An update on the cutaneous manifestations of coeliac disease and non-coeliac gluten sensitivity

Introduction: Coeliac disease is a gluten-induced immune-mediated enteropathy, characterised by the expression of specific genotypes and the production of autoantibodies. The inflammatory process specifically targets the intestinal mucosa, but gastrointestinal and extraintestinal signs and symptoms can also be present. Non-coeliac gluten sensitivity (NCGS) can be diagnosed in individuals who have intestinal and/or extraintestinal symptoms related to the ingestion of gluten, but do not have autoantibodies and do not suffer from lesions in the duodenal mucosa. Among the extraintestinal manifestations, cutaneous manifestations are the most common for both diseases. Purpose: We conducted this review to illustrate the common and uncommon features underlying the association of coeliac disease and NCGS with cutaneous manifestations related to gluten ingestion. Areas covered: The roles of innate and adaptive immunity in the cutaneous appearance of gluten sensitivity will be discussed.     

Two cases of pericarditis associated with inflammatory bowel disease

Extraintestinal manifestations are common complications of inflammatory bowel disease (IBD) whereas the association of cardiac disease with IBD is rarely reported. Cardiac manifestations may be diagnosed before, concomitantly or after the diagnosis of the specific type of inflammatory bowel disease. Pericarditis and myocarditis are potentially serious complications. This extraintestinal manifestation developed in one patient concomitantly with onset of intestinal disease. One patient had ulcerative colitis (UC), while other had Crohn's disease (CD). Indomethacin was effective in one and the other patient required prednisone in addition. Chest symptoms in patients with inflammatory bowel disease should be evaluated to exclude myopericardial disease.     

Humoral immune system and ulcerative colitis activity. III. Immune complexes

Serum immune complexes (IMC) were examined by means of 4.166% polyethylene glycol precipitation. IMC were found in 33.3% of all examined patients (12.8% of inactive and 51.1% of active colitis). Polyethylene glycol serum precipitation was correlated with the activity of the disease, and was found to be increased in patients with extensive morbid process and with duration of the disease. In the patients with extraintestinal manifestations IMC increased particularly in those with skin lesions. Our study confirmed suggestion of other authors on the possible role of the pathogenesis of UC and in extraintestinal complications. Their secondary role however, cannot be excluded.     

Pathologic changes in the liver and kidney produced by immunization with intestinal antigens.

Rabbits were immunized with intestinal antigens derived from rabbits, guinea pigs, and germfree rats. Inflammatory changes throughout the portal tracts of the liver were found in 55% (16 of 29) of the immunized rabbits. Interstitial nephritis was present in 7 of 23 rabbits evaluated. These changes did not occur when nonintestinal antigens were used for immunization. Antigen shared by liver, kidney, duodenum, ileum, and colon were found in each of the species used for immunization. An immune response to the antigen shared by the various tissues may be a factor in the pathogenesis of disease in this experimental system. In man, chronic active hepatitis and interstitial nephritis are found in association with inflammatory bowel disease. A similar mechanism of pathogenesis may be a factor in these extraintestinal manifestations of inflammatory bowel disease in man.     

Dendritic cell function is perturbed by Yersinia enterocolitica infection in vitro

Infection with Yersinia enterocolitica is the cause of intestinal or extraintestinal diseases. We investigated the role of dendritic cells (DC), the most potent antigen-presenting cell (APC), in the course of infection with Y. enterocolitica in vitro. For these studies, DC were isolated from human peripheral blood and infected with green fluorescent protein (GFP)-labelled Y. enterocolitica. Bacteria were found within DC by FACS analysis and viable bacteria could be cultured from lysed cells. Within 24 h after infection, DC upregulated CD83 and CD86 followed at day 3, indicating maturation of DC. In contrast, for MHC class II, a marked but transient downregulation was observed at day 3 after infection, and downregulation to a lesser extent for CD80 at day 5. To assess the immunostimulatory capacity of DC, viable infected and uninfected DC were incubated with autologous T cells in the presence of phytohemagglutinin A (PHA). T cell proliferation was significantly reduced at days 4-6 after infection but not thereafter, whereas nonpathogenic Escherichia coli was not able to mimick this suppressive effect of Y. enterocolitica. The same suppression could be observed when infected DC were used in a mixed leucocyte reaction with allogeneic T cells. Thus Y. enterocolitica is able to invade DC, does not induce necrosis or apoptosis, but affects maturation of DC. However, MHC class II-molecules are downregulated initially, which coincides with a diminished immunostimulatory capacity of DC infected with Y. enterocolitica. The diminished immunostimulatory capacity of DC following infection with Y. enterocolitica in vitro might impair or delay elimination of bacteria thereby contributing to pathogenesis of bacterial enteritis or extraintestinal manifestations such as reactive arthritis.     

