Introduction
The gastrointestinal (GI) tract is a rich lymphoid organ by virtue of the numerous immune cells in the lamina propria and the abundant lymphoid follicles and Peyer patches distributed throughout, collectively referred to as mucosa-associated lymphoid tissue (MALT). Complex interactions between enterocytes, antigen-presenting cells, lymphocytes, and other elements of the immune system occur in this specialized microenvironment.
The GI mucosal immune system has an important role in homeostasis. It is responsible for the regulation of localized immune responses to the numerous antigenic substances that come in contact with the mucosa. To do so successfully, it must mount an immune response against pathogenic antigens (e.g., infectious microorganisms) while actively suppressing the immune response to nonpathogenic antigens (e.g., symbiotic microorganisms, food). Dysregulation of the molecular and cellular mechanisms underlying these processes is associated with the development of disease.
Autoimmune disorders of the GI tract are commonly associated with extraintestinal manifestations, or, rarely, they manifest as primary gutcentric autoimmune disorders. Autoimmune disorders of the GI tract are rare if common conditions—such as idiopathic inflammatory bowel disease and gluten-sensitive enteropathy, which are related to autoimmune mechanisms—are excluded.
Several well-established autoimmune pathologies, including gluten-sensitive enteropathy, autoimmune gastritis, and idiopathic inflammatory bowel disease, are discussed in other sections of this book. In this chapter, we focus on two conditions that have been extensively studied during the past few years: autoimmune enteropathy in its various forms and immunoglobulin G4 (IgG4)–related disease.
Autoimmune Enteropathy
Overview of Autoimmune Enteropathy
Autoimmune enteropathy (AIE) is an uncommon disorder with myriad clinical manifestations. It results from immune-mediated injury to the tubular gut and responds to various degrees to immunosuppressive therapy. Although characteristic histopathologic damage can be recognized, the diagnosis is best made in the context of a broad clinicopathologic correlation.
AIE arises in the setting of abnormal gut humoral and immune regulation, as evidenced by aberrant expression of human leukocyte antigen (HLA) class II molecules by enterocytes, circulating autoantibodies to intestinal cells, and T-cell overactivity (in syndromic forms of the disease). However, widespread consensus regarding the pathogenic and diagnostic significance of autoantibodies is lacking.
AIE was first described in 1982 by Unsworth and colleagues, who reported the case of a 15-month-old child with diarrhea, flattening of the small intestinal mucosa, and a circulating autoantibody to gut epithelium. After recognizing six additional pediatric cases, Unsworth and Walker-Smith proposed a four-point definition of AIE: protracted diarrhea and villous atrophy; no response to a gluten-free diet or total parenteral nutrition; circulating autoantibodies to gut epithelium or associated autoimmune diseases (suggesting a predisposition to autoimmunity); and exclusion of severe immunodeficiency. In 1986, Mirakian reported a series of 14 children with protracted diarrhea and evidence of autoimmunity, a condition that was described as an autoimmune variant of idiopathic protracted diarrhea of infancy.
AIE occurs in adults, but it more commonly affects infants during the first 6 months of life. The estimated incidence is less than 1 case per 100,000 infants, and it affects both sexes equally. Although traditionally considered a disease of the small intestine, the entire gut, pancreas, and liver may be affected.
Syndromic Associations
Two syndromic forms of AIE are recognized: immune dysregulation, polyendocrinopathy, enteropathy, and X-linked (IPEX) syndrome and the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome (APECED), also known as autoimmune polyglandular syndrome type 1 (APS-1). Both are monogenetic disorders caused by loss-of-function mutations in a gene regulating normal T-cell development and function. The defective gene results in T-cell overactivity.
