Primary Disorders of Immune Deficiency
Many of the primary disorders of immune deficiency ( Table 5.1 ) are associated with gastrointestinal (GI) lesions. Manifestations of immune deficiency in the GI tract may be broadly divided into three categories: (1) increased susceptibility to infection, (2) idiopathic chronic inflammatory conditions, and (3) increased risk of neoplasia. Although many GI lesions are infectious ( Table 5.2 ), chronic inflammatory conditions resembling celiac disease and inflammatory bowel disease (IBD) ( Table 5.3 ) are seen in many patients with antibody deficiencies and are probably the result of the inability of dysfunctional mononuclear cells to suppress unwanted immune responses. All patients with primary immune deficiencies are at increased risk of neoplasia ( Table 5.4 ), most commonly non-Hodgkin lymphoma (NHL), and the GI tract is often the primary site of involvement. In addition to the risk of lymphoma, some of the primary immune deficiencies are associated with increased risk of gastric adenocarcinoma and colorectal carcinoma.
| Disease | Proposed Cause |
|---|---|
| Selective IgA deficiency | Impaired IgA synthesis; molecular defect unknown in most cases; mutation in TNFRSF13B in ~5% |
| Common variable immunodeficiency | Impaired B cell maturation; molecular defect unknown in most cases; mutation in TNFRSF13B in ~10-15% |
| X-linked agammaglobulinemia | Mutation in BTK results in absence of BTK in B cells |
| Hyper-IgM syndrome | Mutation in CD40L , leading to absence of CD40 ligand on T cells |
| Hyper-IgE syndrome | Mutation in STAT3 in autosomal dominant form; mutation in DOCK8 in autosomal recessive form. |
| Severe combined immunodeficiency | Multiple defects, most commonly in the common γ chain; others include adenosine deaminase deficiency, purine nucleoside deficiency, and T-cell receptor deficiencies |
| Omenn syndrome | Hypomorphic missense mutation in RAG1/2, IL7RA,RMRP, ADA, DNA ligase IV, Artemis, γc |
| Immune dysregulation, polyendocrinopathy, enteropathy, X-linked | Mutation in FOXP3 |
| DiGeorge syndrome | Thymic hypoplasia; microdeletion in 22q11.2 |
| Chronic mucocutaneous candidiasis | Heterogeneous disorder; mutation in AIRE gene in some; mutation in STAT1 in autosomal dominant form |
| Wiskott-Aldrich syndrome | Mutation in WASP gene involved in cell trafficking and motility |
| Chronic granulomatous disease | Mutation in gene for component of NADPH oxidase; CYBB mutation in X-linked form; mutation in CYBA , NCF1 , NCF2 , or NCF4 in autosomal recessive forms |
| Disease | Gastrointestinal Infections |
|---|---|
| Selective IgA deficiency | Giardia intestinalis ; strongyloidiasis |
| Common variable immunodeficiency | Giardia intestinalis ; Cryptosporidium ; CMV |
| X-linked agammaglobulinemia | Giardia intestinalis ; Cryptosporidium Salmonella , Campylobacter Rotavirus, coxsackievirus, poliovirus |
| Hyper-IgM syndrome | Giardia intestinalis , Cryptosporidium , Entamoeba histolytica , Salmonella , Histoplasma capsulatum |
| Severe combined immunodeficiency | Candida ; Salmonella and other bacterial pathogens; CMV, rotavirus, Epstein-Barr virus |
| DiGeorge syndrome | Candida |
| Chronic mucocutaneous candidiasis | Candida ; Histoplasma capsulatum |
| Disease | Manifestation |
|---|---|
| IgA deficiency |
|
| Common variable immunodeficiency |
|
| X-linked agammaglobulinemia |
|
| Hyper-IgM syndrome |
|
| Severe combined immunodeficiency |
|
| Omenn syndrome |
|
| Chronic mucocutaneous candidiasis |
|
| Immune dysregulation, polyendocrinopathy, enteropathy, X-linked |
|
| Wiskott-Aldrich syndrome |
|
| Chronic granulomatous disease |
|
| Disease | Gastrointestinal Malignancy |
|---|---|
| Immunoglobulin A deficiency |
|
| Common variable immunodeficiency |
|
| X-linked agammaglobulinemia |
|
| Hyperimmunoglobulin M syndrome |
|
| Wiskott-Aldrich syndrome |
|
| Ataxia-telangectasia |
|
Humoral Immunodeficiencies
Selective Immunoglobulin A Deficiency
