Celiac disease and endocrine autoimmune disorders in children: an update

Celiac disease (CD) is a life-long inflammatory condition of the gut that occurs in genetically susceptible individuals. Several autoimmune diseases (AI) are associated with CD. To date, no conclusive evidence is available that proves if the relationship between CD and AI is mediated by gluten exposure, or if CD and AI could co-occur due to other causes, in particular the loss of the intestinal barrier function and the common genetic background. Furthermore, it is not clear yet if CD needs a regular screening program for AI. This review will cover the key studies on both the pathogenetic and clinical evidence explaining this association. We will review the reports including patients aged <18 years with CD and endocrine AI.     

Celiac disease and HLA in a Bedouin kindred

We report the prevalence of celiac disease (CD) and its relationship with other autoimmune diseases and HLA haplotypes in a Bedouin kindred. Of 175 individuals sampled and typed for autoantibodies and HLA class II genotypes, six (3.4%) members had CD, and an additional 10 (5.7%) members tested positive for autoantibodies to transglutaminase (TgAA+). Several CD/TgAA+ relatives also had islet cell antigen or adrenal autoimmunity. Affected relatives are more closely related than expected from the pedigree relationships of all family members and were more often the offspring of consanguineous marriages. Individuals with CD or TgAA+ were enriched for DRB1*0301-DQA1*0501-DQB1*0201, a haplotype previously reported as high risk for CD. There was also an increased frequency of DQB1*0201/DQB1*0201 homozygotes among affected relatives. We found no evidence that DRB1*0701-DQA1*0201-DQB1*0201/DRB1*11-DQA1*0501-DQB1*0301 is a high-risk genotype, consistent with other studies of Arab communities. In addition, a nonparametric linkage analysis of 376 autosomal markers revealed suggestive evidence for linkage on chromosome 12p13 at marker D12S364 (NPL = 2.009, p = 0.0098). There were no other significant results, including the HLA region or any other previously reported regions. This could reflect the reduced power of family-based linkage and association analyses in isolated inbred populations.     

Thyroid-associated ophthalmopathy--a model for the association of organ-specific autoimmune disorders

The development of a characteristic ophthalmopathy is a feature of autoimmune diseases of the thyroid. The link between the conditions has not yet been discovered, but here Jack Wall and colleagues develop the theory that an autoimmune response to a 64 kDa antigen expressed on both thyroid and eye muscle membranes is responsible for this thyroid-associated ophthalmopathy.     

Role of transglutaminase 2 in celiac disease pathogenesis

A number of lines of evidence suggest that transglutaminase 2 (TG2) may be one of the earliest disease-relevant proteins to encounter immunotoxic gluten in the celiac gut. These and other investigations also suggest that the reaction catalyzed by TG2 on dietary gluten peptides is essential for the pathogenesis of celiac disease. If so, several questions are of critical significance. How is TG2 activated in the celiac gut? What are the disease-specific and general consequences of activating TG2? Can local inhibition of TG2 in the celiac intestine suppress gluten induced pathogenesis in a dose-responsive manner? And what are the long-term consequences of suppressing TG2 activity in the small intestinal mucosa? Answers to these questions will depend upon the development of judicious models and chemical tools. They also have the potential of yielding powerful next-generation drug candidates for treating this widespread but overlooked chronic disease.     

Celiac disease: a model disease for gene-environment interaction

Celiac sprue remains a model autoimmune disease for dissection of genetic and environmental influences on disease progression. The 2010 Congress of Autoimmunity included several key sessions devoted to genetics and environment. Several papers from these symposia were selected for in-depth discussion and publication. This issue is devoted to this theme. The 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.     