Genetic variation within TLR10 is associated with Crohn's disease in a New Zealand population

Toll-like receptors (TLRs) play an important role in the induction and regulation of the innate immune system and have been implicated in both infectious and inflammatory diseases. Recently the first association of TLR10 with Crohn's disease (CD) was reported. Here, we attempted to validate this association, using a candidate gene single nucleotide polymorphism (SNP) study of TLR10 in CD. We identified tagging SNPs, and genotyped these SNPs in a Caucasian New Zealand dataset consisting of 406 CD patients and 638 controls. In this sample, we were able to demonstrate an association between CD and several different TLR10 SNPs and haplotypes. Phenotypic analysis showed an association with early age at first diagnosis, inflammatory and ileocolonic CD behavior, requirement of bowel resection, and extra intestinal manifestations. This study provides evidence to suggest that genetic variation in TLR10 plays a role in interindividual differences in CD susceptibility and clinical outcome.     

Acute pancreatitis following azathioprine therapy of crohn's disease--a case report and the overview of the literature

Crohn's disease (CD) is the consequence of intestinal mucosa injury due to incorrect immune response to intestinal bacterial infection with lymphocyte T participation. Azathioprine--an immuno-modulator, is effective in the treatment and prevention of acute exacerbation of CD. It hinders the activity of immune cells, and therefore, the immune response. The use of azathioprine also reduces th necessity for corticosteroid therapy. Despite its efficacy, complications of azathioprine therapy are possible, including acute pancreatitis. In addition, acute pancreatitis is one of the extra-intestinal manifestations of acute exacerbation of CD without the previous use of azathioprine. We present a patient with acute pancreatitis, which occurred three weeks after the start of azathioprine treatment and manifested by clinical signs and symptoms similar to acute CD deterioration, and with elevated serum amylase and lipase levels. The symptoms responded rapidly to treatment with intravenous fluids, analgesics and azathioprine discontinuation after other possible causes were excluded. Thus, it is reasonable to estimate serum amylase and lipase levels frequently during 2 to 3 weeks after the start of azathioprine treatment for CD due to the possibility of acute pancreatitis occurring during this period in order to diagnose and treat acute pancreatitis as soon as possible, including early discontinuation of azathioprine therapy.     

Genetic and immunological processes in the pathomechanism of gluten-sensitive enteropathy and associated metabolic bone disorders

Celiac disease, or gluten sensitive enteropathy is a relatively common disease of the jejunum, leading to malabsorption. It is an immune mediated disease, induced by gluten on the grounds of a specific genetic makeup. After gluten exposition immune processes are induced mainly by T-cells, causing typical intestinal and extra intestinal manifestations. The diagnosis of celiac disease is based on jejunal biopsy histology and the presence of antibodies against endomysium and tissue transglutaminase. Genetically, celiac disease is associated with HLA DQ2/DQ8. Strict gluten-free diet improves the clinical, histological and serological picture and remission may be achieved. In the etiopathogenesis of celiac disease several genetic and immunological mechanisms have been recognized in the recent years. Concerning accompanying diseases/extraintestinal manifestations, several disorders have been shown, including rheumatological diseases. In celiac disease, bone metabolic changes are more frequent compared to the prevalence of inflammatory join disorders. In this review, we aim to give an overview on various aspects of the genetic and immunological processes in the pathomechanism of gluten-sensitive enteropathy and associated metabolic bone disorders.     