Defined as a serum immunoglobulin A (IgA) concentration of less than 50 µg/mL, selective IgA deficiency is the most common primary immunodeficiency ; it occurs in 1 of every 600 people of Northern European ancestry. The disorder is 20 times more common in white Americans than in African Americans. Defects in antibody production in patients with IgA deficiency represent a continuum with those seen in common variable immunodeficiency (CVID), and 20% to 30% of IgA-deficient patients also have deficits in IgG subclasses. Mutations in the gene TNFRSF13B have been identified and associated with IgA deficiency, although the mutational defect remains unknown in many cases. This gene encodes a member of the tumor necrosis factor-receptor (TNFR) superfamily, the transmembrane activator and calcium-modulator and cyclophilin-ligand interactor (TACI), which mediates isotype switching in B lymphocytes (see later discussion).
Clinical manifestations of IgA deficiency range from no symptoms to recurrent infections (typically involving mucosal surfaces), autoimmune disorders, allergic diseases, and malignancy, but are typically milder than those seen with CVID. Recurrent upper and lower respiratory tract infections are common in both disorders. Similarly, GI manifestations of IgA deficiency are the same as those associated with CVID. Infections are less common than might be expected, possibly because of compensation for lack of mucosal IgA by transport of IgM across the mucosa into the gut lumen, but include acute diarrheal illnesses caused by bacterial enterocolitis and chronic diarrhea caused by persistent Giardia intestinalis infection. Chronic strongyloidiasis has also been reported.
Susceptibility to autoimmune disorders such as insulin-dependent diabetes mellitus and celiac disease may be inherited together with IgA deficiency; all three conditions are linked to particular major histocompatibility haplotypes and probably represent genetically linked susceptibilities in certain populations. The prevalence of celiac disease, the most common noninfectious GI complication of IgA deficiency, is 7.7% in children with IgA deficiency, compared with 1 : 500 in the general population, and a novel shared risk locus, CTLA4/ICOS , has been described linking CVID, IgA deficiency, and celiac disease. Antigliadin IgA and endomysial IgA antibodies cannot be used as screening tools in the IgA-deficient population, but the morphology of celiac disease occurring in the setting of IgA deficiency is similar to that seen in immunocompetent patients. In addition, a sprue-like illness characterized by chronic diarrhea with villous atrophy that does not respond to a gluten-free diet may be seen in IgA deficiency, as in CVID. Pernicious anemia complicating chronic atrophic autoimmune gastritis is seen more commonly in IgA deficiency than in CVID, and nodular lymphoid hyperplasia (NLH) in the small bowel is only rarely reported. As with other B cell disorders, the incidence of Crohn disease and gastric adenocarcinoma appears to be increased in IgA deficiency.
X-Linked Agammaglobulinemia
The typical patient with X-linked agammaglobulinemia (XLAG) is susceptible to bacterial infections because of the absence of all circulating immunoglobulin subtypes; mature circulating B cells are low to absent. This disorder is characterized by an inability to make antibodies to virtually all antigens. The molecular basis of most cases of XLAG was elucidated in 1993, when a defect in the BTK (Bruton tyrosine kinase) gene was found ; subsequent studies have identified numerous deleterious mutations. The BTK gene encodes a nonreceptor tyrosine kinase expressed in B-cell and myelomonocytic cell lineages but not in T cells. BTK functions in intracellular signaling pathways essential for pre–B-cell maturation, but the exact mechanism by which the defects in BTK lead to B-cell maturation arrest remains unclear. XLAG may have more phenotypic diversity than has previously been recognized, because adults with mild or no clinical symptoms but with deficiencies in BTK have been described. Age at onset, disease severity, and genotype are roughly associated with mutation severity (as classified based on structural and functional consequences) in some but not all cohorts.
