FW: Systemic autoimmunce disorders in celiac disease - research I mentioned.

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Here is one of the abstracts..From: Bronwyn Syiek Sent: Monday, August 20, 2007 9:53 PMCarolyn (reck1@...)Subject: Systemic autoimmunce disorders in celiac disease - research I mentioned. Systemic Autoimmune Disorders in Celiac Disease Alessio Fasano Curr Opin Gastroenterol. 2006;22(6):674-679. ©2006 Lippincott & WilkinsPosted 11/15/2006Abstract and IntroductionAbstractPurpose of Review: Celiac disease is an immune-mediated disorder clinically characterized by a multitude of symptoms and complications. The comorbidity between celiac disease and other autoimmune disorders has been clearly established.Recent Findings: Two main theories have been postulated to explain this comorbidity: (1) linkage disequilibrium between the genes responsible for celiac disease and those responsible for the coexpressed autoimmune diseases or (2) untreated celiac disease leading to the onset of other autoimmune diseases. This article reviews the current literature supporting either theory and places the current knowledge in the field within the context of the most recent data on the pathogenesis of celiac disease.Summary: The current literature did not clearly establish which of the two theories explain the comorbidity between celiac disease and other autoimmune disorders. There is, however, growing evidence that the loss of the intestinal barrier function typical of celiac disease could be responsible of the onset of other autoimmune disease. This concept implies that the autoimmune response can be theoretically stopped and perhaps reversed if the interplay between autoimmune predisposing genes and trigger(s) is prevented or eliminated by a prompt diagnosis and treatment.IntroductionCeliac disease is an immune-mediated enteropathy triggered by the ingestion of gluten-containing grains (including wheat, rye and barley) in genetically susceptible persons. Celiac disease has several autoimmune features, including the production of highly disease-specific IgA and IgG autoantibodies to tissue transglutaminase (tTG) when patients are on a gluten-containing diet, and the presence of small intestinal intraepithelial lymphocytes which can mediate direct cytotoxicity of enterocytes expressing MIC molecules in an antigen-nonspecific manner.[1*] Similar to typical autoimmune disorders, celiac disease has a multifactorial etiology with complex genetics and comorbidity with autoimmune diseases. Celiac disease is, however, a unique example of autoimmunity, since early serological diagnosis and dietary treatment can revert the autoimmune process and can prevent its severe, sometimes life-threatening complications. Therefore, the common wisdom among experts in the field supports the notion that individuals affected by celiac disease should be treated, irrespective of the presence of symptoms and/or associated conditions. Well-designed prospective clinical studies to address this point have, however, not been performed, nor can they be conceived, given the ethical implications of such a proposition. Celiac disease can manifest itself with a previously unappreciated range of clinical presentations (the so-called celiac iceberg, Fig. 1), including the typical malabsorption syndrome (chronic diarrhea, weight loss, abdominal distension) and a spectrum of symptoms potentially affecting any organ system.[2] Since celiac disease often presents in an atypical or even silent manner, many cases remain undiagnosed, their diet treatment is significantly delayed and, consequently, the risk of long-term complications increases. While evidence-based data support the causative effect of untreated celiac disease for some of these complications, for other conditions this association remains questionable. One of the most controversial issues concerning possible complications of untreated celiac disease involves the association between celiac disease and other autoimmune disorders.Figure 1. The celiac iceberg. The clinical outcome of the interplay between celiac disease genetic makeup and exposure to gluten, the environmental trigger of the disease, is typically represented by the iceberg model, with the symptomatic forms present at the visible part of the iceberg and the silent and potential forms being submerged below the water line. Celiac Disease Comorbidity with Other Autoimmune Diseases: Serendipitous Association or Calculated Design?The two most accredited theories to explain this comorbidity propose: (1) untreated celiac disease leads to the onset of other autoimmune disorders in genetically susceptible individuals or (2) this association is secondary to linkage disequilibrium of genes predisposing for both celiac disease and the associated autoimmune disease(s). The first hypothesis is supported by the evidence that tTG, the recognized autoantigen involved in the pathogenesis of celiac disease, seems to be only one of the autoantigens involved in gluten-dependent autoimmune reactions. Other autoantigens which are normally 'cryptic' can be unmasked and cause a self-aggressive immunological response following the gliadin-initiated inflammatory process.[3] In fact, persistent stimulation by some pro-inflammatory cytokines such as interferon-γ and tumor necrosis factor-α can cause further processing of autoantigens and their presentation to T lymphocytes by macrophage-type immunocompetent cells (so-called antigen-presenting cells). The phenomenon of antigen spreading has been described in well-defined natural models such as Type 1 diabetes (T1D), whose clinical manifestations appear after the patient has produced an autoimmune response to various autoantigens (i.e. anti-insulin, anti-β cell, etc.) and might also be present in celiac disease. This would explain the high incidence of autoimmune diseases and the presence of a large number of organ-specific autoantibodies in a certain number of celiac subjects on a gluten-containing diet.The report by Ventura et al.[4] that studied the prevalence of autoimmune disorders in celiac disease in relation to the duration of exposure to gluten seems to support this theory. Over a 6-month period, 909 pediatric patients with celiac disease, 1268 healthy controls and 163 patients with Crohn's disease were evaluated for the presence of autoimmune disorders. The authors[4] detected a prevalence of autoimmune disorders among celiac disease patients higher than in controls, but similar to that detected in Crohn's disease patients. Prevalence of autoimmune disorders in celiac disease was increased with increasing age at diagnosis. In a logistic regression model, age at diagnosis was the only significant predictor variable of the odds of developing an autoimmune disorder.[4] Based on this evidence, the authors concluded that the prevalence of autoimmune disorders in celiac disease is related to the duration of exposure to gluten. The same group[5] screened sera from 491 subjects with T1D, 824 relatives and 4000 healthy control subjects for antiendomysium antibodies (EMA), followed by confirmatory intestinal biopsy in positive subjects. The authors found that the prevalence of celiac disease was 5.7% among diabetic patients and 1.9% among relatives - values significantly higher than those found among control subjects.[5] The prevalence of autoimmune disorders in diabetic patients with celiac disease was significantly higher than in subjects with T1D alone. The prevalence of autoimmune disorders in relatives that were diagnosed with celiac disease was significantly higher than in those who tested negative for EMA. The authors concluded that it would be appropriate to routinely screen diabetic patients and their relatives for celiac disease in order to prevent the onset of additional autoimmune disorders.A report from Cataldo and Marino[6] suggest that the increased prevalence of autoimmune disorders is also increased in first-degree relatives of celiac disease patients. The authors reported a 6-fold increase of autoimmune diseases among relatives - a risk that increased with age. A subgroup of these relatives was diagnosed with silent celiac disease and their prevalence of autoimmune disorders as compared to first-degree relatives not affected by celiac disease was significantly higher with an odds ratio of 6.3.