Gnotobiotic piglets develop thrombotic microangiopathy after oral infection with enterohemorrhagic Escherichia coli

Oral infection with enterohemorrhagic Escherichia coli (EHEC) may cause severe enteritis, followed in up to 10% of cases by an extraintestinal complication, the hemolytic uremic syndrome (HUS). HUS is characterized by a triad of symptoms: anemia, thrombocytopenia, and acute renalfailure due to thrombotic microangiopathy. EHEC produces several virulence factors, among which a family of phage-encoded cytotoxins, called Shiga toxin 1 and Shiga toxin 2, seems to be most important. However, since an appropriate animal model is not available, pathogenicity of these emerging enteric pathogens is still poorly understood. Germ-free gnotobiotic piglets infected orally with an O1577:H7 or an O26:H11 EHEC wild-type isolate, both producing Shiga toxin 2, developed intestinal and extraintestinal manifestations of EHEC disease, including thrombotic microangiopathy in the kidneys, the morphologic hallmark of HUS in humans. Thus, gnotobiotic piglets are suitable to further study the pathophysiology of EHEC-induced HUS. It can be expected that data obtainedfrom this animal model will improve our current standard of knowledge about this emerging infectious disease.     

Lack of circulating immune complexes in inflammatory bowel disease

Multi-organ involvement and especially extraintestinal manifestations have suggested an immune complex-mediated pathogenesis of ulcerative colitis and Crohn's disease. Using various techniques controversial data have been reported on the incidence and levels of circulating immune complexes and their correlation to clinical presentation. Sera of 131 patients with inflammatory bowel disease (78 Crohn's disease, 53 ulcerative colitis) representing a wide spectrum of disease activity, treatment and presence or absence of extraintestinal manifestations were tested for circulating immune complexes using Raji cell indirect immunofluorescence assay, Raji cell radioimmunoassay, C1q solid phase assay and polyethylene glycol precipitation coupled with measurements of optical density and subsequent immunoelectrophoresis or radial immunodiffusion. Circulating immune complexes in low concentrations were observed in a small number of patients with inflammatory bowel disease, the frequency and concentrations being slightly higher in patients with Crohn's disease than in those with ulcerative colitis. No association of concentrations of circulating immune complexes with disease activity or presence of extraintestinal manifestations could be demonstrated. These data do not support the claim for a major role of circulating immune complexes in the pathogenesis of inflammatory bowel disease.     

Genetic markers linked to rheumatoid arthritis are also strongly associated with articular manifestations in ulcerative colitis patients

Ulcerative colitis is often accompanied by the development of extraintestinal, mainly articular, manifestations. Genetic differences could be underlying that clinical heterogeneity. We performed a case-control study to determine whether TNFab microsatellites or HLA-DR alleles were associated with the development of articular manifestations in patients with ulcerative colitis. With that aim, a total of 84 ulcerative colitis patients with articular manifestations and 172 without them were genotyped for TNFab microsatellites and HLA-DR. A healthy control sample (n = 595) was also included for comparative purposes. Haplotypes were inferred with the Arlequin software. The influence of HLA-DRB1*0103 and HLA-B27, factors previously known to be associated with extraintestinal manifestations, was specifically addressed. We observed that TNFa6b5 minihaplotype increases the susceptibility to developing articular manifestations in ulcerative colitis patients (p = 0.003, OR = 2.39). The locus HLA-DR does not appear to be involved in these extraintestinal manifestations by itself; however, the frequency of subjects carrying TNFa6b5 in combination with DR1, DR7, or DR11 is very significantly increased in patients with articular manifestations (p = 3.9 x 10(-8)). The associations found were independent of DRB1*0103 and HLA-B27. Thus, it seems that the development of articular manifestations in ulcerative colitis patients appears to be influenced by some genetic factor(s) present in some major histocompatibility complex haplotypes.     

New Clues in Celiac Disease Epidemiology,Pathogenesis, Clinical Manifestations,and Treatment

Celiac disease (CD) is an immune-mediated enteropathy triggered by the ingestion of gluten in genetically susceptible individuals. It is one of the most common lifelong disorders on a worldwide basis. Celiac enteropathy is the final consequence of an abnormal immune reaction, showing features of both an innate and an adaptive response to gluten prolamins. The clinical spectrum is wide, including cases with either typical intestinal or atypical extraintestinal features, and silent forms. The only available treatment consists in dietary exclusion of grains containing gluten. New pharmacological treatment are currently under scrutiny.     