GI manifestations are less common in XLAG than in CVID, perhaps because of preserved T-cell function in XLAG, although persistent or recurrent diarrhea is reported in 23% to 29% of patients. Age at onset of GI symptoms is younger than in CVID patients, and autoimmune diseases are less common. Small intestinal and colonic mucosal biopsies in the XLAG patient without GI symptoms are notable only for the lack of plasma cells in the lamina propria, giving the lamina propria an empty appearance. Mucosal architecture is unremarkable, and villous blunting is not seen. Approximately one third of patients are seen initially with GI complaints, most commonly diarrhea or perirectal abscess, and 10% in one study had chronic GI symptoms, either from persistent infection with G. intestinalis , Salmonella , or enteropathic Escherichia coli or secondary to bacterial overgrowth. No cause for chronic diarrhea was found in half of these patients. Chronic infection with rotavirus is also reported in this population. Because biopsies are not routinely performed for this disorder, few descriptions of histopathologic findings are available, but moderate blunting of duodenal villi with crypt hyperplasia and an increase in lamina propria inflammatory cells are reported in acute infections. Degenerative changes may be noted in epithelial cells on the surface of the villus with no increase in crypt apoptosis ; crypt cells are spared, and the crypt zone undergoes a compensatory hyperplasia. The histologic changes of acute rotavirus infection are reported to resemble celiac disease but are patchier and quickly revert to normal with resolution of infection.
In addition to GI infections, a chronic ulcerating inflammatory condition, clinically similar to Crohn disease, that is manifested by recurrent diarrhea, malabsorption, ulcers, and small bowel strictures ( Fig. 5.1 ). A prominent lymphocytic inflammatory infiltrate without plasma cells or granulomas is seen in the affected areas. In one case, enterovirus was found by polymerase chain reaction in inflamed ileum and adjacent mesenteric lymph nodes, suggesting that in some XLAG patients infection may be responsible for these lesions.
Patients with XLAG are at increased risk for malignancy, even in childhood. The most common malignancy in this group is NHL, which often involves the GI tract, and many of these cases occur in children younger than 10 years of age. There are rare reported cases of gastric adenocarcinoma and colorectal adenocarcinoma. The increased incidence of colorectal carcinoma for patients with XLAG was calculated as 30-fold in one study, although other registry studies have reported few or no colorectal cancers in their patients with XLAG. In most of the reported cases, XLAG patients with colorectal carcinoma are young adults in their 20s who are seen with advanced-stage tumors. In one reported case, multiple colorectal adenomas in addition to carcinoma were found.
X-Linked Hyperimmunoglobuin M Syndrome
X-linked hyperimmunoglobulin M syndrome (XHIM) results from a mutation in the gene for CD40 ligand, which leads to loss of isotype switching. T cells from patients with this disorder lack the CD40 ligand and therefore do not interact with CD40 on the B-cell surface, an event necessary for immunoglobulin class switching. These patients have very low levels of IgG and IgA and normal or elevated levels of IgM. They are susceptible to pyogenic infections similar to those encountered in XLAG, and in addition are susceptible to Pneumocystis carinii pneumonia. A variety of intracellular pathogens such as mycobacterial species, fungi, and viruses (e.g., CMV, adenovirus) are implicated in causing disease in these patients. The most common site of infection is the upper or lower respiratory tract (approximately 50% and 80% of cases, respectively). Disseminated infection and esophageal infection with Histoplasma capsulatum are also reported in XHIM.
Diarrhea occurs in one third to one half of patients and follows a chronic course in most. Chronic watery diarrhea may be caused by Cryptosporidium infection; G. intestinalis , Salmonella , and Entamoeba histolytica have also been implicated, although in most patients no pathogen is identified. NLH involving the GI tract is reported in approximately 5% of patients. Lymphoid hyperplasia may also result in hepatosplenomegaly, lymphadenopathy, and enlargement of the tonsils. IBD was reported in two patients with XHIM and chronic diarrhea; clinical details were not provided. Sclerosing cholangitis is a common and serious complication (affecting about 20% of European patients) and is often related to chronic infection with Cryptosporidium ; liver transplantation may be necessary. In one European series, three of five patients infected with hepatitis B developed hepatocellular carcinoma.