IPEX Syndrome
IPEX is an X-linked recessive syndrome characterized by polyendocrinopathy, various autoimmune conditions, and severe, prolonged diarrhea. IPEX is caused by germline loss-of-function mutations in the forkhead box P3 gene ( FOXP3, located at Xp11.23-q13.3). FOXP3 is required for normal development and function of regulatory T cells, a small subset of CD4+ helper T cells of critical importance in the regulation of self-tolerance and immune homeostasis. Loss of FOXP3 activity leads to immune overactivity in response to antigen stimulation and cellular injury through CD4+ effector T cells.
IPEX syndrome classically manifests in early infancy with AIE, insulin-dependent diabetes mellitus, and cutaneous manifestations. Dermatologic involvement may manifest as eczema, atopic dermatitis, psoriasis, alopecia, and pemphigoid nodularis. IPEX syndrome may have a wide array of other manifestations of autoimmunity ( Box 11.1 ). Patients also may have lymphadenopathy, splenomegaly, and thymic involution. The prognosis is usually grim, with most patients dying within the first year of life. However, milder cases with onset later in life (≤24 years of age) have been described.
Thrombocytopenia
Neutropenia
Hypothyroidism
Thyroiditis
Type I diabetes
Lymphadenopathy
Coombs-positive hemolytic anemia
Atopic dermatitis
Pemphigoid nodularis
Arthritis
Myositis
Tubulointerstitial nephritis
Membranous glomerulonephritis
APECED Syndrome
APECED (i.e., APS-1) syndrome is a rare condition that is more prevalent among Finns, Sardinians, and Iranian Jews. This autosomal recessive disease is primarily characterized by the triad of mucocutaneous candidiasis, autoimmune hypoparathyroidism, and Addison disease, although a wide spectrum of autoimmune abnormalities may be seen.
The syndrome is caused by loss-of-function mutations in the autoimmune regulator gene ( AIRE , located at 21q22.3). AIRE is a transcriptional factor that is expressed primarily in thymic medullary epithelial cells and regulates central immune tolerance by directing the expression of peripheral tissue–specific antigens that are presented to thymocytes. When AIRE is lost, thymocytes exhibit abnormal hyperresponsiveness and increased proliferation in response to antigen stimulation, resulting in circulating self-reactive T cells.
Affected patients are commonly diagnosed soon after birth with mucocutaneous candidiasis affecting the tongue, esophagus, and nails. With time, chronic candidiasis predisposes to oral and esophageal squamous cell carcinoma. Autoimmune hypoparathyroidism and adrenocortical failure (Addison disease) typically develop in the first decade of the patient’s life. Enteropathy is diagnosed in approximately 20% of patients. A wide array of other autoimmune diseases may develop ( Box 11.2 ). Various ectodermal abnormalities, including keratoconjunctivitis, vitiligo, alopecia, dental enamel hypoplasia, pitted nail dystrophy, and tympanic membrane calcification, may also develop. Splenic atrophy or asplenia may occur. Unlike IPEX syndrome, the onset of APECED syndrome is less fulminant, and the prognosis is significantly better.
Candidal infection
Addison disease
Keratoconjunctivitis
Vitiligo
Alopecia
Tubulointerstitial nephritis
Hemolytic anemia
Asplenia
Type 1 diabetes
Autoimmune hepatitis
Gonadal dysfunction
Hypopituitarism
Hypoparathyroidism
Autoimmune thyroiditis
Autoimmune gastritis
Clinical Features
The clinical hallmark of AIE is refractory diarrhea, which may be accompanied by malabsorption and weight loss. In infants, low body weight and slow growth may be seen. The disease affects men and women within a broad age range. In the largest series of adult AIE reported, most patients were white, both sexes were affected equally, and the median age at diagnosis was 55 years. A history of autoimmune disease was obtained for 87% of patients. Associated conditions include hypothyroidism, rheumatoid arthritis, myasthenia gravis, idiopathic thrombocytopenic purpura, autoimmune gastritis, and polyneuropathy. Three cases have been associated with thymoma. A delay (median, 1.5 years) in diagnosis is common because patients frequently are misdiagnosed (often with celiac disease).
