ABSTRACT
BACKGROUND: Celiac disease (CeD) has an estimated prevalence of 1%-3%. The classical clinical presentation is malabsorption, but now patients may present with more subtle symptoms such as constipation, osteoporosis, or iron deficiency anemia. Children may also present with poor growth.CeD has a strong genetic component, and high-risk groups include first-degree relatives with CeD, patients with co-existing autoimmune diseases, and patients with chromosomal aberrations. CONTENT: Diagnostic tests for CeD include duodenal histology, serology, and genetic testing. Duodenal histology has traditionally been the gold standard of diagnosis. However, serological tests, especially IgA tissue transglutaminase antibodies (TTG-IgA), are widely used and diagnostic algorithms are based primarily on TTG-IgA as a starting point. Human leukocyte antigen typing may also be incorporated to determine genetic risk for CeD. Guidelines for children endorse biopsy avoidance provided high levels of TTG-IgA, with diagnostic accuracy being comparable to duodenal biopsy. Confirmation may be achieved by identifying IgA endomysial antibodies in a separate blood sample. Subjects with low positive TTG-IgA levels and subjects with IgA deficiency need a biopsy to establish a diagnosis of CeD. The clinical follow-up of CeD usually includes a repeat TTG-IgA examination. In adults, healing may be delayed or incomplete, and a rare consequence of refractory celiac disease is transformation to enteric T-cell lymphoma. SUMMARY: Laboratory testing, in particular TTG-IgA, plays a central role in the diagnosis and has an accuracy comparable to histology. Diagnostic algorithms utilizing laboratory testing are critical for the development of novel strategies to improve diagnosis.
ABSTRACT
PURPOSE: Selective IgA deficiency (IgAD) is the most common primary immunodeficiency, frequently leading to only minor clinical complaints. IgAD may be associated with autoimmune diseases such as celiac disease (CeD). Although IgAD is thought to precede CeD and autoimmunity, the association between the two conditions has not been clarified. METHODS: Routine techniques were used to measure serum IgA and celiac diagnostic markers as transglutaminase 2 IgA (TG2-IgA) and deamidated gliadin IgG and for immunohistochemistry for IgG, IgM, and IgA. RESULTS: We report two childhood cases of complete IgA deficiency that evolved after the diagnosis of CeD and the start of a gluten-free diet. Histology showed persistence of IgA in the intestinal mucosa. CONCLUSION: Both children with CeD showed IgA deficiency that unexpectedly developed after the initiation of a gluten-free diet. This supports IgA deficiency as a process that develops gradually and occurs due to specific defects in immunoregulation.
Subject(s)
Celiac Disease , IgA Deficiency , Autoantibodies , Celiac Disease/complications , Celiac Disease/diagnosis , Child , Gliadin , Humans , IgA Deficiency/complications , IgA Deficiency/diagnosis , Immunoglobulin A , Immunoglobulin G , Immunoglobulin M , TransglutaminasesABSTRACT
The persistence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antibodies is a matter of importance regarding the coronavirus disease 19 (COVID-19) pandemic. To observe antibody dynamics, 105 blood donors, positive for SARS-CoV-2 antibodies by a lateral flow test within a seroprevalence study, were included in this study. Thirty-nine (37%) of 105 the donors were confirmed positive by a total Ig Wantai enzyme-linked immunosorbent assay (ELISA). Three (8%) in this group of 39 reported severe and 26/39 (67%) mild to moderate COVID-19 symptoms. By further ELISA-testing, 33/39 (85%) donors were initially positive for IgG antibodies, 31/39 (79%) for IgA, and 32/39 (82%) for IgM, while 27/39 (69%) were positive for all three isotypes. Persistence of IgG, IgA, and IgM was observed in 73%, 79%, and 32% of donors, respectively, after 6-9 months of observation. For IgM antibodies, the decline in the proportion of positive donors was statistically significant (p = 0.002) during 12 months observation, for IgG only the decline at 3 months was statistically significant (p = 0.042). Four donors exhibited notable increases in antibody levels. In conclusion, persistent SARS-CoV-2 IgA antibodies and IgG antibodies at 6-9 months are present in approximately three of four individuals with previous mild to moderate COVID-19.