Patients with XHIM are prone to autoimmune hematologic diseases, including cyclic or chronic neutropenia, and oral and perianal ulcers are common during neutropenic episodes. Massive proliferation of IgM-producing plasma cells may involve the GI tract, liver, and gallbladder, usually in the second decade of life, and may prove fatal. High-grade neuroendocrine carcinoma of the colon has been reported in this disorder, and there is an increased incidence of liver and biliary tract tumors.
Hyperimmunoglobulin E Syndrome
Also known as Job syndrome, hyperimmunoglobulin E syndrome is a rare, multisystem disorder characterized by recurrent elevated serum IgE, eczema, and sinopulmonary infections. Three genetic etiologies have been identified: loss of function of DOCK8 in the autosomal recessive form of the disorder, mutations in STAT3 in the more common autosomal dominant form, and a single reported case of Tyk deficiency. In addition to findings related to the immune system, characteristic facial features and dental and skeletal abnormalities occur in the autosomal dominant form, and severe viral cutaneous infections are seen in the autosomal recessive form. Chronic diarrhea and disorders resembling IBD are not reported in hyper-IgE syndrome. GI manifestations of the disease appear limited to mucocutaneous candidiasis, tissue-invasive fungal infections with Cryptococcus (reported in the esophagus and colon ), and ileocecal histoplasmosis mimicking Crohn disease. Perforation of the colon, probably related to infection with staphylococcal species, has also been reported, as well as diverticulitis in a young patient. Patients with hyper-IgE syndrome do not appear to be at increased risk for primary GI malignancy.
Common Variable Immunodeficiency
Although CVID is not a common disorder, it is probably the most common symptomatic primary immunodeficiency. Clinical and immunologic features are heterogeneous, but most patients are seen with recurrent bacterial infections, usually involving the upper and lower respiratory tracts and leading to chronic lung disease and bronchiectasis. Patients may be seen with CVID at any age from infancy to late adult life, and males and females are equally affected. Autoimmune manifestations such as thyroid dysfunction, pernicious anemia, autoimmune hemolytic anemia, autoimmune thrombocytopenia, and rheumatoid arthritis are common, and granulomatous involvement of skin and visceral organs mimicking sarcoidosis may be seen in CVID. Chronic GI disorders resulting in malabsorption and weight loss occur in approximately 20% of patients with CVID.
CVID is characterized immunologically by hypogammaglobulinemia involving multiple antibody classes. T-cell abnormalities are common; below-normal proliferative responses to mitogens are found in 40% of patients, and 20% have a relative lack of CD4+ T cells. The common abnormality shared by IgA deficiency and CVID is failure of terminal maturation of B lymphocytes into plasma cells producing various Ig subtypes. A primary B-cell defect is favored in many patients, but in others defective antigen responsiveness in helper T cells may be the underlying basis for the disorder.
A genetic basis has long been suspected, based on the observation that familial inheritance of CVID occurs in 20% of cases and that CVID and IgA deficiency tend to occur in the same family; individual family members may gradually convert from one disorder to the other. In multiple-case families, CVID is often present in the parents and IgA deficiency in the offspring, consistent with the hypothesis that CVID may develop later in life as a more severe manifestation of a common defect involving immunoglobulin class switching. Studies of isotype switching led to the discovery that the gene TNFRSF13B , which encodes the member of the TNFR family, TACI, is mutated in approximately 10% to 15% of patients with CVID and 5% of patients with IgA deficiency. TACI has also been shown to induce apoptosis in B cells, and this may be the basis for the susceptibility of patients with TACI mutations to autoimmune and lymphoproliferative disorders. New gene defects in BAFFR ( TNFRSF13C ), CD81 , and CD20 (now called MS4A1 ) resulting in a CVID phenotype have been described in small numbers of patients, underscoring the genetic heterogeneity of this disorder, and genome-wide association studies have identified numerous candidate causative genes, as well as a strong association of CVID with the major histocompatibility region.