[6] The authors concluded that first-degree relatives of celiac disease patients have an increased risk of autoimmune disease, most likely related to unrecognized and, therefore, untreated celiac disease.Different conclusions were reached by Sategna Guidetti et al.,[7] whose results favor the linkage disequilibrium hypothesis. The authors screened for the presence of autoimmune disorders in 605 healthy controls (16-84 years old) and 422 celiac disease patients (16-84 years old) that had been on a gluten-free diet (GFD) for at least 1 year. A logistic regression analysis, setting the prevalence of autoimmunity as the dependent variable, was employed to control for independent covariates as predictors of the risk of autoimmunity. The authors found a 3-fold higher prevalence of autoimmunity in patients as compared to controls. Mean duration of gluten exposure was 31.2 and 32.6 years for patients with or without autoimmunity. Logistic regression showed that increased age at diagnosis of celiac disease was related to the prevalence of autoimmune disease, whereas 'actual gluten exposure', which takes into account diet compliance, follow up and age at diagnosis of autoimmune disorders, was not predictive for the risk of developing autoimmune diseases.[6] Therefore, the authors concluded that the increased prevalence of autoimmune diseases in patients with a late celiac disease diagnosis does not correlate with duration of gluten intake nor does gluten withdrawal protect patients with a late diagnosis from autoimmune diseases.The Role of Gluten as a Trigger of AutoimmunityFunda et al.[8] explored the role of gluten as a trigger of the autoimmune process outside celiac disease using the nonobese diabetes (NOD) mouse model for diabetes. The authors showed that the early introduction of a GFD substantially lowered diabetes incidence in NOD mice (15%) compared to mice on the standard diet (64%). In addition, mice on the GFD developed diabetes significantly later (244 ± 24 days) compared to those on the standard diet (197 ± 8 days). Based on these results, the authors concluded that a GFD both delayed and to a large extent prevented diabetes in NOD mice that had never been exposed to gluten. These results have been recently confirmed by Maurano et al.,[9*] who demonstrated that NOD mice fed a standard diet showed reduced villous height, increased intraepithelial infiltration by CD3+ cells and enhanced expression of H2-IA and interferon-γ mRNA when compared with mice on the GFD. The cumulative diabetes incidence at 43 weeks of age was 65% in the latter and 97% in the former (P < 0.01). Mice fed a wheat-containing diet also showed increased epithelial infiltration and a higher incidence of diabetes.[9*]The role of gluten exposure in T1D pathogenesis has been also confirmed in human studies. Early introduction of gluten to children at high risk for T1D produces T1D-associated islet autoantibodies.[10] Feeding gluten-containing foods in the first 3 months of life yields a 4-fold greater risk of developing islet cell autoantibodies (and potentially subsequent diabetes) than exclusive breast feeding.[10] Children starting gluten foods between 4 and 6 months of age demonstrated no such association.[10] Similarly, in the absence of overt clinical symptoms of T1D, some celiac disease children produce diabetes autoantibodies in a gluten-dependent manner.[11] In diabetic patients, intestinal challenge with gluten produces mucosal recruitment of lymphocytes, similar to that seen in celiac disease patients.[12] The most direct evidence of the role of gluten as an 'instigator' of the autoimmune response in T1D has, however, been recently provided by Sblattero et al..[13**] The authors monitored the effects of a GFD on anti-tTG antibody synthesis in the intestinal mucosa of a patient with T1D and a subjects at high risk of diabetes [anti-islet cell antibody (ICA)-positive], both carrying HLA-DQ2/DQ8, but lacking serum anti-tTG.[13**] Intestinal specimens from both subjects and samples of peripheral blood lymphocytes were used to make phage-antibody libraries to look for lymphocytes synthesizing anti-tTG antibodies. In both subjects, positive tTG antibody clones were isolated only from the intestinal lymphocyte libraries. After 12 months of GFD the subject at risk of T1D sero-converted from ICA-positive to ICA-negative. In both subjects, biopsies were normal, and analysis of new phage antibody libraries showed complete elimination of anti-tTG clones in the T1D subject and 90% reduction in the subject at risk of T1D.[13**] In this subject, reduced response to tTG and elimination of ICA after GFD suggest that an early intervention may abort and then revert the autoimmune process, indicating a possible temporary protection from the disease if a GFD is promptly implemented.Autoimmune Diseases Associated with Celiac DiseaseThe celiac disease-associated autoimmune disorders can be either organ-specific, in which the autoantibodies are specifically directed against antigens localized in a particular organ and are often detected in circulation (e.g. Hashimoto's thyroiditis and T1D), or nonorgan-specific autoimmune disorders characterized by the presence of autoantibodies directed against ubiquitous antigens (e.g. systemic lupus erythematosus, rheumatoid arthritis, Sjögren's syndrome and scleroderma).[14] The focus of this review will be on the celiac disease-organ-specific autoimmune disorders association, since this association has been extensively studied.Type 1 DiabetesA 10-year, age-matched study[15] found a highly significant correlation between endocrine disorders in celiac disease patients versus controls and concluded that celiac disease patients have a significantly higher prevalence of T1D. More recent studies[16,17] show a similar incidence of celiac disease in T1D patients. Early identification of celiac disease and subsequent treatment improves growth and diabetic control in children with T1D.[18,19] This comorbidity suggests possible genetic polymorphisms that may dictate the risk of celiac disease in subjects with T1D. To address this hypothesis, Sumnik et al.[20*] investigated whether the susceptibility to celiac disease in diabetic children is modified by positivity for HLA-DQB1*02-DQA1*05 and DQB1*0302-DQA1*03, and by alleles of single nucleotide polymorphisms within the genes encoding several cytokines. The authors compared genotypic data between 130 case subjects (children with T1D and celiac disease) and 245 control subjects (children with T1D only). The best-fitting model showed that risk of celiac disease is increased by presence of HLA-DQB1*02-DQA1*05 [odds ratio 4.5 (95% confidence interval 1.8-11) for homozygosity and 2.0 (1.1-3.7) for a single dose] and also independently by tumor necrosis factor -308A [1.9 (1.1-3.2) for phenotypic positivity], whereas interleukin-1α -889T showed a weak negative association [0.6 (0.4-0.9)].[20*] These results indicate that the risk of celiac disease in children with T1D is significantly modified both by the presence of HLA-DQB1*02-DQA1*05 and by a variant of another gene within the major histocompatibility complex, i.e. tumor necrosis factor -308A.ThyroiditisThyroiditis has been repeatedly associated with celiac disease.[15,21-23] A highly significant association exists between celiac disease and autoimmune thyroiditis (Graves' disease and Hashimoto's thyroiditis), as evidenced by elevated EMA antibodies in these thyroid conditions.