Subject(s)
Antibodies, Viral/blood , Blood Donors/statistics & numerical data , COVID-19/immunology , SARS-CoV-2/immunology , Adult , COVID-19/blood , COVID-19/epidemiology , Denmark/epidemiology , Female , Humans , Immunoglobulin A/blood , Immunoglobulin G/blood , Immunoglobulin M/blood , Kinetics , Male , Reinfection/blood , Reinfection/epidemiology , Reinfection/immunology , Seroepidemiologic Studies , Severity of Illness Index , Young AdultABSTRACT
OBJECTIVES: Systemic lupus erythematosus (SLE) is an autoimmune disease with extensive heterogeneity in disease presentation between patients, which is likely due to an underlying molecular diversity. Here, we aimed at elucidating the genetic aetiology of SLE from the immunity pathway level to the single variant level, and stratify patients with SLE into distinguishable molecular subgroups, which could inform treatment choices in SLE. METHODS: We undertook a pathway-centred approach, using sequencing of immunological pathway genes. Altogether 1832 candidate genes were analysed in 958 Swedish patients with SLE and 1026 healthy individuals. Aggregate and single variant association testing was performed, and we generated pathway polygenic risk scores (PRS). RESULTS: We identified two main independent pathways involved in SLE susceptibility: T lymphocyte differentiation and innate immunity, characterised by HLA and interferon, respectively. Pathway PRS defined pathways in individual patients, who on average were positive for seven pathways. We found that SLE organ damage was more pronounced in patients positive for the T or B cell receptor signalling pathways. Further, pathway PRS-based clustering allowed stratification of patients into four groups with different risk score profiles. Studying sets of genes with priors for involvement in SLE, we observed an aggregate common variant contribution to SLE at genes previously reported for monogenic SLE as well as at interferonopathy genes. CONCLUSIONS: Our results show that pathway risk scores have the potential to stratify patients with SLE beyond clinical manifestations into molecular subsets, which may have implications for clinical follow-up and therapy selection.
Subject(s)
Antigen Presentation/genetics , Immunity, Innate/genetics , Interferon Type I/immunology , Lupus Erythematosus, Systemic/genetics , Lymphopoiesis/genetics , T-Lymphocytes/immunology , Adolescent , Adult , Aged , Aged, 80 and over , Blood Coagulation/genetics , Case-Control Studies , Cluster Analysis , Complement Activation/genetics , Female , Humans , Janus Kinases/genetics , Lupus Erythematosus, Systemic/immunology , Male , Middle Aged , Multifactorial Inheritance , Polymorphism, Single Nucleotide , STAT Transcription Factors/genetics , Sequence Analysis, DNA , Signal Transduction/genetics , Sweden , White People , Young AdultABSTRACT
OBJECTIVE: Antibodies to cell surface central nervous system proteins help to diagnose conditions which often respond to immunotherapies. The assessment of antibody assays needs to reflect their clinical utility. We report the results of a multicentre study of aquaporin (AQP) 4 antibody (AQP4-Ab) assays in neuromyelitis optica spectrum disorders (NMOSD). METHODS: Coded samples from patients with neuromyelitis optica (NMO) or NMOSD (101) and controls (92) were tested at 15 European diagnostic centres using 21 assays including live (n=3) or fixed cell-based assays (n=10), flow cytometry (n=4), immunohistochemistry (n=3) and ELISA (n=1). RESULTS: Results of tests on 92 controls identified 12assays as highly specific (0-1 false-positive results). 32 samples from 50 (64%) NMO sera and 34 from 51 (67%) NMOSD sera were positive on at least two of the 12 highly specific assays, leaving 35 patients with seronegative NMO/spectrum disorder (SD). On the basis of a combination of clinical phenotype and the highly specific assays, 66 AQP4-Ab seropositive samples were used to establish the sensitivities (51.5-100%) of all 21 assays. The specificities (85.8-100%) were based on 92 control samples and 35 seronegative NMO/SD patient samples. CONCLUSIONS: The cell-based assays were most sensitive and specific overall, but immunohistochemistry or flow cytometry could be equally accurate in specialist centres. Since patients with AQP4-Ab negative NMO/SD require different management, the use of both appropriate control samples and defined seronegative NMOSD samples is essential to evaluate these assays in a clinically meaningful way. The process described here can be applied to the evaluation of other antibody assays in the newly evolving field of autoimmune neurology.
