Inflammatory bowel disease: progress toward a gene.

Objective. The Human Leukocyte Antigen (HLA) Class II is the major histocompatibility complex surface glycoproteins of humans responsible for presenting exogenous antigenic peptides which help direct specificity of immune response. In immune-cell therapy, the HLA allelic variants are of particular importance as they determine the successful activation of target cells that results to a desired therapeutic response. However, HLA Class II exhibits high polymorphism and has variable distribution in population, constituting these so-called allelic variants. Specifically, the HLA Class II DRB1 is considered the predominant locus among Filipinos. This research aimed to identify the presence of HLA Class II DRB1 allelic variants in the stem cell samples of ten (10) Filipino cancer patients by reverse transcription polymerase chain reaction (RT-PCR) amplification.Method. This study employed a PCR-based HLA Class II typing to identify the HLA Class II DRB1 allelic variant in Filipino cancer patients. Design of forward and reverse primers for HLA Class II DRB1, optimization of PCR conditions for amplifying HLA Class II DRB1, and identification of HLA Class II DRB1 allelic variants from samples by sequencing and database comparison were conducted.Results. PCR optimization showed that optimum annealing temperature for HLA DRB1 was 58.8°C with 1 mM MgCl2. PCR amplification of HLA DRB1 from ten anonymized cancer patient samples and DNA sequencing revealed that Patients 1, 2, 5, 8, 9, and 10 harbor HLA DRB1 allelic variants, particularly, the HLA DRB1*04:06:01, HLA DRB1*12:01:01, HLA DRB1*0813, HLA DRB1*04:05:01, HLA DRB1*09:01:02, and HLA DRB1*16:02:01, allelic variants, respectively.Conclusion. Using the designed primers and optimized RT-PCR protocol, HLA information derived from six out of ten patient samples can be used for further applications in developing personalized or generic antigenic peptides such as dendritic cell cancer vaccine.

Beyond Gene Discovery in Inflammatory Bowel Disease: The Emerging Role of Epigenetics

In cord blood banking, substantial amounts of data on infants and cord blood are gathered at high cost, including birth weights and human leukocyte antigen (HLA) genotypes. As certain HLA alleles have been associated with protective host responses, it is possible that an HLA allele, or another factor linked to it, might even affect normal intrauterine growth. We explored cord blood bank data (n = 1381 infants) to elucidate whether there is an association between birth weight and HLA class II (DRB1) alleles. HLA DRB1 data were available from 1263 infants. We observed an association between birth weight and HLA DRB1*13, which was over-represented among full-term infants with the highest birth weights. The association remained when the birth weight was corrected for varying gestational age (relative birth weight) according to gender (P = 0.015). After correction of the P-value for multiple comparisons, the association was not statistically significant. However, when the birth weights of all infants were analysed for the effect of DRB1*13, infants positive for HLA DRB1*13 (n = 319) were found to have higher birth weights than infants negative for this allele (n = 944; median 3690 g vs. 3650 g, respectively; P = 0.044). Although the difference in median birth weight was only 40 g, it may be considered significant because it appeared after segregation of the infants into two groups according to the single HLA class II allele group earlier associated with protection against, for example, childhood type 1 diabetes and certain infectious diseases. The present finding may thus suggest identification of a new factor affecting normal intrauterine growth.

BackgroundTubulointerstitial nephritis and uveitis (TINU) syndrome is a rare form of uveitis. Previously, the authors had demonstrated a strong association of human leukocyte antigen (HLA) DRB1*0102 with TINU. Here, the...

