild predominance of women (50%) in group 1 versusgroup 2 (38.5%) (NS). Seven patients in group 1 (20%) hadsevere AP, as compared to 27 (17%) in group 2 (NS). The presenceof cholelithiasis in group 1 involved 6 cases (18%), whichwas significantly lower than in group 2 72 cases (45%) (p <0.05). Four patients with GE developed pseudocysts (12%) versus13 (8%) in group 2 (NS).Tissue transglutaminase (tTG) was elevated only in 3 patients(9%). Nine patients (34%) were DQ2 (+) and 4 (12%) DQ8 (+); therest (54%) were all negative for both markers. From an endoscopicperspective there was diffuse duodenitis in 32 patients (95%).Duodenal biopsies revealed villous atrophy (Marsh 3) in 2 patients(6%); submucosal inflammatory infiltration (Marsh 2) in 10(29.4%); increased intraepithelial lymphocytes (Marsh 1) in 8 cases(23.5%), and normal mucosa (Marsh 0) in 14 patients (41.2%).Response to GFD after 1 year was excellent in 30 patients (88%).Conclusions: relapsing AP with GE represents a relativelycommon association that is indistinguishable from other APs froma clinical-evolutive stand point, except for a lower presence ofcholelithiasis (p < 0.05) (AU)
Assuntos
Humanos , Masculino , Feminino , Pessoa de Meia-Idade , Pancreatite/complicações , Doença Celíaca/complicações , Doença Celíaca/diagnóstico , Doença Aguda , Recidiva , Índice de Gravidade de Doença , Doença Celíaca/patologia , Estudos Prospectivos , Biópsia , BiomarcadoresRESUMO
It has been widely reported that the major histocompatibility complex (MHC) class II region provides the main genetic contribution to multiple sclerosis (MS) susceptibility. However, recent studies have suggested that the MHC class I region may also contribute to the development of MS. In this study, we investigated the possible association of the human leukocyte antigen (HLA)-B, MHC class I chain-related gene B (MICB) and MHC class I chain-related gene A (MICA) genes, located in the MHC class I region, with MS susceptibility. For this purpose, we analyzed the distribution of HLA-DR, HLA-B, MICB and MICA alleles in 121 MS patients and 156 healthy controls. Neither HLA-B nor MICA alleles were found to be associated with MS susceptibility, and only the frequency of HLA-DRB1*01 allele was found to be increased in controls (31% vs 14%, P(c) = 0.011). However, MICB*004 allele frequency was significantly increased in MS patients (46.3% vs 23.3%, P(c) < 0.001, odds ratio = 2.82, 95% confidence interval = 1.68-4.73). Although, MICB*004 and HLA-DRB1*15 belong to the AH 7.1 ancestral haplotype, the association of MICB*004 to MS susceptibility was found to be independent of HLA-DRB1*15 in our population. This and previous studies clearly suggest that the MHC class I, in addition to class II, could be involved in MS susceptibility.
Assuntos
Predisposição Genética para Doença , Antígenos de Histocompatibilidade Classe I/genética , Esclerose Múltipla/genética , Adulto , Feminino , Frequência do Gene , Antígenos HLA-B/genética , Antígenos HLA-DR/genética , Cadeias HLA-DRB1 , Humanos , MasculinoRESUMO
Cyclophilin A is secreted by vascular smooth muscle cells in response to inflammatory stimuli, and could thus contribute to atherosclerosis. We hypothesized that the genetic variation at the cyclophilin A gene (PPIA) could affect the risk for developing atherosclerosis and myocardial infarction. This study included 250 myocardial infarction patients (all male and < 60 years; 95% are smokers). All these cases had at least one atherosclerotic diseased coronary vessel. DNA was obtained from patients and from 250 healthy controls. The variation at the PPIA gene was determined in the patients through single-strand conformation analysis and direct sequencing of seven polymerase chain reaction fragments. Allele and genotype frequencies were compared between patients and controls. The effect of a promoter polymorphism (-11 G/C) on gene expression was in vitro analysed with luciferase-reporter assays. We found two common polymorphisms in the PPIA promoter (-11 G/C) and the 5' non-translated (+36 G/A) regions. Cells transfected with luciferase-plasmids containing the -11 G had significantly higher luciferase activity. Genotype frequencies for these polymorphisms did not differ between patients and controls. In conclusion, we reported a functional variant in the PPIA promoter. However, the PPIA variation did not significantly contribute to the risk of suffering from myocardial infarction among patients with atherosclerotic diseased vessels.