Subject(s)
Aquaporin 4/blood , Autoantibodies/blood , Neuromyelitis Optica/blood , Aquaporin 4/immunology , Autoantibodies/immunology , Enzyme-Linked Immunosorbent Assay/methods , Humans , Immunohistochemistry/methods , Neuromyelitis Optica/immunology , Sensitivity and SpecificityABSTRACT
Autoimmune enteropathy (AE) is an immune mediated illness of the intestinal mucosa. The cause is unknown, and the diagnosis is based on typical characteristics displayed. There is no gold standard for treatment. We present two adult cases of AE and demonstrate the challenges in establishing the diagnosis. The extensive diagnostic work up excluded other more common causes of protracted diarrhoea. Wireless capsule endoscopy (WCE) displayed universal small intestinal mucosal damage with shortened villi that led to the suspicion of AE in both patients. The diagnosis was confirmed with microscopy, showing shortened villi, villous blunting and hyperplasia of crypts in both patients. In one patient, deep crypt lymphocytosis with minimal intraepithelial lymphocytosis was found as well. Both patients were successfully treated with high-dose immunosuppressant therapy to induce and maintain remission. Use of WCE as a diagnostic tool was invaluable in establishing the diagnosis of AE.
Subject(s)
Abdominal Pain/etiology , Capsule Endoscopy , Diarrhea/etiology , Intestinal Mucosa/pathology , Intestine, Small/pathology , Polyendocrinopathies, Autoimmune/diagnosis , Abdominal Pain/immunology , Adult , Azathioprine/administration & dosage , Diagnosis, Differential , Diarrhea/immunology , Female , Humans , Immunosuppressive Agents/administration & dosage , Intestinal Mucosa/immunology , Intestine, Small/immunology , Male , Polyendocrinopathies, Autoimmune/immunology , Polyendocrinopathies, Autoimmune/pathology , Prednisone/administration & dosage , Treatment Outcome , Weight GainABSTRACT
We report an infant of consanguineous parents of Turkish decent with a novel immunodeficiency associated with homozygosity for a nonsense mutation of the gene encoding Inhibitor of nuclear factor kappa-B (NF-κB) kinase subunit beta (IKKß). At five months, she presented with respiratory insufficiency and Pneumocystis jirovecii pneumonia which was successfully treated. At nine months, iatrogenic systemic infection with Mycobacterium bovis was found and eventually led to her death at age 14 months. Laboratory findings were reminiscent of hyper-IgM syndrome, but genetic testing gave no explanation before whole exome sequencing revealed a novel mutation abrogating signaling through the canonical NF-κB pathway.
Subject(s)
Codon, Nonsense , I-kappa B Kinase/genetics , Immunologic Deficiency Syndromes/genetics , Fatal Outcome , Female , Humans , Immunologic Deficiency Syndromes/complications , Infant , Mycobacterium bovis , Pneumocystis carinii , Pneumonia, Pneumocystis/complications , Respiratory Insufficiency/complications , Tuberculosis/complications , Tuberculosis/pathology , Vaccination/adverse effectsABSTRACT
Celiac disease (CD) is characterized by an inappropriate immunological reaction against gluten driven by gluten-specific CD4+ T cells. We screened 25 proteases and tested 10 for their potential to degrade gluten in vitro. Five proteases were further tested for their ability to prevent the proliferative response by a gluten-specific CD4+ T cell clone and seven gluten-reactive T cell lines to protease-digested gluten peptides. A proline-specific endo-peptidase from Aspergillus niger (AnP2) was particularly efficient at diminishing proliferation after stimulation with cleaved antigen, and could completely block the response against both native and deamidated gluten peptides. We found that AnP2 was efficient down to a 1:64 protease:substrate ratio (w:w). When AnP2 was tested in assays using seven gluten-reactive T cell lines from individual CD patients (three adults and four children), the response to gluten was diminished in all cases. Our study indicates a therapeutic benefit of AnP2 to CD patients.