Patients with CVID are at particular risk for chronic inflammatory disorders and malignancies affecting the GI tract. The inflammatory disorders may represent a response to acute or chronic infection, but in some patients the GI lesions are probably a manifestation of autoimmunity and are associated with other disorders of autoimmunity. In one large clinical study of patients with CVID, 22% had one or more autoimmune diseases, most commonly idiopathic thrombocytopenia purpura (6%) and autoimmune hemolytic anemia (5%).
Infections in CVID
Chronic infection with G. intestinalis is a common problem in patients with CVID and may or may not cause clinical symptoms. In some cases, malabsorption, steatorrhea, and villous abnormalities can be reversed if Giardia is eradicated. Small bowel mucosal abnormalities in giardiasis include villous blunting, increased intraepithelial lymphocytes, and NLH. The trophozoite form of the organism can be identified on small bowel biopsy ( Fig. 5.2 ). The prevalence of Giardia infection in this population appears to be decreasing, but giardiasis remains a significant cause of chronic diarrhea in CVID.
Other GI infections are less common in CVID. Cryptosporidiosis is occasionally found. The prevalence of common bacterial intestinal infections (e.g., Salmonella, Campylobacter ) does not appear to be increased. Although prolonged antibiotic use is common in these patients, an increase in pseudomembranous colitis has not been reported. On occasion, viral and fungal organisms infect the GI tract in CVID patients, but such infections are less common in CVID than in acquired immunodeficiency syndrome (AIDS). Cytomegalovirus (CMV) infection involving the esophagus, stomach, jejunum, and ileocecal area and resulting in multiple ulcers and obstructing strictures has been reported in a patient with CVID.
Inflammatory Disorders and Malignancy in CVID
Stomach
In the stomach, a nonspecific increase in lamina propria lymphocytes is seen in some patients with CVID ( Fig. 5.3, A ); increased apoptosis of gastric epithelial cells is present in some cases (see Fig. 5.3, B ). In a study of gastric biopsies from 34 patients with CVID and dyspepsia, 41% of patients were infected with Helicobacter pylori . All H. pylori –positive patients and 20% of H. pylori –negative patients had chronic gastritis, and 50% of those infected with H. pylori had multifocal atrophic gastritis. Ten percent of H. pylori –negative patients had multifocal atrophic gastritis. Atrophic gastritis resembling autoimmune atrophic gastritis on clinical and morphologic grounds (see Fig. 5.3, C ) and resulting in pernicious anemia may occur in the absence of demonstrable anti–parietal cell antibodies in these patents. Atrophic gastritis may develop at a very young age in patients with CVID, and it has been reported in a 6-year-old who developed multifocal gastric adenocarcinoma at age 11.
Adults with CVID are also at increased risk for gastric adenocarcinoma. It has been estimated that patients with CVID have a 47-fold increase in gastric carcinoma compared with the general population of Great Britain, and gastric carcinoma ultimately develops in 5% to 10% of CVID patients, usually many years after the onset of hypogammaglobulinemia.
Small Bowel
In the small bowel, a sprue like lesion with villous blunting occurs in some patients with CVID and is associated with severe malabsorption, often requiring parenteral nutrition. Villous atrophy associated with CVID generally lacks the degree of crypt hyperplasia seen in celiac disease ( Fig. 5.4, A ), but may be indistinguishable on biopsy. In general, the lamina propria inflammatory infiltrate is not as prominent as in celiac disease, and enterocyte maturation is normal, with preservation of the brush border. Most CVID patients with this small bowel lesion do not respond to a gluten-free diet, although an elemental diet may be beneficial, and most respond to corticosteroids, at least initially. Plasma cells are absent or are found only in very small numbers in the lamina propria. Surface intraepithelial lymphocytes are often markedly increased (see Fig. 5.4, B ), even in the absence of villous atrophy. In some cases, an increase in apoptotic bodies is found in crypt epithelial cells (see Fig. 5.4, C ). Clinical autoimmune enteritis with loss of goblet cells has also been reported.