[23] In addition, abnormal liver enzymes (transaminases) are common in both thyroid disorders and subclinical celiac disease.[24] Mainardi et al.[25] specifically studied the association of celiac disease with autoimmune thyroid disease. The authors evaluated the prevalence of celiac disease in 100 patients with thyroid autoimmunity (TAI). They found that the prevalence of celiac disease in patients affected by autoimmune thyroid disease was 2% and that the serologic markers for celiac disease became undetectable 6 months after beginning a GFD, while thyroid autoantibodies did not change following the implementation of the diet. More recently, da Silva et al.[26] have studied 52 patients with celiac disease, nine of which were on a GFD. The patients were divided into four groups: Group 1, without thyroid involvement (n = 30), and Groups 2A-C, with thyroid involvement (n = 22) [Group 2A, subclinical hypothyroidism (n = 11); Group 2B, clinical hypothyroidism (n = 10) and Group 2C, other thyroid disorders (n = 1)]. Increased levels of thyroid-stimulating hormone and/or anti-thyroperoxidase antibodies were detected in Groups 2A (21.1%) and 2B (19.2%). The patients of Group 2B presented clinical symptoms of hypothyroidism before the diagnosis of celiac disease and five of these patients were receiving levothyroxine. There was a statistically significant correlation between the age when thyroid disease was diagnosed (current age) and the age of celiac disease diagnosis when Groups 1 and 2B were compared. Patients with thyroid involvement presented associated diseases such as T1D, Down's syndrome, ulcerative colitis and dermatitis herpetiformis.Different conclusions were reached by Sumnik et al.,[27] who performed a multicenter retrospective case-control study comparing data from 84 diabetic children with celiac disease (Group 1) to 167 diabetic children without celiac disease (Group 2), matched by age at T1D onset, duration of T1D and center. Markers of TAI, thyroid function and HbA1c were recorded. The TAI follow-up lasted 4.9 ± 2.8 years. TAI was diagnosed in 13% of children in Group 1 and 19% of children in Group 2. Diabetes control was not influenced by TAI in either group.[27] These results prompted the authors to conclude that occurrence of TAI in diabetic children is not related to coexisting celiac disease.Celiac Disease as a Paradigm Shift in the Pathogenesis of Autoimmune DiseasesA common denominator of autoimmune diseases is the presence of several pre-existing conditions leading to an autoimmune process.[28*] The first is a genetic susceptibility for the host immune system to recognize, and potentially misinterpret, an environmental antigen presented within the gastrointestinal tract. Second, the host must be exposed to the antigen. Finally, the antigen must be presented to the gastrointestinal mucosal immune system following its paracellular passage (normally prevented by the competency of intercellular tight junctions) from the intestinal lumen to the gut submucosa.[29,30] In many cases, increased permeability appears to precede disease and causes an abnormality in antigen delivery that triggers the multiorgan process leading to the autoimmune response.[31**]Therefore, the following hypothesis can be formulated to explain the pathogenesis of autoimmune diseases that encompasses the following three key points:Autoimmune diseases involve a miscommunication between innate and adaptive immunity. Molecular mimicry or bystander effects alone may not explain entirely the complex events involved in the pathogenesis of autoimmune diseases. Rather, the continuous stimulation by nonself antigens (environmental triggers) appears necessary to perpetuate the process. This concept implies that the autoimmune response can be theoretically stopped and perhaps reversed if the interplay between autoimmune predisposing genes and trigger(s) is prevented or eliminated. In addition to genetic predisposition and the exposure to the triggering nonself antigen, the third key element necessary to develop autoimmunity is the loss of the protective function of mucosal barriers that interface with the environment (mainly the gastrointestinal and lung mucosa). Celiac disease represents the best testimonial of this theory. Early in the disease, tight junctions are opened,[32,33] most likely secondary to zonulin upregulation[34] and severe intestinal damage ensues[33] (Fig. 2). The upregulation of the zonulin innate immunity pathway is directly induced by the exposure to the disease's antigenic trigger gliadin.[35] Gliadin has been shown to be also a potent stimulus for macrophage pro-inflammatory gene expression and cytokine release.[36] Our recent data suggest that signaling of both functions is independent of Toll-like receptor (TLR) 4 and 2, but is dependent on MyD88, a key adapter molecule in TLR/interleukin-1 receptor signaling.[37*] These data indicate that gliadin initiates intestinal permeability through a MyD88-dependent release of zonulin that enables paracellular translocation of gliadin and its subsequent interaction with macrophages within the intestinal submucosa (Fig. 2). Gliadin interaction with macrophages initiates signaling through a TLR-like pathway, resulting in the establishment of a pro-inflammmatory (T helper 1-type) cytokine milieu that results in mononuclear cell infiltration into the submucosa. This, in turn, may permit the interaction of T cells with antigen-presenting cells, including macrophages, leading ultimately to the antigen-specific adaptive immune response seen in patients with celiac disease. Once gluten is removed from the diet, serum zonulin levels decrease, the intestine resumes its baseline barrier function, the autoantibody titers are normalized, the autoimmune process shuts off and, consequently, the intestinal damage (that represents the biological outcome of the autoimmune process) heals completely.[28*]Figure 2. Proposed role of abnormal intestinal permeability in the pathogenesis of celiac disease (reproduced from[28*]). Gliadin and its immunomodulatory/inflammatory fragments are present in the intestinal lumen (1), inducing an MyD88-dependent zonulin release (2) that causes opening of tight junctions and gliadin passage across the tight junction barriers in subjects with dysregulation of the zonulin system (3). Following tissue transglutaminase (TTG) deamidation (4), gliadin peptides bind to HLA receptors present on the surface of antigen-presenting cells (APC) (5). Alternatively, gliadin can act directly on antigen-presenting cells (6) causing MyD88-dependent release of both zonulin and cytokines (7). Gliadin peptides are also presented to T lymphocytes (8), followed by an aberrant immune response, both humoral (9) and cell-mediated (10) in genetically susceptible individuals. This interplay between innate and adaptive immunity is ultimately responsible for the autoimmune process targeting intestinal epithelial cells, leading to the intestinal damage typical of celiac disease (11). AEA, anti-endomysium antibodies; AGA, anti-gliadin antibodies; TG, thyroglobulin; Tk, T killer. ConclusionBased on recent findings concerning celiac disease, the classical paradigm of autoimmune pathogenesis involving specific gene makeup and exposure to environmental triggers has been challenged by the addition of a third element - the loss of intestinal barrier function. Whether the increased comorbidity between celiac disease and other autoimmune disorders is related to increased intestinal permeability causing the passage of environmental triggers responsible for the onset of the autoimmune processes or it is secondary to cosegregation of genes remains to be established.ReferencesPapers of particular interest, published within the annual period of review, have been highlighted as:* of special interest** of outstanding interestAdditional references related to this topic can also be found in the Current World Literature section in this issue (pp. 