Because of the association of AIE with other autoimmune diseases, serologic testing for autoantibodies is commonly positive. Autoantibody testing was positive for as many as 67% of patients in one series. The antibodies, which are directed against a variety of antigens in patients’ sera, include ANA, anti-LKM, anti-SMA, anti–parietal cell, and many others ( Box 11.3 ). The relevance of gut epithelial cell antibodies is discussed later.
Antinuclear
Anti–liver-kidney microsomal
Anti–smooth muscle
Anti–gastric parietal cell
Anti–pancreatic islet cell
Anti-insulin
Anti-endoplasmic reticulum
Antireticulin
Antigliadin
Anti-adrenal cell
Antithyroglobulin
Anti–55-kDa protein in the jejunum
Antivillin
Anti-AIE-75
Other laboratory findings include normal B and T lymphocyte counts and complement levels. Some patients may have immunoglobulin A (IgA) deficiency, but a broader immunoglobulin deficiency, especially if the albumin level is relatively normal, suggests common variable immunodeficiency (CVID), which can cause an enteropathy similar to celiac disease or AIE.
The small intestinal endoscopic features, which include duodenal scalloping, erythema, erosions/ulcerations, fissuring, and a mosaic pattern, are nonspecific. Similarly, there may be endoscopic abnormalities of the colonic mucosa, including loss of vascular pattern, mucosal friability, contact bleeding, erythema, and ulceration. Severe macroscopic colitis (including pancolitis) has been reported in IPEX syndrome patients. There may be signs and symptoms of extraintestinal involvement. Abdominal computed tomography (CT) may reveal mesenteric lymphadenopathy.
Gut Epithelial Cell Antibodies
Gut epithelial cell antibodies (GECAs) appear to have clinical significance. Circulating GECAs, which include anti–goblet cell and anti-enterocyte antibodies, are a characteristic finding, but their meaning is controversial. In their original series, Unsworth and Walker-Smith reported anti-enterocyte antibodies in 5 of 6 patients, and anti-enterocyte antibodies were detected in all 14 patients reported in two overlapping British series.
Detection of GECAs has been proposed as a diagnostic criterion by Akram and associates, who detected GECAs in 13 of 14 adult AIE patients. In a series of IPEX syndrome patients, autoantibodies were detected in all 12 patients. Anti-enterocyte antibodies in a brush-border pattern were the most common. A range of autoantibody types has been documented in several series, including anti–goblet cell immunoglobulin G (IgG), anti-enterocyte IgG, anti-enterocyte immunoglobulin M (IgM), and anti-enterocyte IgA.
Arguing in favor of a diagnostic role for GECA testing are several studies that have shown an absence of GECAs in non-AIE patients, including patients with celiac disease, autoimmune hepatitis, chronic hepatitis C virus (HCV) infection, insulin-dependent and non–insulin-dependent diabetes, and inflammatory bowel disease (IBD), as well as healthy controls. However, there are significant concerns regarding the sensitivity and specificity of these antibodies. Patients with clinical and pathologic features otherwise characteristic of AIE may lack detectable autoantibodies. The presence of GECA in non-AIE patients has been documented, including in IBD patients, patients with cow’s milk insensitivity, human immunodeficiency virus (HIV)–infected patients, and one patient with protein-losing enteropathy.
A retrospective study of serum samples of 95 non-AIE patients undergoing testing for antiendomysial antibody revealed positive anti–goblet cell antibodies in 28% of patients. The antibodies were detected in a variety of clinical settings, including 10% of untreated celiac disease patients, 29% of treated celiac disease patients, and 29% of patients not affected by celiac disease (i.e., negative for antiendomysial antibody). These results call into question the specificity of anti–goblet cell antibodies and its potential use as a diagnostic aid, although anti-enterocyte antibodies were not detected in any patients. In another study, autoantibodies to colonic goblet cells were detected in sera from 28 of 109 patients who did not have AIE but had one of several GI diseases (e.g., IBD, protein-losing enteropathy, irritable bowel syndrome) or were healthy. Autoantibodies to small intestinal goblet cells were absent in the same cohort of patients.
