Approach to Pediatric Diarrhea
John F. Pohl, Christopher Jolley, Daniel Gelfond in Pediatric Gastroenterology, 2014
The intestinal barrier that is needed to regulate nutrient absorption can be defective and/or have increased permeability as a result of immunologic processes. Autoimmune enteropathy is characterized by immunoglobulin (Ig) G antibodies specific for components of the enterocyte brush border that initiate a cell-mediated immune dysregulation and damage of the epithelial barrier. Similarly, children with a mutation of the transcription factor FoxP3 (scurfin) which modulates CD4+ T cell proliferation have a propensity for having antienterocyte antibodies resulting in immune dysregulation polyendocrinopathy, enteropathy syndrome. Moreover, the state of inflammation that waxes and wanes in the intestine of patients with inflammatory bowel disease (IBD), ulcerative colitis (56.5), or Crohn disease (56.6) leads to a fluctuating degree of diarrhea.
Role of regulatory T cells in mucosal immunity
Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald in Principles of Mucosal Immunology, 2020
Those early studies culminated in the identification of the transcription factor Foxp3 as a specific molecular marker for Treg enriched within CD25+ and/or CD45RBlowCD4+ T-cell subsets. Foxp3 was originally identified as the gene mutated in the fatal autoimmune, inflammatory, and allergic disease that develops in patients with the immune dysregulation, polyendocrinopathy, and enteropathy (IPEX) syndrome, and in a naturally arising mutant mouse strain, the scurfy mice. Foxp3 not only serves as a specific marker for Treg cells but also functions as a “master” transcription factor for their development and function. Ectopic expression of Foxp3 confers a Treg phenotype and function on conventional T cells, whereas loss-of-function Foxp3 mutations lead to defective development of functional Treg cells. The deficiency of functional Treg cells caused by Foxp3 mutations or inducible ablation of Foxp3+ T cells in genetically modified mice results in the development of severe inflammation in multiple organs including the mucosal tissues. Notably, autoimmune enteropathy, which manifests as watery diarrhea, villous atrophy, and extensive lymphocytic infiltrates of the bowel mucosa, is one of the most common symptoms in IPEX patients. Moreover, in mice, CD4+CD45RBhigh T-cell–mediated colitis can be inhibited by cotransfer of Foxp3+ Treg cells or Foxp3-transduced CD4+CD45RBhigh T cells. These findings have led to the notion that Foxp3+ Treg cells are central to the maintenance of tolerance and homeostasis in the systemic and mucosal immune systems.
Immunomodulating Agents in Gastrointestinal Disease
Thomas F. Kresina in Immune Modulating Agents, 2020
Autoimmune Enteropathy Autoimmune entropathy (AE) is an idiopathic intestinal inflammatory disease occurring in children, characterized by secretory diarrhea, villous atrophy, and evidence of other systemic autoimmune disease (including glomerulonephritis, diabetes, and adrenal insufficiency). Immune abnormalities identified in AE include T lymphocyte activation and antienterocyte antibodies. Whereas corticosteroids and azathioprine have limited efficacy in this disorder, CSA has improved villous histological characteristics, nutrient absorption, and growth [154,155].
The high mortality of patients with common variable immunodeficiency and small bowel villous atrophy
Published in Scandinavian Journal of Gastroenterology, 2019
Maria Vittoria Pensieri, Federica Pulvirenti, Annalisa Schiepatti, Stiliano Maimaris, Salvatore Lattanzio, Isabella Quinti, Catherine Klersy, Gino Roberto Corazza, Federico Biagi
For enrolment in this study, the diagnosis of CVID was based on the presence of a deficiency of at least two immunoglobulin classes with values at least two standard deviations lower than the reference values and on the exclusion of other causes of secondary hypogammaglobulinemia [8,9]. Diagnosis of atrophy of the duodenal mucosa was based on at least four well-oriented endoscopic duodenal biopsies showing frank villous atrophy, crypt hypertrophy and an increased intra-epithelial lymphocyte count. Coeliac disease and other causes of atrophy of the duodenal mucosa such as autoimmune enteropathy and olmesartan enteropathy were excluded on the basis of the patient’s history, the absence of specific antibodies (endomysial and enterocyte antibodies) and HLA genomic typing [10–13]. Flow cytometric analysis of intraepithelial lymphocytes excluded refractory coeliac disease type 2. Finally, infection by Giardia Lamblia was excluded with faecal parasitological examination.
Two cases of monomorphic epitheliotropic intestinal T-cell lymphoma associated with coeliac disease
Published in Scandinavian Journal of Gastroenterology, 2019
Marco Vincenzo Lenti, Federico Biagi, Marco Lucioni, Antonio Di Sabatino, Marco Paulli, Gino Roberto Corazza
Monomorphic epitheliotropic intestinal T-cell lymphoma (MEITL), is an aggressive form of extranodal lymphoma arising from intraepithelial T-lymphocytes [1]. Unlike enteropathy-associated T-cell lymphoma (EATL) [2], MEITL is characterised by an epitheliotropic infiltration of monomorphic, CD8/CD56 positive, small- to medium-sized T-cells, in the absence of inflammation [1]. Although previous studies presumed, on a clinical basis only, an association with coeliac disease (CD) [3,4], this has been officially denied by the latest World Health Organisation classification of lymphoid neoplasms, and MEITL is now considered a sporadic form of lymphoma [1]. However, that of enteropathy-associated lymphomas is a grey area with blurred boundaries: EATL, known to be associated with CD, has been described in two patients with autoimmune enteropathy [5,6], and a case of MEITL concomitant to ulcerative colitis has been recently reported [7].
Diagnostic and therapeutic challenge of unclassifiable enteropathies with increased intraepithelial CD103+ CD8+ T lymphocytes: a single center case series
Published in Scandinavian Journal of Gastroenterology, 2021
Christina Hartl, Jürgen Finke, Peter Hasselblatt, Wolfgang Kreisel, Annette Schmitt-Graeff
Chronic enteropathy associated with intraepithelial lymphocytosis (IEL) and villous atrophy (VA) of the duodenal mucosa and persistent diarrhea may result from many pathologies with celiac disease (CD) being the most prevalent underlying cause. In the absence of CD auto-antibodies and after exclusion of the clinically challenging diagnosis of seronegative CD, e.g., by exposure to gluten-free diet and HLA testing [1], a plethora of differential diagnoses have to be considered in patients with VA and IEL. Gastrointestinal pathology frequently occurs in primary immunodeficiency disorders (PID) such as the IPEX (immune dysregulation polyendocrinopathy enteropathy X-linked) or APECED syndromes (autoimmune polyendocrinopathy candidiasis ectodermal dystrophy) and CVID (common variable immunodeficiency) [2,3]. Potential causes also include medications such as olmesartan or immune checkpoint inhibitors, Crohn’s disease, infections (in particular, HIV infection, mycobacteriosis, giardiasis, Whipple’s disease), food intolerances or autoimmune enteropathy (AIE) [4,5]. The diagnostic work-up should therefore include blood tests for assessing malnutrition, ruling out seropositive or seronegative CD and testing for anti-enterocyte antibodies. In addition, microbiological examinations and endoscopies with duodenal biopsies are mandatory during diagnostic work-up to rule out infections, inflammatory bowel disease or lymphoproliferative disorders (LPD) [6,7].