Assuntos
Doença da Artéria Coronariana/genética , Ciclofilina A/genética , Infarto do Miocárdio/genética , Polimorfismo de Nucleotídeo Único , Polimorfismo Conformacional de Fita Simples , Regiões Promotoras Genéticas/genética , Adulto , Alelos , Regulação da Expressão Gênica/genética , Frequência do Gene , Genótipo , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de RiscoRESUMO
OBJECTIVES: To describe the frequency and the clinical and laboratory characteristics of relapsing acute pancreatitis (AP) associated with gluten enteropathy (GE). PATIENTS AND METHODS: We prospectively examined all acute pancreatitis cases admitted to our Department in 2006. We recorded a total of 185 patients. With recurring forms, 40 (22%) in all, we used a clinical-lab protocol including serologic and genetic markers, and duodenal biopsy to rule out GE. RESULTS: A total of 34 patients (18%) met clinical-biological criteria for GE (group1), and were compared to the remaining non-GE AP cases (n=161) (group2). Mean age in the GE group was 54 +/- 25 years, slightly younger than group 2 (61 +/- 14) (NS). There was a mild predominance of women (50%) in group 1 versus group 2 (38.5%) (NS). Seven patients in group 1 (20%) had severe AP, as compared to 27 (17%) in group 2 (NS). The presence of cholelithiasis in group 1 involved 6 cases (18%), which was significantly lower than in group 2--72 cases (45%) (p < 0.05). Four patients with GE developed pseudocysts (12%) versus 13 (8%) in group 2 (NS). Tissue transglutaminase (tTG) was elevated only in 3 patients (9%). Nine patients (34%) were DQ2 (+) and 4 (12%) DQ8 (+); the rest (54%) were all negative for both markers. From an endoscopic perspective there was diffuse duodenitis in 32 patients (95%). Duodenal biopsies revealed villous atrophy (Marsh 3) in 2 patients (6%); submucosal inflammatory infiltration (Marsh 2) in 10 (29.4%); increased intraepithelial lymphocytes (Marsh 1) in 8 cases (23.5%), and normal mucosa (Marsh 0) in 14 patients (41.2%). Response to GFD after 1 year was excellent in 30 patients (88%). CONCLUSIONS: Relapsing AP with GE represents a relatively common association that is indistinguishable from other APs from a clinical-evolutive standpoint, except for a lower presence of cholelithiasis (p < 0.05). A specific diagnostic protocol is much needed in the identification of these patients since GFD is the only effective therapy to prevent new AP events from developing.
Assuntos
Doença Celíaca/complicações , Pancreatite/diagnóstico , Pancreatite/etiologia , Doença Aguda , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Recidiva , Adulto JovemRESUMO
Before the highly active antiretroviral therapy (HAART) era, kidney transplantation was not considered an option for patients infected with human immunodeficiency virus (HIV) because of its poor outcome. However, recent studies have demonstrated results comparable to those of recipients without HIV infections. They have shown that HIV-positive patients maintained on HAART mount an immune response. Immunosuppressive agents are chosen to minimize aggravation of HIV infection, bearing in mind the potential side effects of the combination of HAART and immunosuppressive drugs. Herein we have reported the case of a 43-year-old HIV- and hepatitis C virus-infected woman with preserved immune function who received a cadaveric kidney transplant and developed an acute humoral rejection, which was successfully treated with Rituximab.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Rejeição de Enxerto/terapia , Infecções por HIV/complicações , Fatores Imunológicos/uso terapêutico , Transplante de Rim/patologia , Plasmaferese , Adulto , Anticorpos Monoclonais Murinos , Terapia Combinada , Creatinina/sangue , Rejeição de Enxerto/tratamento farmacológico , Humanos , Masculino , Rituximab , Resultado do TratamentoRESUMO
The role of MICA antibodies in acute heart allograft rejection was examined utilizing 190 pre- and post-transplant serum samples from 44 patients collected during the first year after transplantation. MICA antibodies were detected by CDC test on recombinant cell lines and by the newly developed Luminex MICA antibody detection assay. Additionally, MICA expression was analyzed by 'real time' RT-PCR and by immunohistochemistry in 10 endomyocardial biopsies. Only two subjects had HLA antibodies post-transplant. Nevertheless, MICA antibodies were found in a significant number of subjects. The prevalence of MICA antibodies was significantly higher among those with severe acute rejection (AR) than in those without rejection (60.7% vs. 14.3%, p = 0.0038 by CDC; 55.5% vs. 5.7%, p = 0.0020 by Luminex). In most cases, the appearance of MICA antibodies post-transplant precedes AR. Following transplantation, MICA up-regulation correlated with histological evidence of severe rejection. Monitoring for MICA antibodies post-transplant may be useful to establish new risk factors for acute rejection.