From genome-wide association studies to disease mechanisms: celiac disease as a model for autoimmune diseases

Celiac disease is characterized by a chronic inflammatory reaction in the intestine and is triggered by gluten, a constituent derived from grains which is present in the common daily diet in the Western world. Despite decades of research, the mechanisms behind celiac disease etiology are still not fully understood, although it is clear that both genetic and environmental factors are involved. To improve the understanding of the disease, the genetic component has been extensively studied by genome-wide association studies. These have uncovered a wealth of information that still needs further investigation to clarify its importance. In this review, we summarize and discuss the results of the genetic studies in celiac disease, focusing on the "non-HLA" genes. We also present novel approaches to identifying the causal variants in complex susceptibility loci and disease mechanisms.     

Characterization of HLA DR3/DQ2 transgenic mice: a potential humanized animal model for autoimmune disease studies

Linkage studies indicate close associations of certain HLA alleles with autoimmune diseases. To better understand how specific HLA alleles are related to disease pathogenesis, we have generated an HLA DR3/DQ2 transgenic mouse utilizing a 550-kb yeast artificial chromosome (YAC) construct containing the complete DRalpha, DRbeta1, DRbeta3, DQalpha, and DQbeta regions. The transgenic mouse (4D1/C2D) in an I-Abeta(o) background appears healthy with no signs of autoimmune diseases. Lymphoid tissues as well as CD4(+) T cells develop normally. Characterization of the transgene expression demonstrates that approximately 90% of B cells express high levels of DR3 and 50-70% of B cells express DQ2. CD11c(+) dendritic cells express high levels of DR and DQ. Approximately 12-18% of resting T cells are positive for DR expression, and further up-regulation to 40-50% expression is seen upon activation with anti-CD3/anti-CD28 mAb. These results suggest that the transgenic construct confers a high fidelity to the normal human temporal and spatial expression profile. Analysis of T cell receptor repertoire in transgenic mice confirms that DR3/DQ2 are able to mediate thymic selection. Furthermore, transgenic mice respond to a DR3-restricted antigen, demonstrating antigen processing and presentation by antigen-presenting cells (APC). Purified T cells from ovalbumin (OVA)-immunized 4D1 mice respond to human APC co-cultured with OVA, suggesting appropriate antigen/DR3 or DQ2 recognition by murine T cells. Immunoglobulin isotype switching is also observed, indicating functional T-B cognate interactions. Thus, the DR3/DQ2 transgenic mouse has normal lymphoid development and functionality that are mediated by HLA transgenes and can be used to investigate HLA-associated immunological questions.     

HLA association of idiopathic Peyronie's disease: An indication of autoimmune phenomena in etiopathogenesis?

Abstract: HLA typing for class I and class II antigens was done in 52 unrelated patients suffering from idiopathic Peyronie's disease. The controversially discussed association with the HLA-B7 cross-reacting group could not be confirmed. Marked deviations of antigen frequencies were observed for HLA-A1, B8, Cw7, DR3 and DQw2 compared to healthy local controls. After correction of p-values, Al (p_c < 0.05) and DQw2 (p_c < 0.01) remained significant. A possible association of Peyronie's disease with markers of the HLA-A1, B8, Cw7, DR3, DQw2 haplotype, as first described here, would suggest autoimmunological factors in this disorder of otherwise unknown etiopathogenesis.     

HLA association of idiopathic Peyronie's disease: an indication of autoimmune phenomena in etiopathogenesis?

HLA typing for class I and class II antigens was done in 52 unrelated patients suffering from idiopathic Peyronie's disease. The controversially discussed association with the HLA-B7 cross-reacting group could not be confirmed. Marked deviations of antigen frequencies were observed for HLA-A1, B8, Cw7, DR3 and DQw2 compared to healthy local controls. After correction of p-values, A1 (pc less than 0.05) and DQw2 (pc less than 0.01) remained significant. A possible association of Peyronie's disease with markers of the HLA-A1, B8, Cw7, DR3, DQw2 haplotype, as first described here, would suggest autoimmunological factors in this disorder of otherwise unknown etiopathogenesis.     