: The objective of the present study was to quantify the national pediatric inpatient inflammatory bowel disease (IBD) burden in terms of the number of IBD-related hospitalizations, the number of days spent in the hospital, and hospitalization costs. : Hospitalizations for children and adolescents 20 years and younger with a primary diagnosis of either Crohn disease (CD) or ulcerative colitis (UC) were selected from the 2006 Kids' Inpatient Database (KID). Length of the hospital stay in days (LOS) and charges for the hospitalization were found directly in the Kids' Inpatient Database, and cost was calculated using the hospital's cost-to-charge ratio. Predictor variables included patient characteristics, such as age and severity of illness, and hospital characteristics. Ordinary-least-squares regressions were developed and estimated to explain hospitalization costs. : In 2006, there were 10,777 IBD-related hospitalizations. The total and mean costs for CD were $66.3 million and $10,176 (95% confidence interval [CI] $9647-$10,705), and for UC were $48.6 million and $11,836 (95% CI $10,760-$12,912). For CD, 0- to 5-year-old patients had the highest mean LOS (8.10, 95% CI 5.53-10.67, days) and mean cost ($13,894, 95% CI $9053-$18,735), whereas, for UC, 11- to 15-year-old patients had the highest mean LOS (7.49, 95% CI 6.88-8.10, 95% CI 5.53-10.67, days) and mean cost ($13,407, 95% CI $11,704-$15,110). : For a pediatric disease with a rather low prevalence rate, the estimated annual inpatient pediatric burden of IBD is a sizeable $152.4 million (2010 US$) and 64,985 days spent in the hospital. As medications and outpatient treatments improve for the treatment of IBD, there is an opportunity for significant reduction in inpatient burden.

Ancestral haplotypes between human leukocyte antigen (HLA) class I and class II alleles are well-recognized in the literature. We previously published a positive association between the class II HLA allele DRB1*03 and the subsequent development of asthma in a retrospective cohort of 383 children. To refine this association, we investigated whether DRB1*03-specific haplotypes extending across the HLA are associated with asthma incidence. We found evidence of strong HLA DRB1*03-dependent linkage disequilibrium across the region, but no association between DRB1*03 ancestral haplotypes and childhood asthma. We did, however, observe a trend toward a positive association between HLA DRB1*03 and asthma by adding non-ancestral DRB1*03 positive haplotypes. Our results suggest that the role of the HLA DRB1*03 in asthma susceptibility is independent of ancestral-haplotype-mediated linkage disequilibrium.

Distinct Autoantibodies Against Endothelial Protein C Receptor in Ulcerative Colitis