Subject(s)
CD4-Positive T-Lymphocytes/immunology , Endopeptidases/immunology , Fungal Proteins/immunology , Glutens/immunology , Peptides/immunology , Adult , Amino Acid Sequence , Aspergillus niger/enzymology , CD4-Positive T-Lymphocytes/drug effects , Celiac Disease/immunology , Celiac Disease/pathology , Cell Line , Cell Proliferation/drug effects , Child , Clone Cells/drug effects , Clone Cells/immunology , Electrophoresis, Polyacrylamide Gel , Endopeptidases/metabolism , Endopeptidases/pharmacology , Fungal Proteins/metabolism , Fungal Proteins/pharmacology , Glutens/chemistry , Glutens/metabolism , Humans , Intestines/immunology , Molecular Sequence Data , Peptides/metabolism , Substrate SpecificityABSTRACT
The presence of unique carbohydrate structures in the glycocalyx/mucous layer of the intestine may be involved in a susceptibility to celiac disease (CD) by serving as attachment sites for bacteria. This host-microbiota interaction may influence the development of CD and possibly other diseases with autoimmune components. We examined duodenal biopsies from a total of 30 children, of which 10 had both celiac disease (CD) and type 1 diabetes (T1D); 10 had CD alone; and 10 were suspected of having gastrointestinal disease, but had normal duodenal histology (non-CD controls). Patients with both CD and T1D were examined before and after remission following a gluten-free diet. We performed lectin histochemistry using peanut agglutinin (PNA) and Ulex europaeus agglutinin (UEA) staining for Gal-ß(1,3)-GalNAc and Fucα1-2Gal-R, respectively, of the glycocalyx/mucous layer. The staining was scored based on dissemination of stained structures on a scale from 0 to 3. Evaluation of the scores revealed no difference between biopsies obtained before and after remission in the group of children with both CD and T1D. A comparison of this pre-remission group with the children who had CD alone or the non-CD controls also showed no significant differences. Based on our material, we found no indication that the presence of Gal-ß(1,3)-GalNAc or Fucα1-2Gal-R is involved in the susceptibility to CD, or that the disease process affects the expression of these carbohydrates.
Subject(s)
Carbohydrate Metabolism , Celiac Disease/pathology , Duodenum/pathology , Glycocalyx/metabolism , Intestinal Mucosa/pathology , Microbiota , Adolescent , Biopsy , Celiac Disease/diet therapy , Celiac Disease/metabolism , Child , Child, Preschool , Diabetes Mellitus, Type 1/metabolism , Diabetes Mellitus, Type 1/pathology , Diet, Gluten-Free , Duodenum/metabolism , Humans , Infant , Intestinal Mucosa/metabolism , Plant Lectins , Remission InductionABSTRACT
The specificity and potential pathogenicity of autoantibodies vary between neurological diseases. It is often unclear whether their detection in cerebrospinal fluid (CSF) is a consequence or a cause of pathology. The goal was to test whether administration of brain-specific antibodies into CSF would be sufficient for pathology. Purified immunoglobulin G from a neuromyelitis optica patient was injected intrathecally with complement to naïve mice. Histopathological analysis at 7 days revealed damage to the ependyma, disruption of the CSF parenchymal barrier and pathologic lesions, distant from the site of injection. In the absence of complement there was no pathology. Autoantibody and complement in CSF are thus sufficient to initiate a pathologic cascade.