691-692). * Sollid LM, Jabri B. Is celiac disease an autoimmune disorder? Curr Opin Immunol 2005; 17:595-600. This is a good review focused on the immunological aspects of celiac disease. The review presents strong arguments on why celiac disease should now be considered an autoimmune disorder. Fasano A. Celiac disease: how to handle a clinical chameleon. N Engl J Med 2003; 348:2568-2570. Fasano A, Catassi C. Current approaches to diagnosis and treatment of celiac disease: an evolving spectrum. Gastroenterology 2001; 120:636-651. Ventura A, Magazzu G, Greco L. Duration of exposure to gluten and risk for autoimmune disorders in patients with celiac disease. SIGEP Study Group for Autoimmune Disorders in Celiac Disease. Gastroenterology 1999; 117:297-303. Not T, Tommasini A, Tonini G, et al. Undiagnosed coeliac disease and risk of autoimmune disorders in subjects with Type I diabetes mellitus. Diabetologia 2001; 44:151-155. Cataldo F, Marino V. Increased prevalence of autoimmune diseases in first-degree relatives of patients with celiac disease. J Pediatr Gastroenterol Nutr 2003; 36:470-473. Sategna Guidetti C, Solerio E, Scaglione N, et al. Duration of gluten exposure in adult coeliac disease does not correlate with the risk for autoimmune disorders. Gut 2001; 49:502-505. Funda DP, Kaas A, Bock T, et al. Gluten-free diet prevents diabetes in NOD mice. Diabetes Metab Res Rev 1999; 15:323-327. * Maurano F, Mazzarella G, Luongo D, et al. Small intestinal enteropathy in nonobese diabetic mice fed a diet containing wheat. Diabetologia 2005; 48:931-937. This paper shows that the effect of gluten on intestinal mucosal inflammation is not limited to celiac disease genetic background, but can also occur on a T1D genetic background. Ziegler A, Schmid S, Huber D, et al. Early infant feeding and risk of developing type 1 diabetes-associated autoantibodies. JAMA 2003; 290:1721-1728. Ventura A, Neri E, Ughi C, et al. Gluten-dependent diabetes-related and thyroid-related autoantibodies in patients with celiac disease. J Pediatr 2000; 137:263-265. Auricchio R, Paparo F, Maglio M, et al. In vitro deranged intestinal immune response to gliadin in type 1 diabetes. Diabetes 2004; 53:1680-1683. ** Sblattero D, Ventura A, Tommasini A. Cryptic gluten intolerance in type 1 diabetes: identifying suitable candidates for a gluten free diet. Gut 2006; 55:133-134. This paper shows for the first time a direct link between the exposure to gluten and an immune response at the intestinal level in subjects affected by T1D. Kumar V, Rajadhyaksha M, Wortman J. Celiac disease-associated autoimmune endocrinopathies. Clin Diagn Lab Immunol 2001; 8:678-685. Collin P, Reunala T, Pukkala E, et al. Coeliac disease-associated disorders and survival. Gut 1994; 35:1215-1218. Tanure MG, Silva IN, Bahia M, Penna FJ. Prevalence of celiac disease in Brazilian children with type 1 diabetes mellitus. J Pediatr Gastroenterol Nutr 2006; 42:155-159. Mahmud FH, Murray JA, Kudva YC, et al. Celiac disease in type 1 diabetes mellitus in a North American community: prevalence, serologic screening, and clinical features. Mayo Clin Proc 2005; 80:1429-1434. Saadah OI, Zacharin M, O'Callaghan A, et al. Effect of gluten-free diet and adherence on growth and diabetic control in diabetics with celiac disease. Arch Dis Child 2004; 89:871-876. Peretti N, Bienvenu F, Bouvet C, et al. The temporal relationship between the onset of type 1 diabetes and celiac disease: a study based on immunoglobulin a antitransglutaminase screening. Pediatrics 2004; 113:E418-E422. * Sumnik Z, Cinek O, Bratanic N, et al. Risk of celiac disease in children with type 1 diabetes is modified by positivity for HLA-DQB1*02-DQA1*05 and TNF -308A. Diabetes Care 2006; 29:858-863. A well-designed study aimed at establishing whether genetic polymorphirms are responsible of celiac disease–T1D comorbidity. Kaspers S, Kordonouri O, Schober E, et al. Anthropometry, metabolic control, and thyroid autoimmunity in type 1 diabetes with celiac disease: a multicenter survey. J Pediatr 2004; 145:790-795. Aycan Z, Berberoglu M, Adiyaman P, et al. Latent autoimmune diabetes mellitus in children (LADC) with autoimmune thyroiditis and celiac disease. J Pediatr Endocrinol Metab 2004; 17:1565-1569. Berti I, Trevisiol C, Tommasini A, et al. Usefulness of screening program for celiac disease in autoimmune thyroiditis. Dig Dis Sci 2000; 45:403-406. Verslype C. Evaluation of abnormal liver-enzyme results in asymptomatic patients. Acta Clin Belg 2004; 59:285-289. Mainardi E, Montanelli A, Dotti M, et al. Thyroid-related autoantibodies and celiac disease: a role for a gluten-free diet? J Clin Gastroenterol 2002; 35:245-248. da Silva Kotze LM, Nisihara RM, Da Utiyama SR, et al. Thyroid disorders in Brazilian patients with celiac disease. J Clin Gastroenterol 2006; 40:33-36. Sumnik Z, Cinek O, Bratanic N, et al. Thyroid autoimmunity in children with coexisting type 1 diabetes mellitus and celiac disease: a multicenter study. J Pediatr Endocrinol Metab 2006; 19:517-522. * Fasano A, Shea-Donohue T. Mechanisms of disease: the role of intestinal barrier function in the pathogenesis of gastrointestinal autoimmune diseases. Nat Clin Pract Gastroenterol Hepatol 2005; 2:416-422. This is a good review on the role of intestinal permeability and the gut-associated lymphoid tissue in the pathogenesis of autoimmune diseases, including celiac disease and T1D. Bjarnason I, Takeuchi K, Bjarnason A, et al. The G.U.T. of gut. Scand J Gastroenterol 2004; 39:807-815. Wendling D. Role of the intestine in the physiopathology of inflammatory rheumatism. Rev Rhum Mal Osteoartic 1992; 59:389-392. ** Watts T, et al. Role of the intestinal tight junction modulator zonulin in the pathogenesis of type I diabetes in BB diabetic-prone rats. Proc Natl Acad Sci USA 2005; 102:2916-2921. This paper demonstrates the key role of the impairment of intestinal barrier function secondary to the zonulin effect on tight junctions on the pathogenesis of T1D. Madara JL, Trier JS. Structural abnormalities of jejunal epithelial cell membranes in celiac sprue. Lab Invest 1980; 43:254-261. Schulzke JD, Bentzel CJ, Schulzke I, et al. Epithelial tight junction structure in the jejunum of children with acute and treated celiac sprue. Pediatr Res 1980; 43:435-441. Fasano A, et al. Zonulin, a newly discovered modulator of intestinal permeability, and its expression in coeliac disease. Lancet 2000; 355:1518-1519. Clemente MG, et al. Early effects of gliadin on enterocyte intracellular signalling involved in intestinal barrier function. Gut 2003; 52:218-223. Nikulina M, Habich C, Flohe SB, et al. Wheat gluten causes dendritic cell maturation and chemokine secretion. J Immunol 2004; 173:1925-1933. * KE, Sapone A, Fasano A, Vogel SN. Gliadin stimulation of murine macrophage inflammatory gene expression and intestinal permeability are MyD88-dependent: role of the innate immune response in celiac disease. J Immunol 2006; 176:2512-2521. This paper reports the effect of the celiac disease trigger gliadin on macrophage inflammatory gene expression and intestinal barrier function in a normal murine animal model, and the dependence of this effect on the MyD88 signaling. AcknowledgementsWork by the author was supported in parts by grant from the National Institutes of Health Grants DK-48373.Abbreviation NotesEMA = antiendomysium antibodies; GFD = gluten-free diet; ICA = islet cell antibody; NOD = nonobese diabetes; T1D = Type 1 diabetes; TAI = thyroid autoimmunity; TLR = Toll-like receptor; tTG = tissue transglutaminase.Reprint AddressAlessio Fasano, MD, Mucosal Biology Research Center, University of land School of Medicine, 20 Penn Street HSF II Building, Room S345, Baltimore, MD 21201, USA Tel: + 1 410 706 5501; e-mail: afasano@...Alessio Fasano, Center for Celiac Research and Mucosal Biology Research Center and Department of Physiology, University of land School of Medicine, Baltimore, land, USA