Article1 August 1954ULCERATIVE COLITIS: THERAPEUTIC EFFECTS OF CORTICOTROPIN (ACTH) AND CORTISONE IN 120 PATIENTSJOSEPH B. KIRSNER, M.D., Ph.D., F.A.C.P., WALTER L. PALMER, M.D., Ph.D., F.A.C.P.JOSEPH B. KIRSNER, M.D., Ph.D., F.A.C.P., WALTER L. PALMER, M.D., Ph.D., F.A.C.P.Author, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-41-2-232 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptINTRODUCTIONThe effects of corticotropin (ACTH) and cortisone in ulcerative colitis have been characterized as beneficial,1-5 indifferent6-8 and unfavorable.9-14 Numerous studies also have emphasized the complications of therapy and the recurrences.15-20 The observation of 40 patients in 19511 indicated that, while ACTH and cortisone do not cure ulcerative colitis, they may be useful adjuncts, initiating rapid and occasionally dramatic clinical improvement. The present report summarizes our experience with corticotropin and cortisone in 120 patients with ulcerative colitis observed during the past four years.PATIENTS STUDIEDGeneral Data:The series includes 65 females and 55 males; the majority were between 20...Bibliography1. KirsnerPalmerKlotz JBWLAP (a) : ACTH and cortisone in chronic ulcerative colitis. A comparison of clinical effects, J. Lab. and Clin. Med. 36: 846, 1950. (b) Kirsner, J. B., and Palmer, W. L.: ACTH in ulcerative colitis. Report of progress, Gastroenterology 18: 143, 1951. (c) Kirsner, J. B.: Discussion of "ACTH in chronic ulcerative colitis," Proc. Second Clinical ACTH Conference, 1951, The Blakiston Co., Philadelphia, p. 500. (d) Kirsner, J. B., and Palmer, W. L.: Effect of corticotropin (ACTH) in chronic ulcerative colitis. Observations in forty patients, J. A. M. A. 147: 541, 1951. MedlineGoogle Scholar2. 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Report of case, New England J. Med. 233: 87, 1945. (b) Jobb, E., and Finkelstein, A.: Interesting x-ray findings in a case of acute fulminating ulcerative colitis, Gastroenterology 8: 213, 1947. (c) Griffiths, L. L., and Gilchrist, L.: Fatal case of acute ulcerative colitis with multiple perforations, Brit. M. J. 1: 1366, 1951. (d) McEwen, K. L., and Lodwell, E. A.: Acute fulminating idiopathic ulcerative colitis, Radiology 59: 185, 1952. CrossrefGoogle Scholar33. JankelsonMcClureSweetsir IRCWF: Idiopathic ulcerative colitis. Perforation of the bowel, Rev. Gastroenterol. 12: 31, 1945. Google Scholar34. SalassaKeatingSprague RMFRRG: Clinical aspects of suppression of adrenal cortical function after use of cortisone, Proc. Staff Meet., Mayo Clin. 28: 662, 1953. MedlineGoogle Scholar35. Blanco HG: Considerations on the pathogenesis of ulcerative colitis: its treatment with ACTH and cortisone, Ap. de la des. Clinica No. 3-15, 1953. Google Scholar36. KirsnerPalmerMaimonRicketts JBWLSNWE: Clinical course of chronic non-specific ulcerative colitis, J. A. M. A. 137: 922, 1948. CrossrefMedlineGoogle Scholar37. LevineKirsnerKlotz MJBAP: A new concept of the pathogenesis of ulcerative colitis, Science 144: 552, 1951. CrossrefGoogle Scholar38. Machella TE: Problems in ulcerative colitis, Am. J. Med. 13: 760, 1952. CrossrefMedlineGoogle Scholar39. KirsnerPalmer JBWL: Ulcerative colitis: consideration of its etiology and treatment, J. A. M. A. 155: 341, 1954. CrossrefMedlineGoogle Scholar This content is PDF only. To continue reading please click on the PDF icon. Author, Article, and Disclosure InformationAffiliations: Chicago, Illinois*Received for publication February 23, 1954. (Presented at Midwest Regional Meeting, American College of Physicians, Milwaukee, Wisconsin, November 21, 1953.)From the Department of Medicine, University of Chicago.†This study was supported in part by the Wallach Fund for Gastrointestinal Research.Dr. David Klein, of Wilson Laboratories, Chicago, Illinois, very generously supplied much of the corticotropin (ACTH).Merck and Company provided a portion of the cortisone. PreviousarticleNextarticle Advertisement FiguresReferencesRelatedDetails Metrics Cited byInflammatory bowel disease part II: Clinical and therapeutic aspectsBlood eosinophilia and ulcerative colitis--influence of ethnic origin.Clinical Observations on Inflammatory Bowel DiseaseThe Treabnent of Ulcerative ColitisChronic ulcerative colitis in elderly patientsEosinophilia in Peripheral Blood and Inflammatory Exudate in Non-specific ProctocolitisImmediate and Prolonged Therapeutic Effects of Corticotrophin and Adrenal Steroids in Ulcerative ColitisEOSINOPHIL LEUCOCYTES IN ULCERATIVE COLITISCORTICOTROPIN (ACTH) AND THE ADRENAL STEROIDS IN THE MANAGEMENT OF ULCERATIVE COLITIS: OBSERVATIONS IN 240 PATIENTS*†JOSEPH B. KIRSNER, M.D., F.A.C.P., WALTER L. PALMER, M.D., F.A.C.P., JEAN A. SPENCER, M.D., RICHARD O. BICKS, M.D., CHARLES F. JOHNSON, M.D.Response to Drugs and PsychiatryGeneralized scleroderma associated with chronic ulcerative colitisSteroid hormones in the management of chronic ulcerative colitisThe Use of ACTH and Adrenocorticosteroids in Diseases of the Digestive SystemThe Role of Acth and Adrenal Steroids in Perforation of the Colon in Ulcerative Colitis a Clinical-Pathologic StudyUlcerative Colitis; Observations on Its Etiology, Course and ManagementThe Use of the Adrenocorticosteroids in GastroenterologyThe use of ACTH, cortisone, hydrocortisone and related compounds in the management of ulcerative colitisGastroenterologyToxic Psychosis Under Cortisone and CorticotrophinObservations on the Influence of Corticotropins upon the Course of Chronic Ulcerative ColitisTHE PRESENT STATUS OF ACTH AND ADRENAL STEROID THERAPY IN MEDICINE*J. C. BECK, M.D., F.R.C.P.(C)THE RÔLE OF ACTH, CORTISONE AND HYDROCORTISONE IN SURGERY*†WILLIAM E. ABBOTT, M.D., HARVEY KRIEGER, M.D., STANLEY LEVEY, Ph.D.THE USE OF HYDROCORTISONE IN ULCERATIVE COLITIS: PRELIMINARY OBSERVATIONS 1 August 1954Volume 41, Issue 2Page: 232-250KeywordsAdrenocorticotropic hormoneResearch fundingUlcerative colitis Issue Published: 1 August 1954 PDF downloadLoading ...