Inflammatory bowel disease in Thai children: presentations and outcomes of treatment

Inflammatory bowel disease (IBD) is characterized by idiopathic chronic intestinal inflammation, due to abnormalities in gastrointestinal immunoregulation. Pediatric IBD has been rarely reported in Thailand. We describe eight children, five girls and three boys, who were diagnosed with IBD at Ramathibodi Hospital during 1999-2005 and had a follow-up of more than one year. Four cases had Crohn's disease (CD) and four cases had ulcerative colitis (UC). The ages at diagnosis ranged from 3.5 to 15.5 years. Diagnosis of IBD was delayed for more than 12 months in five patients. Five out of eight patients had early onset of disease, before 6 years of age. The manifestations included chronic diarrhea, abdominal pain, rectal bleeding and perianal lesions. The common extraintestinal manifestations were oral ulcer, anemia, weight loss and failure to thrive. Most patients had moderate to severe diseases and ileocolic fistula developed in one patient with CD. The disease was controlled with 5-aminosalicylic acid and corticosteroid in most patients. Four patients required additional therapy with azathioprine. Infliximab was used in two patients who were chronically steroid-dependent CD, one also had persistent ileocolic fistula and both patients responded well. During the follow-up period ranging from 1.1 to 5.8 years, three patients remained growth retardation; all had early onset of disease before 6 years of age, long duration of symptoms of more than 3 years before diagnosis and had multiple relapses. It is concluded that there is an increasing number of IBD in Thai children during the recent years. Most patients had moderate to severe diseases. Early onset of disease, delay in diagnosis and treatment are responsible for more complications, particularly persistent growth impairment. Early recognition of IBD and treatment are essential for a satisfactory long-term outcome.     

New clues in celiac disease epidemiology, pathogenesis, clinical manifestations, and treatment

Celiac disease (CD) is an immune-mediated enteropathy triggered by the ingestion of gluten in genetically susceptible individuals. It is one of the most common lifelong disorders on a worldwide basis. Celiac enteropathy is the final consequence of an abnormal immune reaction, showing features of both an innate and an adaptive response to gluten prolamins. The clinical spectrum is wide, including cases with either typical intestinal or atypical extraintestinal features, and silent forms. The only available treatment consists in dietary exclusion of grains containing gluten. New pharmacological treatment are currently under scrutiny.     

Autoimmune polyendocrine syndrome type 1: Clinical manifestations,pathogenetic features,and management approach

Autoimmune polyendocrine syndrome type 1 (APS-1) is an autosomal recessive hereditary pathology that develops with endocrine and non-endocrine manifestations in childhood. The classic triad of APS-1 includes chronic candidiasis of the skin and mucous membranes, adrenal insufficiency, and hypoparathyroidism. APS-1 is often accompanied by hypogonadism, type 1 diabetes, autoimmune thyroiditis, vitiligo, alopecia, asplenia, pneumonitis, gastritis, pernicious anemia, and intestinal dysfunction, nephritis, and hepatitis. The prevalence rate is highest in genetically isolated populations (up to 1:6500–1:9000). APS-1 occurs because of mutations in the autoimmune regulator (AIRE) gene, leading to a disrupted mechanism of normal antigen expression, the formation of abnormal clones of immune cells, and autoimmune damage to various organs. Analysis of the AIRE gene is the main diagnostic method for early detection of APS-1 and the choice of methods for its treatment. Timely genetic counseling makes it possible to identify the disease early, prescribe appropriate treatment and prevent serious complications. This paper analyzes scientific information characterizing clinical manifestations of autoimmune polyendocrine syndrome type 1 in association with its pathogenetic features, epidemiology, and current management.     