Celiac disease: association with adult-onset Still's disease: apropos of a clinical case

Adult-onset Still's disease (AOSD) is a rheumatic disorder of unknown etiology characterized by a triad of fever, polyarthritis and evanescent rash. We present a case report of a 28-year-old female who presented with complaints of fever, joint pains, rash, weakness for the past 4 years and diarrhea for the past 2 years. On investigation the patient was diagnosed to be a case of AOSD. Duodenal biopsy report was suggestive of celiac disease with a positive IgA tissue transglutaminase and anti-endomysial antibody. The patient was started on weekly methotrexate and gluten-free diet and her symptoms gradually improved. The patient remains in our follow-up and is doing well.     

HLA and disease associations: Detecting the strongest association

Abstract: A major aim of HLA and disease association studies is to identify the causative HLA factor truly responsible for the association. This is usually difficult due to the pronounced linkage disequilibrium between most HLA determinants. The causative factor must show the strongest association compared to all other factors. Here we describe a simple analysis which can be used to identify which of two factors, say A and B, shows the strongest association. The basic data for the analysis are the entries of the two-by-four table giving the four phenotypic combinations of A and B in patients and controls, respectively. These data are analyzed in various two-by-two tables involving stratification of each of the two factors against the other. A stronger increase of factor A is established if A is significantly associated with the condition both in B-positives and in B-negatives, when this is not true for B in A-positives and A-negatives. Using simulation with control data, it is demonstrated how linkage disequilibrium may influence secondary associations. The analysis may also be used to investigate interaction between HLA factors, but linkage disequilibrium complicates the interpretation in such cases. The method is exemplified using various published data. Finally, some statistical recommendations are given. Thus, we advise that phenotype (marker) frequencies are generally used instead of gene (i.e. allele, or haplotype) frequencies. The importance of correcting p-values, the levels of significance, and the power of Fisher's exact test are discussed.     

HLA antigens and Bf allotypes in SLE: evidence for the association being with specific haplotypes

The clinical features and HLA types of 67 unrelated patients with Systemic Lupus Erythematosus (SLE) were analyzed. The results showed:
1. An increase in frequencies of A1, B8, and DR3. These antigens are in close linkage disequilibrium and our data show that susceptibility to SLE is associated with the presence of all three antigens, implicating the specific haplotype which bears these antigens.
2. An increase in frequency of DR2, but not A3 or B7, these latter two antigens being in linkage disequilibrium with DR2.
3. 73.3% of the 54 Caucasoid SLE group were either B8 and/or DR2. This is in comparison with 37.5% in the controls and the difference is significant (p < 0.001).
4. There was no association apparent between extent of disease, particular organ involvement and level of circulating antibodies to double stranded DNA with any HLA region product.     

CD4 T cells and their antigens in the pathogenesis of autoimmune diabetes

Pathogenesis of type 1 diabetes (T1D) is mediated by effector T cells and CD4 Th1 and Th17T cells have important roles in this process. While effector function of Th1 cells is well established, because of their inherent plasticity Th17 cells have been more controversial. Th17 cells contribute to pathogenicity, but several studies indicate that Th17 cells transfer disease through conversion to Th1 cells in vivo. CD4T cells are attracted to islets by β-cell antigens which include insulin and the two new autoantigens, chromogranin A and islet amyloid polypeptide, all proteins of the secretory granule. Peptides of insulin and ChgA bind to the NOD class II molecule in an unconventional manner and since autoantigenic peptides may typically bind to MHC with low affinity, it is postulated that post-translational modifications of β-cell peptides could contribute to the interaction between peptides, MHC, and the autoreactive TCR.     