Subject(s)
Aquaporin 4/immunology , Brain/pathology , Complement System Proteins/cerebrospinal fluid , Immunoglobulin G/cerebrospinal fluid , Animals , Brain/immunology , Brain/metabolism , Complement System Proteins/immunology , Complement System Proteins/toxicity , Demyelinating Diseases/chemically induced , Demyelinating Diseases/immunology , Demyelinating Diseases/metabolism , Ependyma/pathology , Female , Glial Fibrillary Acidic Protein/metabolism , HEK293 Cells , Humans , Immunoglobulin G/toxicity , Injections, Spinal , Mice , Mice, Inbred C57BL , Neuromyelitis Optica/blood , Neuromyelitis Optica/immunology , TransfectionABSTRACT
AIM: To determine the prevalence and incidence of diagnosed coeliac disease (CD) in Danish children and adolescents and to describe trends over time. METHODS: All children with a CD diagnosis registered in the Danish National Patient Registry (DNPR) were included in the study. Data were validated by combining this information with registrations of small-bowel biopsies in the National Registry of Pathology (NRP) and with a selected sample of hospital records. RESULTS: Data were obtained from 1996 to 2010. The prevalence of CD registered in DNPR increased from 43.2 [95% CI 39.3-47.1] to 83.6 [95% CI 78.4-88.7] per 100,000, and the incidence increased from 2.8 [95% CI 1.9-3.9] to 10.0 [95% CI 8.4-12.0] per 100,000; 56% of the children had at least one biopsy compatible with CD registered in NRP. The incidence of biopsy-verified CD increased from 0.8 [95% CI 0.3-1.4] to 6.9 [95% CI 5.4-8.4] per 100,000. The mean age at diagnosis increased from 5.1 [95% CI 3.5-6.6] to 8.1 [95% CI 7.2-9.0] years of age. The proportion of children with associated diseases did not change over time. CONCLUSION: The prevalence of diagnosed CD in Danish children and adolescents has increased over the last 15 years.
Subject(s)
Celiac Disease/epidemiology , Adolescent , Age Distribution , Child , Child, Preschool , Data Collection , Denmark/epidemiology , Female , Humans , Infant , Male , Prevalence , RegistriesABSTRACT
BACKGROUND: Transient elastography (TE) is a new noninvasive method to assess the degree of liver fibrosis by measuring liver stiffness. The objective of this study was to determine whether increased liver stiffness in patients admitted to medical wards was associated with increased 30-day mortality. MATERIALS AND METHODS: A prospective cohort study at the medical admissions ward at Odense University Hospital, Denmark, covering a population of 300 000 inhabitants. Consecutive patients ≥ 18 years of age were examined by TE (Fibroscan) at admission. Outcome measure was 30-day mortality. RESULTS: Among 568 patients admitted during 24 days, 289 (50·8%) were included in the study, 212 (73·4%) with valid TE measurement. Increased liver stiffness (TE value > 8 kPa) was found in 22·6% (48/212). This was independently associated with cirrhosis of the liver (P < 0·001) and congestive heart failure (CHF) (P < 0·001). The estimated prevalence of cirrhosis was 7% (95% CI 4-11%). The 30-day mortality among patients with TE value > 8 kPa was 20·8% (10/48, 95%CI 10·5-35·0%) compared to patients with TE value ≤ 8 kPa 3·7% (6/164, 95%CI 1·3-7·8%) (P < 0·001), and TE value > 8 kPa was an independent predictor of death. CONCLUSIONS: Elevated TE value at admission is associated with increased mortality, cirrhosis of the liver and CHF. This information may potentially be used to improve the outcome of high-risk patients admitted to hospital.
