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Increased density of tolerogenic dendritic cells in the small bowel mucosa of celiac patients

World Journal of Gastroenterology 2015年第2期21卷 439-452页

作者： Tamara Vorobjova Oivi uibo Kaire Heilman raivo uibo Department of Immunology Institute of Biomedicine and Translational MedicineUniversity of Tartu51014 TartuEstonia Department of Pediatrics University of TartuTartuEstoniaChildren’s Clinic of Tartu University Hospital51014 TartuEstonia Department of Pediatrics University of TartuTartuEstoniaTallinn’s Children’s Hospital13419 TallinnEstonia

AIM: To investigate the densities of dendritic cells(DCs) and FOXP3+ regulatory T cells(Tregs) and their interrelations in the small bowel mucosa in untreated celiac disease(CD) patients with and without type 1 diabetes(T1D).METHODS: Seventy-four patients(45 female, 29 male, mean age 11.1 ± 6.8 years) who underwent small bowel biopsy were studied. CD without T1 D was diagnosed in 18 patients, and CD with T1 D was diagnosed in 15 patients. Normal small bowel mucosa was found in two T1 D patients. Thirty-nine patients(mean age 12.8 ± 4.9 years) with other diagnoses(functional dyspepsia, duodenal ulcer, erosive gastritis, etc.) formed the control group. All CD patients had partial or subtotal villous atrophy according to the Marsh classification: Marsh grade Ⅲa in 9, grade Ⅲb in 21 and grade Ⅲc in 3 cases. Thirty-nine patients without CD and 2 with T1 D had normal small bowel mucosa(Marsh grade 0). The densities of CD11c+, IDO+, CD103+, Langerin(CD207+) DCs and FOXP3+ Tregs were investigated by immunohistochemistry(on paraffin-embedded specimens) and immunofluorescence(on cryostat sections) methods using a combination of mono- and double-staining. Sixtysixserum samples were tested for Ig A-tissue transglutaminase(t TG) using a fully automated Eli ATM Celikey Ig A assay(Pharmacia Diagnostics, Freiburg, Germany). RESULTS: The density of CD11c+ DCs was significantly increased in CD patients compared with patients with normal mucosa(21.67 ± 2.49 vs 13.58 ± 1.51, P = 0.007). The numbers of FOXP3+ cells were significantly higher in CD patients(10.66 ± 1.50 vs 1.92 ± 0.37, P = 0.0002) and in patients with CD and coexisting T1D(8.11 ± 1.64 vs 1.92 ± 0.37, P = 0.002) compared with patients with normal mucosa. The density of FOXP3+ cells significantly correlated with the histologicalgrade of atrophic changes in the small bowel mucosa according to the March classification(r = 0.62; P < 0.0001) and with levels of Ig A antibody(r = 0.55; P < 0.0001). The densities of IDO+ DCs were

关键词： CD11c+,CD103+,IDO+,Langerin(CD207+) dendritic cell

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Celiac disease:a model disease for gene-environment interaction

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Cellular & Molecular Immunology 2011年第2期8卷 93-95页

作者： raivo uibo Zhigang Tian M Eric Gershwin Immunology Group IGMPUniversity of TartuRavila 19TartuEstonia University of Science and Technology of China HefeiChina Division of Rheumatology Allergy and Clinical ImmunologyUniversity of California at Davis School of MedicineDavisCAUSA

Celiac sprue remains a model autoimmune disease for dissection of genetic and environmental influences on disease *** 2010 Congress of Autoimmunity included several key sessions devoted to genetics and *** papers from these symposia were selected for in-depth discussion and *** issue is devoted to this *** goal is not to discuss genetic and environmental interactions,but rather to focus on key elements of diagnosis,the inflammatory response and the mechanisms of autoimmunity.

关键词： environment andautoimmunity geoepidemiology autoimmunity

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Celiac disease in patients with type 1 diabetes:a condition with distinct changes in intestinal immunity?