[Guest guest]

Thank you,

This is so useful to me, having just had a series of CC's and gotten

sick as a result, including my old kidney inflammation I had first

overcome throughdiet years and years agol This helps a lot.

I also want to send the info to my doubting sister the Stanford

research nurse...who eldest son who has diabetes.

>

> Here is one of the abstracts..

>

> ________________________________

>

> From: Bronwyn Syiek

> Sent: Monday, August 20, 2007 9:53 PM

> Carolyn (reck1@...)

> Subject: Systemic autoimmunce disorders in celiac disease - research

I mentioned.

>

>

>

>

> Systemic Autoimmune Disorders in Celiac Disease

>

>

>

> Alessio Fasano

>

> Curr Opin Gastroenterol. 2006;22(6):674-679. ©2006 Lippincott

& Wilkins

>

> Posted 11/15/2006

>

>

>

>

> Abstract and Introduction

>

>

> Abstract

>

>

> Purpose of Review: Celiac disease is an immune-mediated disorder

clinically characterized by a multitude of symptoms and complications.

The comorbidity between celiac disease and other autoimmune disorders

has been clearly established.

> Recent Findings: Two main theories have been postulated to explain

this comorbidity: (1) linkage disequilibrium between the genes

responsible for celiac disease and those responsible for the

coexpressed autoimmune diseases or (2) untreated celiac disease

leading to the onset of other autoimmune diseases. This article

reviews the current literature supporting either theory and places the

current knowledge in the field within the context of the most recent

data on the pathogenesis of celiac disease.

> Summary: The current literature did not clearly establish which of

the two theories explain the comorbidity between celiac disease and

other autoimmune disorders. There is, however, growing evidence that

the loss of the intestinal barrier function typical of celiac disease

could be responsible of the onset of other autoimmune disease. This

concept implies that the autoimmune response can be theoretically

stopped and perhaps reversed if the interplay between autoimmune

predisposing genes and trigger(s) is prevented or eliminated by a

prompt diagnosis and treatment.

>

>

> Introduction

>

>

> Celiac disease is an immune-mediated enteropathy triggered by the

ingestion of gluten-containing grains (including wheat, rye and

barley) in genetically susceptible persons. Celiac disease has several

autoimmune features, including the production of highly

disease-specific IgA and IgG autoantibodies to tissue transglutaminase

(tTG) when patients are on a gluten-containing diet, and the presence

of small intestinal intraepithelial lymphocytes which can mediate

direct cytotoxicity of enterocytes expressing MIC molecules in an

antigen-nonspecific manner.[1*] Similar to typical autoimmune

disorders, celiac disease has a multifactorial etiology with complex

genetics and comorbidity with autoimmune diseases. Celiac disease is,

however, a unique example of autoimmunity, since early serological

diagnosis and dietary treatment can revert the autoimmune process and

can prevent its severe, sometimes life-threatening complications.

Therefore, the common wisdom among experts in the field supports the

notion that individuals affected by celiac disease should be treated,

irrespective of the presence of symptoms and/or associated conditions.

Well-designed prospective clinical studies to address this point have,

however, not been performed, nor can they be conceived, given the

ethical implications of such a proposition. Celiac disease can

manifest itself with a previously unappreciated range of clinical

presentations (the so-called celiac iceberg, Fig. 1), including the

typical malabsorption syndrome (chronic diarrhea, weight loss,

abdominal distension) and a spectrum of symptoms potentially affecting

any organ system.[2] Since celiac disease often presents in an

atypical or even silent manner, many cases remain undiagnosed, their

diet treatment is significantly delayed and, consequently, the risk of

long-term complications increases. While evidence-based data support

the causative effect of untreated celiac disease for some of these

complications, for other conditions this association remains

questionable. One of the most controversial issues concerning possible

complications of untreated celiac disease involves the association

between celiac disease and other autoimmune disorders.

>

>

>

> Figure 1.

>

> The celiac iceberg. The clinical outcome of the interplay between

celiac disease genetic makeup and exposure to gluten, the

environmental trigger of the disease, is typically represented by the

iceberg model, with the symptomatic forms present at the visible part

of the iceberg and the silent and potential forms being submerged

below the water line.

>

>

>

>

> Celiac Disease Comorbidity with Other Autoimmune Diseases:

Serendipitous Association or Calculated Design?

>

>

> The two most accredited theories to explain this comorbidity

propose: (1) untreated celiac disease leads to the onset of other

autoimmune disorders in genetically susceptible individuals or (2)

this association is secondary to linkage disequilibrium of genes

predisposing for both celiac disease and the associated autoimmune

disease(s). The first hypothesis is supported by the evidence that

tTG, the recognized autoantigen involved in the pathogenesis of celiac

disease, seems to be only one of the autoantigens involved in

gluten-dependent autoimmune reactions. Other autoantigens which are

normally 'cryptic' can be unmasked and cause a self-aggressive

immunological response following the gliadin-initiated inflammatory

process.[3] In fact, persistent stimulation by some pro-inflammatory

cytokines such as interferon-γ and tumor necrosis factor-α can cause

further processing of autoantigens and their presentation to T

lymphocytes by macrophage-type immunocompetent cells (so-called

antigen-presenting cells). The phenomenon of antigen spreading has

been described in well-defined natural models such as Type 1 diabetes

(T1D), whose clinical manifestations appear after the patient has

produced an autoimmune response to various autoantigens (i.e.

anti-insulin, anti-β cell, etc.) and might also be present in celiac

disease. This would explain the high incidence of autoimmune diseases

and the presence of a large number of organ-specific autoantibodies in

a certain number of celiac subjects on a gluten-containing diet.

>

> The report by Ventura et al.[4] that studied the prevalence of

autoimmune disorders in celiac disease in relation to the duration of

exposure to gluten seems to support this theory. Over a 6-month

period, 909 pediatric patients with celiac disease, 1268 healthy

controls and 163 patients with Crohn's disease were evaluated for the

presence of autoimmune disorders. The authors[4] detected a prevalence

of autoimmune disorders among celiac disease patients higher than in

controls, but similar to that detected in Crohn's disease patients.

Prevalence of autoimmune disorders in celiac disease was increased

with increasing age at diagnosis. In a logistic regression model, age

at diagnosis was the only significant predictor variable of the odds

of developing an autoimmune disorder.[4] Based on this evidence, the

authors concluded that the prevalence of autoimmune disorders in

celiac disease is related to the duration of exposure to gluten. The

same group[5] screened sera from 491 subjects with T1D, 824 relatives

and 4000 healthy control subjects for antiendomysium antibodies (EMA),

followed by confirmatory intestinal biopsy in positive subjects. The

authors found that the prevalence of celiac disease was 5.7% among

diabetic patients and 1.9% among relatives - values significantly

higher than those found among control subjects.[5] The prevalence of

autoimmune disorders in diabetic patients with celiac disease was

significantly higher than in subjects with T1D alone. The prevalence

of autoimmune disorders in relatives that were diagnosed with celiac

disease was significantly higher than in those who tested negative for

EMA. The authors concluded that it would be appropriate to routinely

screen diabetic patients and their relatives for celiac disease in

order to prevent the onset of additional autoimmune disorders.

>

> A report from Cataldo and Marino[6] suggest that the increased

prevalence of autoimmune disorders is also increased in first-degree

relatives of celiac disease patients. The authors reported a 6-fold

increase of autoimmune diseases among relatives - a risk that

increased with age. A subgroup of these relatives was diagnosed with

silent celiac disease and their prevalence of autoimmune disorders as

compared to first-degree relatives not affected by celiac disease was

significantly higher with an odds ratio of 6.3.[6] The authors

concluded that first-degree relatives of celiac disease patients have

an increased risk of autoimmune disease, most likely related to

unrecognized and, therefore, untreated celiac disease.

>

> Different conclusions were reached by Sategna Guidetti et al.,[7]

whose results favor the linkage disequilibrium hypothesis. The authors

screened for the presence of autoimmune disorders in 605 healthy

controls (16-84 years old) and 422 celiac disease patients (16-84

years old) that had been on a gluten-free diet (GFD) for at least 1

year. A logistic regression analysis, setting the prevalence of

autoimmunity as the dependent variable, was employed to control for

independent covariates as predictors of the risk of autoimmunity. The

authors found a 3-fold higher prevalence of autoimmunity in patients

as compared to controls. Mean duration of gluten exposure was 31.2 and

32.6 years for patients with or without autoimmunity. Logistic

regression showed that increased age at diagnosis of celiac disease

was related to the prevalence of autoimmune disease, whereas 'actual

gluten exposure', which takes into account diet compliance, follow up

and age at diagnosis of autoimmune disorders, was not predictive for

the risk of developing autoimmune diseases.[6] Therefore, the authors

concluded that the increased prevalence of autoimmune diseases in

patients with a late celiac disease diagnosis does not correlate with

duration of gluten intake nor does gluten withdrawal protect patients

with a late diagnosis from autoimmune diseases.