Assuntos
Rejeição de Enxerto/imunologia , Transplante de Coração/imunologia , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/imunologia , Adulto , Linfócitos B/imunologia , Biópsia , Linhagem Celular , Feminino , Antígenos HLA/imunologia , Células HeLa , Transplante de Coração/patologia , Humanos , Isoanticorpos/sangue , Masculino , Pessoa de Meia-Idade , EspanhaRESUMO
INTRODUCTION: celiac disease (CD) is an autoimmune condition that is triggered by the ingestion of gluten, a substance present in most cereals, and that affects genetically predisposed individuals. As a result, this condition is clearly familial, and mainly associated with HLA class II markers. OBJECTIVES: in this work we set out to analyze the prevalence of CD in an extensive family based on an index subject who had already died from this disease a few years ago, where CD had been complicated by the development of a small-bowel malignancy, namely an adenocarcinoma. METHODS: nineteen members were studied. They all were subjected to a diagnostic protocol including a detailed medical history, hemogram, coagulation tests, and blood biochemistry (including liver function tests, serum iron metabolism, circulating folic acid and vitamin B12 levels, thyroid function tests, tissue transglutaminase measurement, and genetic markers (DQ2 and DQ8). Suspect cases underwent gastroscopy plus multiple duodenal biopsy for confirmation. RESULTS: overall we encountered CD in 9/19 studied members, which represents 47.4% with the following distribution according to degree of kinship -four of seven siblings (57%); one of three children (33.3%); three of eight nephews and nieces (37.5%), and the only grandnephew, who was 9 years old. CONCLUSIONS: from all this it may be seen that family studies are needed every time a patient is diagnosed with celiac disease; these studies should include both first- and second-degree relatives, given the high prevalence encountered and the fact that these tests are relatively straighforward to perform.
Assuntos
Doença Celíaca/genética , Adolescente , Adulto , Idoso , Doença Celíaca/diagnóstico , Doença Celíaca/epidemiologia , Criança , Família , Feminino , Genes MHC da Classe II/genética , Humanos , Masculino , Pessoa de Meia-Idade , LinhagemRESUMO
This part of the workshop addressed the results of a study on killer immonoglobulin-like receptors and hepatitis C virus disease progression.
Assuntos
Hepatite C/imunologia , Antígenos de Histocompatibilidade Classe I/metabolismo , Células Matadoras Naturais/imunologia , Receptores Imunológicos/metabolismo , Hepacivirus/fisiologia , Hepatite C/genética , Hepatite C/virologia , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/imunologia , Humanos , Ligantes , Receptores Imunológicos/genética , Receptores KIRRESUMO
Introducción: la enfermedad celiaca (EC) es un proceso autoinmune, desencadenado por la ingesta del gluten contenido en la mayor parte de los cereales, que afecta a individuos genéticamente predispuestos. Por todo ello, muestra una clara tendencia familiar, centrada fundamentalmente en marcadores del sistema HLA de clase II. Objetivos: nos propusimos en el presente trabajo analizar la prevalencia de EC en una familia extensa, a partir de un caso índice fallecido hacía unos años, como consecuencia de padecer la misma enfermedad, complicada además con el desarrollo de un tumor maligno del intestino delgado, del tipo del adenocarcinoma. Métodos: se estudiaron un total de 19 miembros. Se les realizó un protocolo diagnóstico que incluía un historia clínica detallada, junto con una hemograma y estudio de coagulación, una bioquímica amplia incluyendo pruebas de función hepática, estudio sérico del metabolismo del hierro, niveles circulantes de ácido fólico y vitamina B12, pruebas de función tiroidea, determinación de la transglutaminasa tisular y marcadores genéticos (DQ2 y DQ8). En los casos sospechosos y para su confirmación se realizó gastroscopia completada con toma de biopsias duodenales múltiples. Resultados: encontramos una prevalencia global de EC en 9/19 de los familiares estudiados, lo que representa un 47,4%, distribuidos de la siguiente manera en función del parentesco con el caso índice: cuatro de siete hermanos (57%); uno de tres hijos (33,3%); tres de ocho sobrinos (37,5%); y el único sobrino-nieto estudiado de nueve años de edad, también estaba afecto. Conclusiones: de todo ello se deduce la necesidad de hacer estudios amplios familiares, cada vez que se diagnostica un paciente de enfermedad celiaca, incluyendo familiares de primero y segundo grado, dada la relativa facilidad actual para llevarlos a cabo y la elevada prevalencia encontrada
Introduction: celiac disease (CD) is an autoimmune condition that is triggered by the ingestion of gluten, a substance present in most cereals, and that affects genetically predisposed individuals. As a result, this condition is clearly familial, and mainly associated with HLA class II markers. Objectives: in this work we set out to analyze the prevalence of CD in an extensive family based on an index subject who had already died from this disease a few years ago, where CD had been complicated by the development of a small-bowel malignancy, namely an adenocarcinoma. Methods: nineteen members were studied. They all were subjected to a diagnostic protocol including a detailed medical history, hemogram, coagulation tests, and blood biochemistry (including liver function tests, serum iron metabolism, circulating folic acid and vitamin B12 levels, thyroid function tests, tissue transglutaminase measurement, and genetic markers (DQ2 and DQ8). Suspect cases underwent gastroscopy plus multiple duodenal biopsy for confirmation. Results: overall we encountered CD in 9/19 studied members, which represents 47.4% with the following distribution according to degree of kinship four of seven siblings (57%); one of three children (33.3%); three of eight nephews and nieces (37.5%), and the only grandnephew, who was 9 years old. Conclusions: from all this it may be seen that family studies are needed every time a patient is diagnosed with celiac disease; these studies should include both first- and second-degree relatives, given the high prevalence encountered and the fact that these tests are relatively straighforward to perform