Granulomatous enteropathy has also been reported in patients with CVID and may be associated with protracted diarrhea unresponsive to antibiotic therapy. Poorly formed non-necrotizing granulomas are found in the lamina propria in multiple sites in the GI tract, including the stomach, small intestine, and colon ; the diarrhea usually resolves with intravenous immunoglobulin therapy.
NLH in the GI tract is characterized by multiple discrete hyperplastic lymphoid nodules in the lamina propria and submucosa of the small intestine ( Fig. 5.5 ), large intestine, or both, and is probably a result of chronic antigenic stimulation. The germinal centers of the follicles are composed of proliferating B cells with scattered tingible body macrophages; the mantle zones contain mature and immature B cells, and the extramantle zones contain a mixture of cell types including B cells, T cells, and macrophages. NLH is found in as many as 60% of patients with CVID but may be seen in the setting of giardiasis without antibody deficiency. In contrast to NLH in CVID patients, plasma cells are present in the extramantle zones in nonimmunodeficient patients. NLH is not considered a malignant disorder. However, malignant lymphomas of the GI tract in patients with immunodeficiencies often arise in a background of NLH, and clonal immunoglobulin gene rearrangement has been demonstrated in NLH in the GI tract of a child with CVID. Consistent with these observations, the most common malignancy in CVID is NHL, which affects approximately 8% of patients ; these lymphomas often originate in extranodal sites, with small bowel the most common GI site. Most of these lymphomas are of B-cell origin; they include diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma.
Chronic inflammatory processes involving small or large bowel that are clinically similar to IBD develop in some patients with CVID. In some patients, the small bowel is the primary site of involvement and the lesions resemble Crohn disease, with transmural inflammation and small bowel obstruction. Granulomas usually are not present in these Crohn disease-like disorders.
Large Bowel
The colitis occurring in CVID is variable in morphology. In some patients, the inflammatory process is limited to the colon and clinically mimics ulcerative colitis. Mucosal architectural distortion with crypt destruction is present, although crypt distortion is less pronounced than in most cases of ulcerative colitis, with less crypt branching ( Fig. 5.6, A ). Neutrophils are present in the lamina propria and crypt epithelium (see Fig. 5.6, B ). In contrast to ulcerative colitis, plasma cells are not present in the lamina propria in CVID-associated colitis, and an increase in CD8+ T cells (compared with normal controls and those with IBD) has been reported in the colon of CVID patients. In some cases, the crypt destruction and mucosal distortion is accompanied by increased apoptosis, and the histology is similar to that of colonic graft-versus-host disease (GVHD). Milder cases of colitis in CVID may resemble lymphocytic colitis, characterized by increased intraepithelial lymphocytes and minimal mucosal distortion, and an atypical form of collagenous colitis with pseudomembranes has been reported in one patient. The etiology and pathogenesis of colitis in these patients remain largely unknown. The association of chronic GI inflammatory disorders and autoimmune disorders in these patients, and the resemblance of the lesions to other disorders of immune dysregulation, imply that the colitis of CVID may be autoimmune in origin.
Adenocarcinoma of the colon is reported in young patients with CVID. Small cell neuroendocrine carcinoma of the cecum was reported in a 16-year-old boy, who died of liver metastases 5 months after diagnosis. In another case, 9 adenocarcinomas and 20 adenomas were present synchronously in the colon of a 22-year-old man with CVID.
Combined Cellular/Humoral Immunodeficiencies
Severe Combined Immunodeficiency
Severe combined immunodeficiency (SCID) is a heterogeneous group of congenital disorders characterized by defects in both B- and T-cell function. Children with SCID typically are seen in the first year of life with severe recurrent bacterial or viral infections. A number of molecular defects may result in SCID. Most are autosomal recessive, including adenosine deaminase deficiency, which accounts for 50% of autosomal recessive SCID; purine nucleoside deficiency; T-cell receptor deficiencies; Zap70 deficiency; JAK3 deficiency; and IL-7 receptor deficiency. However, X-linked SCID, resulting from a defect in the common γ chain, is the single most common type of SCID in the United States. It has a characteristic phenotype of absence of T cells and natural killer (NK) cells but normal B-cell numbers, although the B cells are dysfunctional.