>

>

> The Role of Gluten as a Trigger of Autoimmunity

>

>

> Funda et al.[8] explored the role of gluten as a trigger of the

autoimmune process outside celiac disease using the nonobese diabetes

(NOD) mouse model for diabetes. The authors showed that the early

introduction of a GFD substantially lowered diabetes incidence in NOD

mice (15%) compared to mice on the standard diet (64%). In addition,

mice on the GFD developed diabetes significantly later (244 ± 24

days) compared to those on the standard diet (197 ± 8 days). Based on

these results, the authors concluded that a GFD both delayed and to a

large extent prevented diabetes in NOD mice that had never been

exposed to gluten. These results have been recently confirmed by

Maurano et al.,[9*] who demonstrated that NOD mice fed a standard diet

showed reduced villous height, increased intraepithelial infiltration

by CD3+ cells and enhanced expression of H2-IA and interferon-γ mRNA

when compared with mice on the GFD. The cumulative diabetes incidence

at 43 weeks of age was 65% in the latter and 97% in the former (P <

0.01). Mice fed a wheat-containing diet also showed increased

epithelial infiltration and a higher incidence of diabetes.[9*]

>

> The role of gluten exposure in T1D pathogenesis has been also

confirmed in human studies. Early introduction of gluten to children

at high risk for T1D produces T1D-associated islet autoantibodies.[10]

Feeding gluten-containing foods in the first 3 months of life yields a

4-fold greater risk of developing islet cell autoantibodies (and

potentially subsequent diabetes) than exclusive breast feeding.[10]

Children starting gluten foods between 4 and 6 months of age

demonstrated no such association.[10] Similarly, in the absence of

overt clinical symptoms of T1D, some celiac disease children produce

diabetes autoantibodies in a gluten-dependent manner.[11] In diabetic

patients, intestinal challenge with gluten produces mucosal

recruitment of lymphocytes, similar to that seen in celiac disease

patients.[12] The most direct evidence of the role of gluten as an

'instigator' of the autoimmune response in T1D has, however, been

recently provided by Sblattero et al..[13**] The authors monitored the

effects of a GFD on anti-tTG antibody synthesis in the intestinal

mucosa of a patient with T1D and a subjects at high risk of diabetes

[anti-islet cell antibody (ICA)-positive], both carrying HLA-DQ2/DQ8,

but lacking serum anti-tTG.[13**] Intestinal specimens from both

subjects and samples of peripheral blood lymphocytes were used to make

phage-antibody libraries to look for lymphocytes synthesizing anti-tTG

antibodies. In both subjects, positive tTG antibody clones were

isolated only from the intestinal lymphocyte libraries. After 12

months of GFD the subject at risk of T1D sero-converted from

ICA-positive to ICA-negative. In both subjects, biopsies were normal,

and analysis of new phage antibody libraries showed complete

elimination of anti-tTG clones in the T1D subject and 90% reduction in

the subject at risk of T1D.[13**] In this subject, reduced response to

tTG and elimination of ICA after GFD suggest that an early

intervention may abort and then revert the autoimmune process,

indicating a possible temporary protection from the disease if a GFD

is promptly implemented.

>

>

> Autoimmune Diseases Associated with Celiac Disease

>

>

> The celiac disease-associated autoimmune disorders can be either

organ-specific, in which the autoantibodies are specifically directed

against antigens localized in a particular organ and are often

detected in circulation (e.g. Hashimoto's thyroiditis and T1D), or

nonorgan-specific autoimmune disorders characterized by the presence

of autoantibodies directed against ubiquitous antigens (e.g. systemic

lupus erythematosus, rheumatoid arthritis, Sjögren's syndrome and

scleroderma).[14] The focus of this review will be on the celiac

disease-organ-specific autoimmune disorders association, since this

association has been extensively studied.

>

>

> Type 1 Diabetes

>

>

> A 10-year, age-matched study[15] found a highly significant

correlation between endocrine disorders in celiac disease patients

versus controls and concluded that celiac disease patients have a

significantly higher prevalence of T1D. More recent studies[16,17]

show a similar incidence of celiac disease in T1D patients. Early

identification of celiac disease and subsequent treatment improves

growth and diabetic control in children with T1D.[18,19] This

comorbidity suggests possible genetic polymorphisms that may dictate

the risk of celiac disease in subjects with T1D. To address this

hypothesis, Sumnik et al.[20*] investigated whether the susceptibility

to celiac disease in diabetic children is modified by positivity for

HLA-DQB1*02-DQA1*05 and DQB1*0302-DQA1*03, and by alleles of single

nucleotide polymorphisms within the genes encoding several cytokines.

The authors compared genotypic data between 130 case subjects

(children with T1D and celiac disease) and 245 control subjects

(children with T1D only). The best-fitting model showed that risk of

celiac disease is increased by presence of HLA-DQB1*02-DQA1*05 [odds

ratio 4.5 (95% confidence interval 1.8-11) for homozygosity and 2.0

(1.1-3.7) for a single dose] and also independently by tumor necrosis

factor -308A [1.9 (1.1-3.2) for phenotypic positivity], whereas

interleukin-1α -889T showed a weak negative association [0.6

(0.4-0.9)].[20*] These results indicate that the risk of celiac

disease in children with T1D is significantly modified both by the

presence of HLA-DQB1*02-DQA1*05 and by a variant of another gene

within the major histocompatibility complex, i.e. tumor necrosis

factor -308A.

>

>

> Thyroiditis

>

>

> Thyroiditis has been repeatedly associated with celiac

disease.[15,21-23] A highly significant association exists between

celiac disease and autoimmune thyroiditis (Graves' disease and

Hashimoto's thyroiditis), as evidenced by elevated EMA antibodies in

these thyroid conditions.[23] In addition, abnormal liver enzymes

(transaminases) are common in both thyroid disorders and subclinical

celiac disease.[24] Mainardi et al.[25] specifically studied the

association of celiac disease with autoimmune thyroid disease. The

authors evaluated the prevalence of celiac disease in 100 patients

with thyroid autoimmunity (TAI). They found that the prevalence of

celiac disease in patients affected by autoimmune thyroid disease was

2% and that the serologic markers for celiac disease became

undetectable 6 months after beginning a GFD, while thyroid

autoantibodies did not change following the implementation of the

diet. More recently, da Silva et al.[26] have studied 52 patients with

celiac disease, nine of which were on a GFD. The patients were divided

into four groups: Group 1, without thyroid involvement (n = 30), and

Groups 2A-C, with thyroid involvement (n = 22) [Group 2A, subclinical

hypothyroidism (n = 11); Group 2B, clinical hypothyroidism (n = 10)

and Group 2C, other thyroid disorders (n = 1)]. Increased levels of

thyroid-stimulating hormone and/or anti-thyroperoxidase antibodies

were detected in Groups 2A (21.1%) and 2B (19.2%). The patients of

Group 2B presented clinical symptoms of hypothyroidism before the

diagnosis of celiac disease and five of these patients were receiving

levothyroxine. There was a statistically significant correlation

between the age when thyroid disease was diagnosed (current age) and

the age of celiac disease diagnosis when Groups 1 and 2B were

compared. Patients with thyroid involvement presented associated

diseases such as T1D, Down's syndrome, ulcerative colitis and

dermatitis herpetiformis.