Chapter 9 - Human leukocyte antigen-typing: a significant immunogenetic application in clinical medicine

Pemphigus vulgaris (PV) is a severe autoimmune blistering skin disorder that is strongly associated with major histocompatibility complex class II alleles. Human leukocyte antigen (HLA) subtypes vary with racial/ethnic backgrounds. The purpose of this study was to determine the association of HLA class II alleles and haplotypes with PV in Turkish patients. Twenty-five patients with PV and 113 healthy transplant donors were genotyped for HLA class II alleles. HLA DNA typing was performed by the polymerase chain reaction/sequence specific primer method. The frequency of HLA DRB1*04 allele was 68.00% in patients compared to 30.97% in controls (P = 0.0012) and the frequency of HLA DRB1*14 allele was 32.00% in the patient group compared to 8.85% in the control group (P = 0.0054). Also, the frequency of HLA DRB1*04/DQB1*03 and HLA DRB1*14/DQB1*05 haplotypes in PV patients was significantly higher than controls (32.0% vs 6.2%, chi(2) = 28.142, P < 0.001; and 16% vs 2.7%, chi(2) = 15.143, P = 0.001, respectively). A preventive allele or haplotype for the manifestation of PV has not been identified in this study. Our findings suggest that HLA DRB1*04 and DRB1*14 alleles, and HLA DRB1*04/DQB1*03 and HLA DRB1*14/DQB1*05 haplotypes are genetic markers for general susceptibility to PV in the Turkish population.

AGA Clinical Practice Update on Management of Inflammatory Bowel Disease in Elderly Patients: Expert Review

The human leukocyte antigen (HLA) region has been implicated in the disease susceptibility of inflammatory bowel disease by several linkage and association studies. In Caucasians, HLA-DRB1 has been reported to determine the clinical phenotypes of ulcerative colitis (UC). Others and we previously reported that HLA-DRB1*1502 was strongly associated with UC in the Japanese population. However, the contribution of HLA-DRB1 to the clinical phenotypes in Japanese UC has not been elucidated yet. The aim of this study was to determine whether HLA-DRB1 alleles were associated with the clinical phenotypes in Japanese patients with UC. A total of 353 patients with UC were recruited. Patients were classified into subgroups by sex, age at diagnosis, disease extent, need for steroid therapy or need for surgical treatment. The allele frequency of HLA-DRB1*08 was significantly higher in patients whose disease extended beyond the rectum (left-sided and extensive UC) than in those with proctitis [odds ratio (OR)=2.20, Pc=0.043). The allele frequency of HLA-DRB1*09 was significantly higher in patients with UC diagnosed at the age of 40 years or older than in those with UC diagnosed before the age of 40 years (OR=2.31, Pc=0.022). Besides these positive associations, no significant differences were found in the allele frequencies between the other subgroups. We conclude that HLA-DRB1*09 is associated with the age at diagnosis and HLA-DRB1*08 is associated with the disease extent of UC in Japanese. These results indicate that HLA-DRB1 is not only associated with the overall UC susceptibility but also associated with the clinical phenotypes in Japanese.