Subject(s)
Elasticity Imaging Techniques/methods , Heart Failure/mortality , Liver Cirrhosis/mortality , Aged , Aged, 80 and over , Cohort Studies , Denmark , Female , Heart Failure/complications , Hospitalization , Humans , Liver Cirrhosis/complications , Male , Middle Aged , Prospective Studies , Regression Analysis , Time FactorsSubject(s)
Antigens, CD/physiology , Apoptosis Regulatory Proteins/physiology , Arthritis, Rheumatoid/immunology , Lymphocyte Activation , Synovial Fluid/immunology , T-Lymphocytes/immunology , Antigens, CD/analysis , Apoptosis Regulatory Proteins/analysis , Enzyme-Linked Immunosorbent Assay , Humans , Programmed Cell Death 1 ReceptorABSTRACT
Individual variations in the ability to cope with DNA damage by DNA repair may be essential for the response to chemotherapy, since cancer cells from patients with an effective DNA repair may survive treatment. We have studied the effect on time to treatment failure (TTF) and overall survival (OS) of polymorphism in the DNA repair genes ERCC1, ERCC2 and XRCC3, and in the apoptotic genes PPP1R13L and CD3EAP in 348 patients with multiple myeloma undergoing autologous bone marrow transplantation. Carriers of the variant C-allele of ERCC2 K751Q, the variant T-allele of XRCC3 T241M and the variant A-allele of CD3EAP G-21A had a 1.3-fold, 1.8-fold and 1.9-fold longer TTF, respectively, than homozygous wild type carriers (p = 0.006, p = 0.004, p < 0.001). The polymorphism CD3EAP G-21A also had significant effect on OS (p < 0.045). The polymorphism ERCC2 K751Q may to be related to sex, since the prolonged TTF was only seen in women (p = 0.001). Carriers of the combination of variant alleles of ERCC2 K751Q and XRCC3 T241M had 2.8-fold longer TTF (p = 0.0002). This indicates that suboptimal repair of both DNA mechanisms favors prolonged TTF and that polymorphism in ERCC2, XRCC3 and CD3EAP predicts the outcome for patients treated with autologous stem cell transplantation.
Subject(s)
Biomarkers, Tumor/genetics , Bone Marrow Transplantation , DNA-Binding Proteins/genetics , Intracellular Signaling Peptides and Proteins/genetics , Multiple Myeloma/surgery , Xeroderma Pigmentosum Group D Protein/genetics , Aged , Alleles , Denmark , Female , Humans , Male , Middle Aged , Multiple Myeloma/genetics , Multivariate Analysis , Polymorphism, Single Nucleotide , RNA Polymerase I , Transplantation, Autologous , Treatment OutcomeABSTRACT
OBJECTIVE: This study was performed to 1) determine the prevalence of celiac disease in Danish children with type 1 diabetes and 2) estimate the clinical effects of a gluten-free diet (GFD) in patients with diabetes and celiac disease. RESEARCH DESIGN AND METHODS: In a region comprising 24% of the Danish population, all patients <16 years old with type 1 diabetes were identified and 269 (89%) were included in the study. The diagnosis of celiac disease was suspected in patients with endomysium and tissue transglutaminase antibodies in serum and confirmed by intestinal biopsy. Patients with celiac disease were followed for 2 years while consuming a GFD. RESULTS: In 28 of 33 patients with celiac antibodies, an intestinal biopsy showed villous atrophy. In 5 patients, celiac disease had been diagnosed previously, giving an overall prevalence of 12.3% (95% CI 8.6-16.9). Patients with celiac disease had a lower SD score (SDS) for height (P < 0.001) and weight (P = 0.002) than patients without celiac disease and were significantly younger at diabetes onset (P = 0.041). A GFD was obtained in 31 of 33 patients. After 2 years of follow-up, there was an increase in weight SDS (P = 0.006) and in children <14 years old an increase in height SDS (P = 0.036). An increase in hemoglobin (P = 0.002) and serum ferritin (P = 0.020) was found, whereas HbA(1c) remained unchanged (P = 0.311) during follow-up. CONCLUSIONS: This population-based study showed the highest reported prevalence of celiac disease in type 1 diabetes in Europe. Patients with celiac disease showed clinical improvements with a GFD. We recommend screening for celiac disease in all children with type 1 diabetes.