凋亡相关因子参与自身免疫性甲状腺疾病发病的研究

目的:了解细胞凋亡相关蛋白Fas,FasL和Bcl-2表达在自身免疫性甲状腺疾病发病机制及病理变化中的作用及意义。方法:采用免疫组织化学方法,检测20例桥本甲状腺炎,20例Graves病以及20例甲状腺腺瘤(作为对照组)患者甲状腺标本中Fas、FasL和Bcl-2表达及分布。结果:Fas在所有的标本中表达,主要分布于甲状腺滤泡细胞表面和细胞质上。除3例甲状腺瘤标本外,其余均表达FasL。Bcl-2表达于15例桥本甲状腺炎、19例Graves病以及17例甲状腺瘤滤泡细胞上。在甲状腺瘤滤泡细胞上表达中等强度Fas,很少或是没有表达FasL。在桥本甲状腺炎中Fas和FasL免疫染色强阳性甲状腺滤泡细胞多分布于浸润淋巴滤泡附近,浸润淋巴细胞中Fas、FasL免疫染色相对较弱。在Graves病中,Fas表达强度与桥本甲状腺炎类似,但FasL表达却更弱。在Graves病和甲状腺瘤组织中,Bcl-2表达两者类似。但在桥本甲状腺炎组织中,分布于浸润淋巴细胞附近的甲状腺滤泡细胞以及生发中心的淋巴细胞上,Bcl-2表达很弱。结论:Fas、FasL和Bcl-2表达在桥本甲状腺炎和Graves病中相似。FasL高表达和Bcl-2低表达可能引起桥本甲状腺炎滤泡细胞凋亡。进一步证明3种凋亡相关因子在自身免疫性甲状腺疾病发病机制中的作用。在桥本甲状腺炎中,滤泡细胞凋亡并非由浸润淋巴细胞其FasL发挥作用直接杀伤,但是它们能分泌细胞因子促进滤泡细胞自身Fas、FasL表达,从而导致滤泡细胞凋亡。     

Prototypic disorders of gastrointestinal mucosal immune function: Celiac disease and Crohn's disease

Celiac disease is a disorder of the small intestine characterized by chronic inflammation of the mucosa and protean clinical manifestations caused by loss of tolerance to dietary antigens. Two strongly associated cofactors have been identified: the presence of HLA-DQ2 or HLA-DQ8 in the host and specific antigenic peptides in the diet that are present in wheat, rye, and barley. Most patients have complete remission after dietary elimination of these foods. Crohn's disease is characterized by chronic, relapsing, recurrent, focal, transmural inflammation of the gastrointestinal tract that can lead to multiple serious problems requiring chronic medical and surgical therapy. Crohn's disease is associated with multiple genetic mutations, at least one of which has been clearly implicated in innate immunity. Multiple lines of evidence suggest that the disease involves abnormal immune responses to gut microbial flora.     

Induction of Ia antigens on thyroid cultures by syngeneic T lymphocytes: a model of autoimmune disease

We previously reported that the expression of Ia antigens on cultured monolayers of murine thyroid epithelial cells (TEC) occurred with a particular distribution exclusively on the basal part of the cultured thyroid cells, while class I antigens of the major histocompatibility complex (MHC) are only detected on the apical surface. It appears that deposition of syngeneic lymphocytes induces, 24 h later, Ia expression on the apical side of cultured TEC, the surface that is in direct contact with the responder lymphocytes during syngeneic sensitization of T lymphocytes. We hypothesized that this phenomenon could represent, in syngeneic situations, the restriction process in antigen recognition by T cells, as demonstrated by Ia restricted primary syngeneic sensitization (PSS) on murine TEC.     

Interaction between food antigens and the immune system: Association with autoimmune disorders