GI disorders in SCID are caused by a variety of infectious pathogens. Oral, esophageal, and perianal candidiasis is common, and profound diarrhea may develop in children with SCID early in life. In general, GI biopsy specimens from these patients show a hypocellular lamina propria without plasma cells or lymphocytes. Because these patients are susceptible to viral infections, examination of stool for viral particles may be indicated. In particular, rotavirus, normally a self-limited infection, may cause chronic diarrhea in these children. Although villous blunting has been described in acute rotavirus infection in normal children and in animal models, the intestinal pathology of chronic rotavirus infection has not been described in SCID patients. Cytopathic viral infections that may be identified on GI biopsy include CMV and adenovirus ( Fig. 5.7 ). Salmonella may also cause chronic GI infection in SCID patients. Patients receiving nonirradiated blood products or allogeneic bone marrow transplants are susceptible to GVHD. Furthermore, a GVHD-like process affecting the colon and small intestine has been described in patients with SCID who had not undergone bone marrow transplantation. Children with SCID may be a greater risk for reflux esophagitis than the normal population.
Omenn Syndrome
Omenn syndrome is an autosomal recessive type of SCID with clinical and pathologic features of GVHD. The immunologic hallmark of the disease is expansion of an oligoclonal population of T cells and a near absence of B cells. Infants with Omenn syndrome are seen with diffuse erythroderma, hepatosplenomegaly, lymphadenopathy, and failure to thrive ; chronic diarrhea and alopecia are common. Hypereosinophilia and hypogammaglobulinemia are characteristic. Paradoxically, serum IgE levels are increased, although B lymphocytes are not detectable in the circulation, lymph nodes, or skin. Activated circulating T cells are normal to increased in number but constitute an oligoclonal population. The underlying basis for these findings in Omenn syndrome is impairment but not complete loss of the V(D)J recombination process as a result of mutations in RAG1 or RAG2 , the recombination activating genes. Mutations in these genes were first identified in a subset of SCID patients with T − B − SCID. The occurrence of this type of SCID and Omenn syndrome in the same kindred furnished the clue that Omenn syndrome was caused by mutations in the same genes. Differences between T − B − SCID and Omenn syndrome can be explained by the presence of two entirely defective alleles in SCID and the presence of one marginally functional allele that is capable of establishing the oligoclonal T-cell population in patients with Omenn syndrome. Infants with SCID with maternal T-cell engraftment may exhibit GVHD symptoms indistinguishable on clinical grounds from Omenn syndrome, and a diagnosis of Omenn syndrome depends on excluding this possibility by appropriate human leukocyte antigen typing or molecular analysis. Published accounts of the histopathologic changes in Omenn syndrome are scant, but skin changes resemble those of GVHD, and numerous apoptotic crypt cells are found in colonic biopsies in a pattern similar to that of GVHD (unpublished observations). Crypt injury and an increase in lamina propria eosinophils may also be seen ( Fig. 5.8 ).
Other Primary Immunodeficiencies
DiGeorge Syndrome
DiGeorge syndrome is caused by a microdeletion in chromosome 22q11.2, which leads to a congenital malformation of the third and fourth pharyngeal pouch, resulting in thymic and parathyroid hypoplasia. This disease is the most common microdeletion syndrome in humans, and is estimated to affect 1 of every 4000 live births. T cells are markedly reduced in number, but B cells are normal in number and functionality. Midline anomalies affecting the GI tract (e.g., esophageal atresia, imperforate anus) are seen in some cases in association with DiGeorge syndrome, and water diarrhea and malabsorption have been described but not well characterized. Oral candidiasis is common. Dysphagia and feeding difficulties have been reported in infants with 22q11.2 deletion.