Subject(s)
Celiac Disease/diet therapy , Celiac Disease/epidemiology , Diabetes Mellitus, Type 1/diet therapy , Diabetes Mellitus, Type 1/epidemiology , Diet, Diabetic/methods , Adolescent , Biopsy , Celiac Disease/pathology , Child , Child, Preschool , Denmark/epidemiology , Female , Follow-Up Studies , Glutens , Humans , Male , Mass Screening , PrevalenceABSTRACT
PD-1 is an immunoregulatory receptor expressed on the surface of activated T cells, B cells, and monocytes. We describe four alternatively spliced PD-1 mRNA transcripts (PD-1Deltaex2, PD-1Deltaex3, PD-1Deltaex2,3, and PD-1Deltaex2,3,4) in addition to the full length isoform. PD-1Deltaex2 and PD-1Deltaex3 are generated by alternative splicing where exon 2 (extracellular IgV-like domain) and exon 3 (transmembrane domain) respectively are spliced out. PD-1Deltaex3 is therefore likely to encode a soluble form of PD-1. PD-1Deltaex2,3 lacks exon 2 and 3. These three variants have unaffected open reading frames. PD-1Deltaex2,3,4 lacks exon 2, 3, and 4 (intracellular domain) and contains a premature stop codon in exon 5. Activation of human PBMCs with anti-CD3+anti-CD28 monoclonal antibodies induces an increased level of each PD-1 transcript. A parallel increase in the expression of PD-1Deltaex3 and flPD-1 upon activation suggests an important interplay between the putative soluble PD-1 and flPD-1 possibly involved in maintenance of peripheral self-tolerance and prevention of autoimmunity.
Subject(s)
Alternative Splicing/genetics , Antigens, Surface/genetics , Apoptosis Regulatory Proteins/genetics , Antigens, CD , Exons/genetics , Gene Expression Regulation , Humans , Leukocytes/metabolism , Polymerase Chain Reaction , Programmed Cell Death 1 Receptor , RNA, Messenger/genetics , RNA, Messenger/metabolism , Reproducibility of Results , SolubilityABSTRACT
Celiac disease (CD) is a complex inflammatory disorder of the small intestine, induced by dietary gluten in genetically susceptible individuals. CD is strongly associated with HLA-DQ2 and it has recently been established that gut-derived DQ2-restricted T cells from patients with CD predominantly recognize gluten-derived peptides in which specific glutamine residues are deamidated to glutamic acid by tissue transglutaminase. Recently, intestinally expressed human genes with high homology to DQ2-gliadin celiac T-cell epitopes have been identified. Single or double point mutations which would increase the celiac T-cell epitope homology, and mutation in these genes, leading to the expression of glutamic acid at particular positions, could hypothetically be involved in the initiation of CD in HLA-DQ2-positive children. Six gene regions with high celiac T-cell epitope homology were investigated for single-nucleotide polymorphisms using direct sequencing of DNA from 20 CD patients, 27 type 1 diabetes mellitus (T1DM) patients with associated CD, 24 patients with T1DM without CD and 110 healthy controls, all of Caucasian origin. No variants in any of these genes in any of the investigated groups were found. We conclude that gut-expressed human celiac epitope homologous peptides are unlikely to represent non-HLA risk factors in the development of celiac disease in Caucasians.
Subject(s)
Celiac Disease/genetics , Diabetes Mellitus, Type 1/genetics , Genetic Predisposition to Disease , Genetic Variation , Gliadin/genetics , HLA-DQ Antigens/genetics , HumansABSTRACT
BACKGROUND: Hemovigilance has shown that bacteria cause more fatalities than other infections together. Surveillance for detection of bacteria in platelets (PLTs) was initiated. Concomitantly, the storage period for PLTs was extended from 5 to 7 days to reduce cost. STUDY DESIGN AND METHODS: Analysis was performed of all cases of a positive signal in a screening procedure for contaminated PLTs taking into account results of confirmative cultures and results of culture from blood components including bacteria strains. Records were assessed from patients transfused with blood components issued before the screening culture became positive. RESULTS: Samples were collected from 22,057 PLT units. An initial reaction was seen in 84 (0.38%). Growth was confirmed in 70 of these. Of the associated PLT units, 26 had been issued or outdated at the time when the culture was found to be reactive, in 27 bacteria were found, and in 17 cultures were negative. The bacteria found were mainly from normal skin flora. Sixty-six patients received 75 blood components issued before the screening system alarmed. None of these patients had a transfusion reaction reported. The outdating fell to less than 5 percent. CONCLUSION: A screening system for detection of bacterial contamination was implemented without increase in cost owing to extension of storage time to 7 days. Transfusion of several contaminated blood components was prevented.