Cutaneous manifestations of Crohn's disease, its spectrum, and its pathogenesis: intracellular consensus bacterial 16S rRNA is associated with the gastrointestinal but not the cutaneous manifestations of Crohn's disease

The classic pathology of skin disease discontinuous from the inflamed gastrointestinal (GI) tract in patients with Crohn's disease (CD) includes pyoderma gangrenosum (PG), erythema nodosum (EN), and so-called metastatic Crohn's disease. The purpose of this study was two-fold: First, we explored the full spectrum of cutaneous lesions associated with Crohn's disease, and second, we sought to explore a potential molecular basis of the skin lesions in patients with CD. In this regard, we analyzed skin and GI tract biopsies from affected patients for the consensus bacterial SrRNA to determine whether direct bacterial infection was associated with either condition. Formalin-fixed, paraffin-embedded sections were studied and correlated to clinical presentation and histories from 33 patients with CD. Consensus bacterial RNA sequences were analyzed using an RT in situ PCR assay on both skin biopsy and GI biopsy material. The GI tract material included biopsies from 3 patients who had skin lesions and from 7 patients in whom there were no known skin manifestations. There were 8 cases of neutrophilic dominant dermal infiltrates, including pyoderma gangrenosum, 6 cases of granuloma annulare/necrobiosis lipoidica-like lesions, 5 cases of sterile neutrophilic folliculitis, 5 cases of panniculitis, 4 cases of vasculitis, 2 cases of psoriasis, 2 cases of lichenoid and granulomatous inflammation, and 1 case of classic metastatic CD. Intracellular bacterial 16S rRNA was detected in 8 of 10 tissues of active CD in the GI tract, of which 3 of the cases tested were from patients who also developed skin lesions at some point in their clinical course; in contrast, none of the skin biopsies had detectable bacterial RNA. The dermatopathological manifestations of CD discontiguous from the involved GI tract mucosa have in common a vascular injury syndrome, typically with a prominent extravascular neutrophilic and/or histiocytic dermal infiltrate. In addition, this study, the first to document in situ intracellular consensus bacterial SrRNA in the GI tract in CD, suggests that hematogenous dissemination of viable microbes is not associated with the cutaneous manifestations of this disease. Bacteria do, however, appear to play a role in bowel lesions of patients with CD.     

Predominant donor CD103+CD8+ T cell infiltration into the gut epithelium during acute GvHD: a role of gut lymph nodes

The existence of donor effector cell subsets responsible foreither gut or skin graft-versus-host disease (GvHD) is stillundetermined. We examined the trafficking and role of donorCD8⁺ intra-epithelial lymphocytes (IELs) in the gut and skinepithelia concerning Eβ7 integrin (CD103) expression, usinga rat acute lethal GvHD model. Most CD103⁺ donor cells wereCD8⁺ and showed a proliferative activity in the target epithelia.On the other hand, activated donor T cells in the host lymphoidtissues did not express CD103, indicating the presence of CD8⁺IEL precursors in the lymphoid tissues that may up-regulateCD103 only after migrating to the target organs. At the latestage of GvHD, while >80% of the donor CD8⁺ IELs were CD103⁺in the gut epithelium, both CD4⁺ and CD103⁺CD8⁺ T cells evenlyaccumulated in the skin epidermis. The CD103 expression by donorCD8⁺ IELs especially in the gut was also correlated with theclinical GvHD manifestations. Furthermore, the selective removalof gut lymph nodes (LNs) but not skin LNs suppressed the infiltrationof CD103⁺ donor IELs in the gut and alleviated intestinal GvHD.In conclusion, CD103⁺CD8⁺ donor T cells predominantly infiltrateinto the gut epithelium and are responsible for the manifestationsof intestinal GvHD. This pathology is at least partly dependenton the gut LNs.     

Aplasia cutis congenita, skull defect, brain heterotopia, and intestinal lymphangiectasia

We describe a female infant with a previously unreported combination of manifestations characterized by aplasia cutis, skull defect, brain heterotopia, mild congenital lymphedema, and intestinal lymphangiectasia. The association of intestinal lymphangiectasia and aplasia cutis, and the association of intestinal lymphangiectasia with brain heterotopia in the lymphedema-lymphangiectasia-mental retardation syndrome have been described in single reports. In one family, the association of cortical dysplasia and congenital lymphedema have been related to mutations in the RELN gene.