The utility of autoantibody testing in very young infants has been questioned. IgG levels in the first 3 months of life may largely reflect maternal IgG that has crossed the placenta rather than IgG produced by the infant. Adding to the skepticism regarding the significance of GECAs, there is a delay between onset of symptoms and detection of autoantibodies in some AIE patients, and no consistent correlation between disease severity and autoantibody titers has been found.
Pathogenesis
Although the precise molecular mechanisms underlying AIE remain unknown, several pieces of evidence point to an alteration of gut immunity. The intestinal mucosa is a site of complex interactions between the immune system and the environment, including dietary antigens. Expression of HLA class II molecules usually is restricted to cells of the immune system, in which they mediate antigen presentation and induction of the immune response. Mature enterocytes at the tips of small intestinal villi are an exception because they constitutively express these molecules under normal physiologic conditions and present antigens to autologous CD4+ helper T cells. Antigen presentation by enterocytes leads to suppression of T-cell activity, which presumably allows for tolerance to dietary antigens encountered by small intestinal epithelium, a phenomenon referred to as oral tolerance .
In contrast, enterocytes of AIE patients exhibit aberrant expression of HLA class II molecules, with inappropriate expression of HLA-DR in crypt enterocytes. It has been hypothesized that aberrant HLA class II expression by crypt enterocytes induces CD4+ T-cell overactivity and subsequent T-cell–mediated injury of the intestinal epithelium through direct cytotoxicity or cytokine secretion. Increased numbers of CD25+ T cells have been documented in small intestinal biopsies of AIE patients, and in at least one case, CD25+ T cells regressed with therapy. Enterocyte injury by overactive T cells is emerging as a possible unifying mechanism to explain AIE.
Pathologic Features
Small Intestine
The pathologic features of AIE vary, but some patterns of injury may be considered characteristic, particularly in the duodenum, ileum, and jejunum. The most common pattern of injury consists of a predominantly lymphoplasmacytic inflammatory infiltrate with villous blunting and crypt hyperplasia, which may be described in broad terms as an active chronic enteritis ( Fig. 11.1 ). Neutrophilic inflammation may be prominent and sometimes occur with crypt abscesses. Surface erosions and gastric foveolar metaplasia may be observed. Eosinophils are typically seen but are not prominent.
Increased apoptosis in crypt epithelium is common, justifying the comparison with acute graft-versus-host disease (GVHD). Apoptosis may be a striking feature in terms of the number of cells affected, and partial or total glandular destruction may be seen.
Other nonspecific reactive or regenerative epithelial changes include mucin depletion, crypt architectural irregularity, enlarged nuclei without inclusions, and increased mitotic activity. The number of intraepithelial lymphocytes may be increased in surface epithelium, but the cells should not be a prominent feature, which distinguishes AIE from celiac disease.
In most patients, goblet cells and Paneth cells are substantially decreased in numbers or absent. In some cases, the absence of goblet cells on biopsy coincides with the detection of anti–goblet cell antibodies. The absence of endocrine cells has been reported. Gastric metaplasia has been observed. An absence of plasma cells in the lamina propria may be an indication of concurrent CVID.
Two attempts at objectively codifying the morphologic features of AIE have been put forward. Akram and co-workers favor the following histopathologic diagnostic criteria for small bowel biopsies: partial or complete villous blunting, deep crypt lymphocytosis, increased crypt apoptotic bodies, and minimal intraepithelial lymphocytosis. Patey-Mariaud de Serre and colleagues summarized this pattern and additionally emphasized the moderate inflammation of the lamina propria, the presence of crypt abscesses, and the loss of goblet cells. In our experience, the features most helpful in suggesting a diagnosis of AIE are villous blunting, lamina propria expansion by mixed but predominantly mononuclear inflammation, neutrophilic cryptitis with crypt abscesses, and a comparatively minor increase in intraepithelial lymphocytes. Although it can be a helpful feature, increased apoptosis is not consistently observed. The absence of goblet cells or Paneth cells may be considered practically diagnostic, but we would not include it as a diagnostic criterion because it is observed only in a few cases.