>

> Different conclusions were reached by Sumnik et al.,[27] who

performed a multicenter retrospective case-control study comparing

data from 84 diabetic children with celiac disease (Group 1) to 167

diabetic children without celiac disease (Group 2), matched by age at

T1D onset, duration of T1D and center. Markers of TAI, thyroid

function and HbA1c were recorded. The TAI follow-up lasted 4.9 ± 2.8

years. TAI was diagnosed in 13% of children in Group 1 and 19% of

children in Group 2. Diabetes control was not influenced by TAI in

either group.[27] These results prompted the authors to conclude that

occurrence of TAI in diabetic children is not related to coexisting

celiac disease.

>

>

> Celiac Disease as a Paradigm Shift in the Pathogenesis of Autoimmune

Diseases

>

>

> A common denominator of autoimmune diseases is the presence of

several pre-existing conditions leading to an autoimmune process.[28*]

The first is a genetic susceptibility for the host immune system to

recognize, and potentially misinterpret, an environmental antigen

presented within the gastrointestinal tract. Second, the host must be

exposed to the antigen. Finally, the antigen must be presented to the

gastrointestinal mucosal immune system following its paracellular

passage (normally prevented by the competency of intercellular tight

junctions) from the intestinal lumen to the gut submucosa.[29,30] In

many cases, increased permeability appears to precede disease and

causes an abnormality in antigen delivery that triggers the multiorgan

process leading to the autoimmune response.[31**]

>

> Therefore, the following hypothesis can be formulated to explain the

pathogenesis of autoimmune diseases that encompasses the following

three key points:

>

> 1. Autoimmune diseases involve a miscommunication between innate and

adaptive immunity.

> 2. Molecular mimicry or bystander effects alone may not explain

entirely the complex events involved in the pathogenesis of autoimmune

diseases. Rather, the continuous stimulation by nonself antigens

(environmental triggers) appears necessary to perpetuate the process.

This concept implies that the autoimmune response can be theoretically

stopped and perhaps reversed if the interplay between autoimmune

predisposing genes and trigger(s) is prevented or eliminated.

> 3. In addition to genetic predisposition and the exposure to the

triggering nonself antigen, the third key element necessary to develop

autoimmunity is the loss of the protective function of mucosal

barriers that interface with the environment (mainly the

gastrointestinal and lung mucosa).

>

> Celiac disease represents the best testimonial of this theory. Early

in the disease, tight junctions are opened,[32,33] most likely

secondary to zonulin upregulation[34] and severe intestinal damage

ensues[33] (Fig. 2). The upregulation of the zonulin innate immunity

pathway is directly induced by the exposure to the disease's antigenic

trigger gliadin.[35] Gliadin has been shown to be also a potent

stimulus for macrophage pro-inflammatory gene expression and cytokine

release.[36] Our recent data suggest that signaling of both functions

is independent of Toll-like receptor (TLR) 4 and 2, but is dependent

on MyD88, a key adapter molecule in TLR/interleukin-1 receptor

signaling.[37*] These data indicate that gliadin initiates intestinal

permeability through a MyD88-dependent release of zonulin that enables

paracellular translocation of gliadin and its subsequent interaction

with macrophages within the intestinal submucosa (Fig. 2). Gliadin

interaction with macrophages initiates signaling through a TLR-like

pathway, resulting in the establishment of a pro-inflammmatory (T

helper 1-type) cytokine milieu that results in mononuclear cell

infiltration into the submucosa. This, in turn, may permit the

interaction of T cells with antigen-presenting cells, including

macrophages, leading ultimately to the antigen-specific adaptive

immune response seen in patients with celiac disease. Once gluten is

removed from the diet, serum zonulin levels decrease, the intestine

resumes its baseline barrier function, the autoantibody titers are

normalized, the autoimmune process shuts off and, consequently, the

intestinal damage (that represents the biological outcome of the

autoimmune process) heals completely.[28*]

>

>

>

> Figure 2.

>

> Proposed role of abnormal intestinal permeability in the

pathogenesis of celiac disease (reproduced from[28*]). Gliadin and its

immunomodulatory/inflammatory fragments are present in the intestinal

lumen (1), inducing an MyD88-dependent zonulin release (2) that causes

opening of tight junctions and gliadin passage across the tight

junction barriers in subjects with dysregulation of the zonulin system

(3). Following tissue transglutaminase (TTG) deamidation (4), gliadin

peptides bind to HLA receptors present on the surface of

antigen-presenting cells (APC) (5). Alternatively, gliadin can act

directly on antigen-presenting cells (6) causing MyD88-dependent

release of both zonulin and cytokines (7). Gliadin peptides are also

presented to T lymphocytes (8), followed by an aberrant immune

response, both humoral (9) and cell-mediated (10) in genetically

susceptible individuals. This interplay between innate and adaptive

immunity is ultimately responsible for the autoimmune process

targeting intestinal epithelial cells, leading to the intestinal

damage typical of celiac disease (11). AEA, anti-endomysium

antibodies; AGA, anti-gliadin antibodies; TG, thyroglobulin; Tk, T killer.

>

>

>

>

> Conclusion

>

>

> Based on recent findings concerning celiac disease, the classical

paradigm of autoimmune pathogenesis involving specific gene makeup and

exposure to environmental triggers has been challenged by the addition

of a third element - the loss of intestinal barrier function. Whether

the increased comorbidity between celiac disease and other autoimmune

disorders is related to increased intestinal permeability causing the

passage of environmental triggers responsible for the onset of the

autoimmune processes or it is secondary to cosegregation of genes

remains to be established.

>

>

> References

>

>

> Papers of particular interest, published within the annual period of

review, have been highlighted as:

>

> * of special interest

> ** of outstanding interest

>

> Additional references related to this topic can also be found in the

Current World Literature section in this issue (pp. 691-692).

>

> 1. * Sollid LM, Jabri B. Is celiac disease an autoimmune disorder?

Curr Opin Immunol 2005; 17:595-600. This is a good review focused on

the immunological aspects of celiac disease. The review presents

strong arguments on why celiac disease should now be considered an

autoimmune disorder.

> 2. Fasano A. Celiac disease: how to handle a clinical chameleon. N

Engl J Med 2003; 348:2568-2570.

> 3. Fasano A, Catassi C. Current approaches to diagnosis and

treatment of celiac disease: an evolving spectrum. Gastroenterology

2001; 120:636-651.

> 4. Ventura A, Magazzu G, Greco L. Duration of exposure to gluten and

risk for autoimmune disorders in patients with celiac disease. SIGEP

Study Group for Autoimmune Disorders in Celiac Disease.

Gastroenterology 1999; 117:297-303.

> 5. Not T, Tommasini A, Tonini G, et al. Undiagnosed coeliac disease

and risk of autoimmune disorders in subjects with Type I diabetes

mellitus. Diabetologia 2001; 44:151-155.

> 6. Cataldo F, Marino V. Increased prevalence of autoimmune diseases

in first-degree relatives of patients with celiac disease. J Pediatr

Gastroenterol Nutr 2003; 36:470-473.

> 7. Sategna Guidetti C, Solerio E, Scaglione N, et al. Duration of

gluten exposure in adult coeliac disease does not correlate with the

risk for autoimmune disorders. Gut 2001; 49:502-505.

> 8. Funda DP, Kaas A, Bock T, et al. Gluten-free diet prevents

diabetes in NOD mice. Diabetes Metab Res Rev 1999; 15:323-327.

> 9. * Maurano F, Mazzarella G, Luongo D, et al. Small intestinal

enteropathy in nonobese diabetic mice fed a diet containing wheat.