It has been shown that environmental factors such as infections, chemicals, and diet play a major role in autoimmune diseases; however, relatively little attention has been given to food components as the most prevalent modifiers of these afflictions. This review summarizes the current body of knowledge related to different mechanisms and associations between food proteins/peptides and autoimmune disorders. The primary factor controlling food-related immune reactions is the oral tolerance mechanism. The failure of oral tolerance triggers immune reactivity against dietary antigens, which may initiate or exacerbate autoimmune disease when the food antigen shares homology with human tissue antigens. Because the conformational fit between food antigens and a host's self-determinants has been determined for only a few food proteins, we examined evidence related to the reaction of affinity-purified disease-specific antibody with different food antigens. We also studied the reaction of monoclonal or polyclonal tissue-specific antibodies with various food antigens and the reaction of food-specific antibodies with human tissue antigens. Examining the assembled information, we postulated that chemical modification of food proteins by different toxicants in food may result in immune reaction against modified food proteins that cross-react with tissue antigens, resulting in autoimmune reactivity. Because we are what our microbiome eats, food can change the gut commensals, and toxins can breach the gut barrier, penetrating into different organs where they can initiate autoimmune response. Conversely, there are also foods and supplements that help maintain oral tolerance and microbiome homeostasis. Understanding the potential link between specific food consumption and autoimmunity in humans may lay the foundation for further research about the proper diet in the prevention of autoimmune diseases.     

Celiac disease associated antibodies in persons with latent autoimmune diabetes of adult and type 2 diabetes

BACKGROUND: Celiac Disease (CD) is present in 1-16.4% of patients with type 1 diabetes mellitus. The most important serological markers of CD are anti-endomysial (EMA), anti-tissue transglutaminase (tTGA) and antigliadin antibodies (AGA). AIM/HYPOTHESIS: The objective of this work is to determine the frequency of tTGA and/or AGA in latent autoimmune diabetes of adult (LADA) and subjects with type 2 diabetes (T2DM), as well as to evaluate their relation with several clinical and biochemical characteristics. SUBJECTS AND METHODS: Forty three subjects with LADA and 99 with T2DM were studied. The presence of AGA, tTGA was determined in the sera of these patients. The variables: sex, age, duration of diabetes, treatment, body mass index (BMI) and fasting blood glucose concentration were also recorded. RESULTS: No differences were found in the frequency of celiac disease associated antibodies between LADA and T2DM subjects. The presence of celiac disease related antibodies was more frequent in patients with a normal or low BMI. CONCLUSIONS: Celiac disease does not seem to be related with pancreatic autoimmunity in type 2 diabetes. Celiac disease causes a decrease of body mass index in type 2 diabetes while pancreatic islet autoimmunity in this entity masks this effect.     

Analysis of the expression of Fas, FasL and Bcl-2 in the pathogenesis of autoimmune thyroid disorders

To investigate the expression of apoptosis-related protein (Fas, FasL, and Bcl-2) in the pathogenesis of autoimmune thyroid disorders (ATDs), immunohistochemical staining was performed on 20 Hashimoto‘s thyroiditis (HT), 20 Graves‘ disease (GD), and 20 thyroid follicular adenoma (TFA, as control). All the cases expressed Fas, mainly on the cell surface and cytoplasm. FasL was found in 17 cases of the TFA. Bcl-2 was detected in 15 cases of HT, 19 of GD and 17 of TFA. In T FA, a moderate Fas expression and a minimal or no FasL expression was detected on follicular cells. In HT, the follicles adjacent to infiltrating lymphocytes showed increased levels of Fas and FasL expression. A weaker staining of Fas and FasL was exhibited on infiltrating lymphocytes than on thyrocytes. In a comparison of GD with HT, thyrocytes and lymphocytes showed similar Fas staining, but for FasL the staining was rather weaker in HT. The expression of Bcl-2 was nearly identical in GD and TFA, but much weaker on the follicular cells in vicinity of lymphocytes and on the lymphocytes located in germinal centers of HT tissues. The expression of Fas, FasL, Bcl-2 in Hashimoto‘s thyroiditis and Graves‘ disease were almost same. FasL strong expression and Bcl-2 weak expression on the follicles in HT may induce apoptosis. These results provided evidence for expression of Fas, FasL and Bcl-2 in the pathogenesis of autoimmune thyroid disease. The lymphocytes seem not to be directly engaged in the process v/a their own FasL, but they may provide some cytokines that, in turn, upregulate Fas and/or FasL expression to induce apoptosis.