Other Sites in the Tubular Gut
Colonic involvement has been reported in a relatively large number of cases, and affects most patients with AIE and IPEX syndrome. The histologic features include lymphoplasmacytic expansion of the lamina propria, neutrophilic cryptitis with or without crypt abscesses, and increased apoptosis in crypt epithelium ( Fig. 11.2 ). Increased apoptosis sometimes may be a striking and predominant feature, reminiscent of acute GVHD. Absence of goblet cells in the colon and appendix may be seen in patients with anti–goblet cell antibodies.
Colonic biopsies may exhibit features that are not immediately identifiable as AIE, such as severe colitis with glandular destruction or gastric metaplasia with glandular atrophy. A lymphocyte-predominant pattern of inflammation essentially indistinguishable from lymphocytic colitis may be seen. A case with thickening of the subepithelial collagen table in the duodenal mucosa and entire colorectal mucosa, which is essentially indistinguishable from collagenous colitis, has been reported. In our experience, colonic involvement of AIE may be reminiscent of IBD, with crypt architectural irregularities, multinucleated epithelioid giant cells, and Paneth cell metaplasia. However, the full-blown histologic features of active chronic colitis of the IBD type are not seen.
Involvement of the stomach may occur in the form of a nonspecific, moderate to severe gastritis with mixed inflammation and glandular destruction, although autoimmune atrophic gastritis has also been reported ( Fig. 11.3 ). Active gastritis with glandular destruction has been reported. Other patients exhibit a peculiar form of atrophic gastritis that resembles autoimmune atrophic gastritis but involves the entire stomach and lacks neuroendocrine cell hyperplasia. In our experience, the stomach may also exhibit an acute GVHD-like appearance, with near-normal mucosa with increased apoptosis in glandular epithelium, with or without glandular atrophy. The esophagus may show inflammatory infiltrates, and severe ulcerative esophagitis has been reported in one case. We have seen patients with a mild neutrophilic esophagitis and occasional apoptotic cells.
Liver and Pancreas
Chronic sclerosing cholangitis has been reported in patients with elevated transaminase and alkaline phosphatase levels and liver biopsies showing portal mononuclear inflammation and fibrosis. Hepatitis with fibrosis has been described in several cases.
Involvement of the exocrine pancreas may manifest clinically as elevation of amylase and lipase levels or as evidence of pancreatic exocrine insufficiency. Histologic examination shows various degrees of lymphocytic inflammation. The inflammation may be ductcentric and associated with squamous metaplasia of pancreatic ducts. In one case, postmortem examination revealed marked atrophy of the exocrine pancreas with diminished content of zymogen granules. In patients with diabetes, islets of Langerhans may be absent.
Differential Diagnosis
The diagnosis of AIE requires exclusion of celiac disease, which may manifest in a similar manner. The distinction may be difficult in the subset of AIE patients with histologic features mimicking celiac disease ( Fig. 11.4 ) and with positive celiac serology, which may be found for 33% of AIE patients. A particularly problematic aspect is that these patients may meet the diagnostic criteria for refractory sprue by virtue of positive celiac serology but do not respond to a gluten-free diet. In this setting, awareness of additional clinical, laboratory, and pathologic features of AIE may be essential to arrive at the correct diagnosis, despite the problematic aspects of GECA testing. In some cases, exclusion of celiac disease may necessitate the trial of a gluten-free diet or exclusion of HLA DQ2 and DQ8 phenotypes. Significant neutrophilic inflammation on small intestinal biopsies, particularly in the setting of crypt abscesses, may help to suggest a diagnosis of AIE rather than celiac disease. Although neutrophilic inflammation may be seen in celiac disease, crypt abscesses are rare, occurring in less than 1% of cases.