Diabetologia 2005; 48:931-937. This paper shows that the effect of

gluten on intestinal mucosal inflammation is not limited to celiac

disease genetic background, but can also occur on a T1D genetic

background.

> 10. Ziegler A, Schmid S, Huber D, et al. Early infant feeding and

risk of developing type 1 diabetes-associated autoantibodies. JAMA

2003; 290:1721-1728.

> 11. Ventura A, Neri E, Ughi C, et al. Gluten-dependent

diabetes-related and thyroid-related autoantibodies in patients with

celiac disease. J Pediatr 2000; 137:263-265.

> 12. Auricchio R, Paparo F, Maglio M, et al. In vitro deranged

intestinal immune response to gliadin in type 1 diabetes. Diabetes

2004; 53:1680-1683.

> 13. ** Sblattero D, Ventura A, Tommasini A. Cryptic gluten

intolerance in type 1 diabetes: identifying suitable candidates for a

gluten free diet. Gut 2006; 55:133-134. This paper shows for the first

time a direct link between the exposure to gluten and an immune

response at the intestinal level in subjects affected by T1D.

> 14. Kumar V, Rajadhyaksha M, Wortman J. Celiac disease-associated

autoimmune endocrinopathies. Clin Diagn Lab Immunol 2001; 8:678-685.

> 15. Collin P, Reunala T, Pukkala E, et al. Coeliac

disease-associated disorders and survival. Gut 1994; 35:1215-1218.

> 16. Tanure MG, Silva IN, Bahia M, Penna FJ. Prevalence of celiac

disease in Brazilian children with type 1 diabetes mellitus. J Pediatr

Gastroenterol Nutr 2006; 42:155-159.

> 17. Mahmud FH, Murray JA, Kudva YC, et al. Celiac disease in type 1

diabetes mellitus in a North American community: prevalence, serologic

screening, and clinical features. Mayo Clin Proc 2005; 80:1429-1434.

> 18. Saadah OI, Zacharin M, O'Callaghan A, et al. Effect of

gluten-free diet and adherence on growth and diabetic control in

diabetics with celiac disease. Arch Dis Child 2004; 89:871-876.

> 19. Peretti N, Bienvenu F, Bouvet C, et al. The temporal

relationship between the onset of type 1 diabetes and celiac disease:

a study based on immunoglobulin a antitransglutaminase screening.

Pediatrics 2004; 113:E418-E422.

> 20. * Sumnik Z, Cinek O, Bratanic N, et al. Risk of celiac disease

in children with type 1 diabetes is modified by positivity for

HLA-DQB1*02-DQA1*05 and TNF -308A. Diabetes Care 2006; 29:858-863. A

well-designed study aimed at establishing whether genetic

polymorphirms are responsible of celiac disease†" T1D comorbidity.

> 21. Kaspers S, Kordonouri O, Schober E, et al. Anthropometry,

metabolic control, and thyroid autoimmunity in type 1 diabetes with

celiac disease: a multicenter survey. J Pediatr 2004; 145:790-795.

> 22. Aycan Z, Berberoglu M, Adiyaman P, et al. Latent autoimmune

diabetes mellitus in children (LADC) with autoimmune thyroiditis and

celiac disease. J Pediatr Endocrinol Metab 2004; 17:1565-1569.

> 23. Berti I, Trevisiol C, Tommasini A, et al. Usefulness of

screening program for celiac disease in autoimmune thyroiditis. Dig

Dis Sci 2000; 45:403-406.

> 24. Verslype C. Evaluation of abnormal liver-enzyme results in

asymptomatic patients. Acta Clin Belg 2004; 59:285-289.

> 25. Mainardi E, Montanelli A, Dotti M, et al. Thyroid-related

autoantibodies and celiac disease: a role for a gluten-free diet? J

Clin Gastroenterol 2002; 35:245-248.

> 26. da Silva Kotze LM, Nisihara RM, Da Utiyama SR, et al.

Thyroid disorders in Brazilian patients with celiac disease. J Clin

Gastroenterol 2006; 40:33-36.

> 27. Sumnik Z, Cinek O, Bratanic N, et al. Thyroid autoimmunity in

children with coexisting type 1 diabetes mellitus and celiac disease:

a multicenter study. J Pediatr Endocrinol Metab 2006; 19:517-522.

> 28. * Fasano A, Shea-Donohue T. Mechanisms of disease: the role of

intestinal barrier function in the pathogenesis of gastrointestinal

autoimmune diseases. Nat Clin Pract Gastroenterol Hepatol 2005;

2:416-422. This is a good review on the role of intestinal

permeability and the gut-associated lymphoid tissue in the

pathogenesis of autoimmune diseases, including celiac disease and T1D.

> 29. Bjarnason I, Takeuchi K, Bjarnason A, et al. The G.U.T. of gut.

Scand J Gastroenterol 2004; 39:807-815.

> 30. Wendling D. Role of the intestine in the physiopathology of

inflammatory rheumatism. Rev Rhum Mal Osteoartic 1992; 59:389-392.

> 31. ** Watts T, et al. Role of the intestinal tight junction

modulator zonulin in the pathogenesis of type I diabetes in BB

diabetic-prone rats. Proc Natl Acad Sci USA 2005; 102:2916-2921. This

paper demonstrates the key role of the impairment of intestinal

barrier function secondary to the zonulin effect on tight junctions on

the pathogenesis of T1D.

> 32. Madara JL, Trier JS. Structural abnormalities of jejunal

epithelial cell membranes in celiac sprue. Lab Invest 1980; 43:254-261.

> 33. Schulzke JD, Bentzel CJ, Schulzke I, et al. Epithelial tight

junction structure in the jejunum of children with acute and treated

celiac sprue. Pediatr Res 1980; 43:435-441.

> 34. Fasano A, et al. Zonulin, a newly discovered modulator of

intestinal permeability, and its expression in coeliac disease. Lancet

2000; 355:1518-1519.

> 35. Clemente MG, et al. Early effects of gliadin on enterocyte

intracellular signalling involved in intestinal barrier function. Gut

2003; 52:218-223.

> 36. Nikulina M, Habich C, Flohe SB, et al. Wheat gluten causes

dendritic cell maturation and chemokine secretion. J Immunol 2004;

173:1925-1933.

> 37. * KE, Sapone A, Fasano A, Vogel SN. Gliadin stimulation

of murine macrophage inflammatory gene expression and intestinal

permeability are MyD88-dependent: role of the innate immune response

in celiac disease. J Immunol 2006; 176:2512-2521. This paper reports

the effect of the celiac disease trigger gliadin on macrophage

inflammatory gene expression and intestinal barrier function in a

normal murine animal model, and the dependence of this effect on the

MyD88 signaling.

>

> Acknowledgements

>

> Work by the author was supported in parts by grant from the National

Institutes of Health Grants DK-48373.

>

> Abbreviation Notes

>

> EMA = antiendomysium antibodies; GFD = gluten-free diet; ICA = islet

cell antibody; NOD = nonobese diabetes; T1D = Type 1 diabetes; TAI =

thyroid autoimmunity; TLR = Toll-like receptor; tTG = tissue

transglutaminase.

>

> Reprint Address

>

> Alessio Fasano, MD, Mucosal Biology Research Center, University of

land School of Medicine, 20 Penn Street HSF II Building, Room

S345, Baltimore, MD 21201, USA Tel: + 1 410 706 5501; e-mail: afasano@...

>

>

>

> Alessio Fasano, Center for Celiac Research and Mucosal Biology

Research Center and Department of Physiology, University of land

School of Medicine, Baltimore, land, USA

>

>

>

>

>

> ________________________________

>