The genetic contributions to pediatric onset ulcerative colitis (UC), characterized by severe disease and extensive colonic involvement, are largely unknown. In adult onset UC, Genome Wide Association Study (GWAS) has identified numerous loci, most of which have a modest susceptibility risk (OR 0.84-1.14), with the exception of the human leukocyte antigen (HLA) region on Chromosome 6 (OR 3.59). To study the genetic contribution to exclusive pediatric onset UC, a GWAS was performed on 466 cases with 2099 healthy controls using UK Biobank array. SNP2HLA was used to impute classical HLA alleles and their corresponding amino acids, and the results are compared with adult onset UC. HLA explained the almost entire association signal, dominated with 191 single nucleotide polymorphisms (SNPs) (p = 5 x 10-8 to 5 x 10-10). Although very small effects, established SNPs in adult onset UC loci had similar direction and magnitude in pediatric onset UC. SNP2HLA imputation identified HLA-DRB1*0103 (odds ratio [OR] = 6.941, p = 1.92*10-13) as the most significant association for pediatric UC compared with adult onset UC (OR = 3.59). Further conditioning showed independent effects for HLA-DRB1*1301 (OR = 2.25, p = 7.92*10-9) and another SNP rs17188113 (OR = 0.48, p = 7.56*10-9). Two HLA-DRB1 causal alleles are shared with adult onset UC, while at least 2 signals are unique to pediatric UC. Subsequent stratified analyses indicated that HLA-DRB1*0103 has stronger association for extensive disease (E4: OR = 8.28, p = 4.66x10-10) and female gender (OR = 8.85, p = 4.82x10-13). In pediatric onset UC, the HLA explains almost the entire genetic associations. In addition, the HLA association is approximately twice as strong in pediatric UC compared with adults, due to a combination of novel and shared effects. We speculate the paramount importance of antigenic stimulation either by infectious or noninfectious stimuli as a causal event in pediatric UC onset.

Blood oxygen level dependent (BOLD) signal in functional magnetic resonance imaging (fMRI) is frequently used as a proxy for underlying neural activity. Although this is a plausible assumption for experiments where a task is performed, it may not hold to the same degree for conditions of fMRI recording in a task-free, "resting" state where neural synaptic events are weak and, hence, neurovascular coupling and endothelial vascular factors become more prominent (Hillman Annu Rev Neurosci 37:161-181, 2014, 10.1146/annurev-neuro-071013-014111). Here we investigated the magnitude of change of BOLD in consecutive samples over the acquisition time period (turnover of BOLD, "TBOLD") by first-order differencing of single-voxel BOLD time series acquired in 70 areas of the cerebral cortex of 57 cognitively healthy women in a task-free resting state. More specifically, we evaluated (a) the variation of TBOLD among different cortical areas, (b) its dependence on age, and (c) its dependence on the presence (or absence) of the neuroprotective Human Leukocyte Antigen (HLA) gene DRB1*13 (DRB1*13:02 and DRB1*13:01). We found that TBOLD (a) varied substantially by 2.2 × among cortical areas, being highest in parahippocampal and entorhinal areas and lowest in parietal-occipital areas, (b) was significantly reduced in DRB1*13 carriers across cortical areas (from ~ 15% reduction in orbitofrontal cortex to 2% reduction in cuneus), and (c) increased with age in noncarriers of DRB1*13 but decreased with age in DRB1*13 carriers. These findings document significant dependencies of TBOLD on cortical area location, HLA DRB1*13 and age.

M2042 The Role of Pregnane X Receptor (PXR/NR1i2) Gene Variants in Inflammatory Bowel Disease