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Cellular & Molecular Immunology 2011年第2期8卷 150-156页

作者： raivo uibo Marina Panarina Kaupo Teesalu Ija Talja Epp Sepp Meeme Utt Marika Mikelsaar Kaire Heilman Oivi uibo Tamara Vorobjova Department of Immunology University of TartuTartuEstonia Department of Microbiology University of TartuTartuEstonia Children’s Clinic of Tartu University Hospital TartuEstonia Department of Pediatrics University of TartuTartuEstonia

Two common chronic childhood diseases-celiac disease(CD)and type 1 diabetes(T1D)-result from complex pathological mechanisms where genetic susceptibility,environmental exposure,alterations in intestinal permeability and immune responses play central *** this study,we investigated whether these characteristics were universal for CD independently of T1D *** this purpose,we studied 36 children with normal small-bowel mucosa and 26 children with active CD,including 12 patients with *** samples from the small-bowel mucosa,we detected the lowest expression of tight junction protein 1(TJP1)mRNA in CD patients with T1D,indicating an increase in intestinal ***,these samples displayed the highest expression of forkhead box P3(FoxP3)mRNA,a marker for regulatory T cells,as compared with other patient *** the same time,serum levels of IgA antibodies specific for the CD-related antigens deamidated gliadin and tissue transglutaminase(tTG)were the highest in CD patients with *** contrast,no significant differences were found in IgA or IgG antibodies specific for bovine beta-lactoglobulin or Bifidobacterium adolescentis DSM 20083-derived *** were also no differences in the transamidating activity of serum autoantibodies between patients and control *** results show that patients with T1D and newly detected CD exhibit severely altered intestinal permeability,strong local immune activation and increased immunoregulatory mechanisms in the small *** study is required to determine whether these extreme changes in this CD subgroup are due to some specific environmental factors(virus infections),unknown genetic effects or autoimmune reactions to antigenic targets in intracellular tight junctions.

关键词： autoimmunity celiac disease immunoregulation intestinal mucosa type 1 diabetes

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Screening for celiac disease in Down's syndrome patients revealed cases of subtotal villous atrophy without typical for celiac disease HLA-DQ and tissue transglutaminase antibodies

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World Journal of Gastroenterology 2006年第9期12卷 1430-1434页

作者： Oivi uibo Kaupo Teesalu Kaja Metsküla Tiia Reimand Riste Saat Tarvo Sillat Koit Reimand Tiina Talvik raivo uibo Department of Paediatrics University of Tartu TartuEstonia Department of Immunology University of Tartu TartuEstonia Children's Clinic Tartu University Clinics TartuEstonia

A1M： To investigate the prevalence of celiac disease （CD） as well as CD marker antibodies and susceptibility HLA-DQ haplotypes in 134 karyotyped Down＇s syndrome （DS） patients. METHODS： Immunoglobulin A （IgA） and G （IgG） type anti-gliadin antibodies （AGA）, IgA type anti-tissue transglutaminase （tTG） antibodies （anti-tTG） with antigen of guinea pig and human source were determined by enzyme-linked immunosorbent assay and endomysium antibodies （EHA） by indirect immunofiuoresence test. HLA-DQA1＊0501/DQB1＊0201 （DQ2） was revealed by polymerase chain reaction. Celiac disease was diagnosed by revised ESPGHAN criteria. RESULTS： 41% of DS patients had AGA, 6.0% IgA anti-tTG with guinea pig antigen, and 3.0 % [gA EMA （all positive for anti-tTG with human tTG）. Subtotal villous atrophy was found in 5 out of 9 DS patients who had agreed to small bowel biopsy. One of them had DQA1＊0S01/DQB1＊0201 and anti-tTG and EMA i.e. typical for CD markers （this case also fulfilled the ESPGHAN diagnostic criteria）, but other four lacked these markers. Three non-biopsied DS patients had also most probably CD because DQA1＊0S01/DQB1＊0201 and IgA anti-tTG （EMA） were detected. Thus, the prevalence of CD among our DS patients population is 3.0 % （95 % of confidence interval [CI]： 0.1-5.9 %）. CONCLUSION： We confirm the increased frequency of CD among DS patients. In addition, we have revealed a subgroup of patients with subtotal villous atrophy but without characteristic for CD immunological and genetic markers. Whether these cases represent CD （with atypical immunopathogenesis） or some other immune enteropathy, requires further investigations.

关键词： Down's syndrome Subtotal villous atrophy Celiac disease Screening Autoantibodies Anti-gliadin antibodies HLA

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