Chronic Mucocutaneous Candidiasis
Chronic mucocutaneous candidiasis is a heterogeneous group of disorders characterized by persistent Candida infection of the skin, nails, and mucous membranes. Autoimmune disorders and a polyglandular endocrinopathy syndrome including pernicious anemia are common, occurring in more than 50% of patients. There is a high frequency of association with thymoma and systemic lupus erythematosus. Mutations in STAT1 have been identified in the autosomal dominant form of the disease, and the autosomal recessive form has been linked to deficiency in interleukin-17 receptor A. Immune defects include disorders of T-cell immunity with variable B-cell involvement. The most common GI manifestation is esophageal candidiasis. Although superficial infection with Candida is a defining characteristic, infections with other fungi (e.g., H. capsulatum ) and bacteria are common.
Wiscott-Aldrich Syndrome
Wiskott-Aldrich syndrome, characterized by early onset of profound thrombocytopenia with small platelets, eczema, and recurrent infections, is inherited as an X-linked recessive disease. Platelets and T cells are most severely affected. The genetic basis of Wiskott-Aldrich syndrome, described in 1994, is a mutation of the WASP gene, which encodes an intracellular protein expressed exclusively in hematopoietic cells. This protein is involved in transduction of signals from cell surface receptors to the actin cytoskeleton and is important in cytoskeletal architecture and cell trafficking and motility. Diarrhea is reported in patients with this disorder but has been poorly characterized. Bloody diarrhea in these patients is often attributed to thrombocytopenia, and biopsies may not be performed because of the risk of hemorrhage. A Crohn’s disease-like inflammatory process with cobblestone appearance and inflammatory pseudopolyps involving the descending and transverse colon has been reported in Wiskott-Aldrich syndrome. Massive hemorrhage from aneurysms involving the liver, small bowel mesentery, and kidney has been reported.
Chronic Granulomatous Disease
In chronic granulomatous disease (CGD), phagocytic cells are unable to reduce molecular oxygen to create the superoxide anion and its metabolites necessary for eradication of certain catalase-positive intracellular microbes. CGD is genetically heterogeneous, resulting from a mutation in any of four components of reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. The most common form of the disease, accounting for 70% of cases, is X-linked recessive; four other forms are autosomal recessive. As a result of this defect, patients with CGD suffer from recurrent bacterial and fungal infections; abscesses in a variety of sites and pneumonia are common. They are also prone to develop inflammatory and rheumatic diseases, such as an IBD-like condition and a lupus-like syndrome. GI manifestations are relatively rare in CGD, but reported cases can be broadly grouped into obstructive and inflammatory categories.
Obstruction can occur in patients with CGD at a number of levels of the GI tract, from esophagus to small bowel. Gastric outlet obstruction is more common in the X-linked form of the disease. In some cases, the obstruction is caused by infiltration of the viscus wall by pigment-laden macrophages (the histologic hallmark of CGD) or by granulomatous inflammation. In other cases, the obstruction is reportedly secondary to a functional disturbance in GI motility, although infiltration of the deep layers of the organ by macrophages often cannot be excluded. Esophageal obstruction occurs in 1% of CGD patients ; biopsies of the esophageal mucosa usually show nonspecific findings or reflux esophagitis but may demonstrate pigmented macrophages. Involvement of the gastric antrum and pylorus is somewhat more common, occurring in 16% of patients, and gastric outlet obstruction may be the first manifestation of CGD. Granulomas, giant cells, and macrophages laden with brown-yellow fine pigment are commonly present in gastric biopsy specimens, but in some cases only nonspecific inflammation is seen. Small bowel obstruction is relatively rare in CGD but is occasionally reported in the context of an inflammatory process. In a review of small bowel and rectal biopsies from nine patients with CGD, pigment-laden macrophages were found in the lamina propria at both sites. In the small bowel, the macrophages were located deep in the mucosa adjacent to crypts, but when numerous, they also extended into the villus core ( Fig. 5.9 ). In rectal biopsies, the number of pigmented histiocytes was quite variable, ranging from rare scatted cells to large numbers of histiocytes accumulating between the base of the crypts and the muscularis mucosae. Granulomas with giant cells were also present in rectal biopsies from some patients. In one of eight cases, distortion of crypt architecture without crypt abscesses was seen.
