Since the last edition of this book, advances in the understanding of the adaptive and innate immune systems have led to the characterization of a number of novel primary immune deficiencies, including interleukin 10 (IL-10) receptor mutation (IL10R), XIAP mutation, and TTC-7 mutation. In addition, it is now recognized that “idiopathic inflammatory bowel disease” (aka Crohn’s disease and ulcerative colitis) may also be in part caused by genetic mutations in the innate and adaptive immune system. An expert panel of the World Health Organization (WHO) has identified more than 80 primary and secondary immunodeficiency syndromes. The most common of these primary immune deficiencies is selective immunoglobulin A (IgA) deficiency, which is very often asymptomatic. However, other primary immune deficiency syndromes have more severe complications, and frequently affect the intestine and liver. This chapter first provides an overview of the immunologic pathways that can be affected in primary immune deficiency, and then reviews the gastrointestinal manifestations and complications of the more common primary immunodeficiency syndromes ( Table 40-1 ). Also incorporated into this chapter is the prior edition’s more detailed chapter on secondary immune deficiencies (e.g., human immunodeficiency virus [HIV]). A more detailed discussion of the systemic complications of each specific syndrome can be found elsewhere.
| Immunodeficiency | Mechanism | Laboratory Findings | Gastrointestinal Manifestations | Extraintestinal Manifestations |
|---|---|---|---|---|
| Humoral | ||||
| Selective IgA deficiency | Inability of B cells to differentiate into IgA-secreting plasma cells | Low or absent IgA with normal IgM and IgG levels | Diarrhea, celiac sprue, nodular lymphoid hyperplasia, cholelithiasis, primary biliary cirrhosis | Recurrent sinusitis and other respiratory tract infections, atopy, anaphylaxis to blood products and intravenous immunoglobulin (IVIG), achlorhydria, Henoch-Schönlein purpura, multiple autoimmune disorders other than celiac disease, including Graves’ disease, systemic lupus erythematosus, type 1 diabetes, myasthenia gravis, and rheumatoid arthritis |
| X-linked agammaglobulinemia | Arrest of cell maturation in pre-B-lymphocyte stage | Decreased levels of all serum immunoglobulins, reduced number of B cells with normal precursor levels | Diarrhea, malabsorption, sclerosing cholangitis | Recurrent sinusitis and other respiratory tract infections, arthritis, enteroviral encephalitis, dermatomyositis, skin and bone infections as well as bacteremia can be secondary to rare organism related to Helicobacter organism |
| Hyper-IgM syndrome | Defective expression of CD154 on T cells, impaired B-cell isotype switching | Normal/elevated IgM with low IgA and IgG levels | Diarrhea, sclerosing cholangitis, abnormal aminotransaminases, hepatosplenomegaly, recurrent oral ulcers, severe hepatitis B infections | Chronic encephalitis and meningitis, lymphoid hyperplasia, autoimmune diseases (diabetes mellitus, rheumatoid arthritis, uveitis) |
| Transient hypogammaglobulinemia of infancy | Accentuation and prolongation of “physiologic” hypogammaglobulinemia of infancy as IgG derived from mother declines and infant production is not fully developed | Low serum IgG levels; IgA and IgM levels may be low | Chronic diarrhea, lactose intolerance | Recurrent respiratory tract infections |
| Cellular | ||||
| DiGeorge syndrome | Thymic aplasia with impaired T-lymphocyte maturation | Decreased levels of T lymphocytes with normal B and natural killer (NK) cells, normal immunoglobulin levels | Mucocutaneous candidiasis | Cardiac defects (e.g., truncus arteriosus), hypocalcemia, tetany, seizures, facial abnormalities |
| IL-10 receptor mutations | Mutations in the IL-10 receptor resulting in diminished IL-10 signaling | Decreased IL-10 pathway activation demonstrated by decreased STAT3 signaling, increased proinflammatory cytokine secretion | Early onset colitis in children, enteroenteric fistulae, severe perianal disease, diarrhea | Folliculitis, arthritis |
| X-linked lymphoproliferative disease | Mutation of the XLP gene on the X chromosome encoding the protein SH2D1A (SAP-signaling lymphocyte activation molecule [SLAM]–associated protein, SAP) important for cellular activation of T, B, and/or NK cells | Exaggerated Epstein-Barr virus (EBV)–induced infectious mononucleosis in males, hypogammaglobulinemia | Fulminant hepatitis, hepatic necrosis | Infectious mononucleosis, lymphocyte activation and proliferation resulting in organ lymphocyte infiltration with resultant T-cell cytotoxicity leading to multiorgan failure, intestinal lymphoma, non-Hodgkin’s lymphoma, Burkitt’s lymphoma |
| Chronic mucocutaneous candidiasis | Failure of T cells to proliferate or stimulate cytokines in response to Candida albicans (in particular IL-17 family members and IL-22) | Mucosal swabs, scrapings, and biopsy specimens positive for Candida | Candidal thrush and esophagitis | Skin lesions, autoimmune endocrinopathies (e.g. thyroiditis, adrenal insufficiency), dental enamel dysplasia, vitiligo |
| Combined Cellular-Humoral | ||||
| Common variable immunodeficiency | Normal levels of B cells (or in small percentage absence of B cells) that are unable to differentiate into plasma cells | Reduced levels of IgG accompanied by low IgA and/or low IgM levels, normal or reduced B-cell numbers | Diarrhea, IBD-like disease, pernicious anemia, nodular lymphoid hyperplasia, malabsorption, B-cell lymphoma, mucosa-associated lymphoid tissue (MALT) lymphoma | Chronic respiratory tract infections, granulomatous and lymphocytic interstitial lung disease, autoimmune cytopenias, leukopenia, thrombocytopenia |
| Severe combined immunodeficiency | Failure of maturation of lymphoid stem cells | Reduced T cells with normal B and NK cells | Diarrhea, oral candidiasis, esophageal candidiasis | Pneumonia, bronchitis, failure to thrive, illnesses following vaccinations |
| Disorders of Phagocyte Function | ||||
| Chronic granulomatous disease | Defects in NADPH oxidase activity, impairing oxidative burst and killing activity | Dihydrorhodamine reductase (DHR) or nitroblue tetrazolium (NBT) tests show diminished neutrophil respiratory burst activity | Colitis, hepatic abscess, gastric outlet obstruction, small bowel obstruction, granulomatous stomatitis, oral ulcers, esophageal dysmotility | Recurrent skin infections and abscesses, lymphadenitis |
| Leukocyte adhesion deficiency | Defects in adhesion to endothelium and migration into tissue | Increased neutrophils | Mucositis, necrotizing enterocolitis, perirectal abscesses | Delayed separation of umbilical cord, periodontitis, absent pus formation, impaired wound healing |
| Other | ||||
| Wiskott-Aldrich syndrome | Disruption of membrane receptors, interrupting integrity of cytoskeletal elements, which may have effects in elements of the formation of lymphoid effector and suppressor cells | Thrombocytopenia with small platelets | Colitis, bloody diarrhea, malabsorption | Eczema, recurrent upper respiratory tract infections, bleeding |
| NF-kB essential modifier (NEMO) mutations | Impaired B-cell switching and antigen-presenting cell (APC) activation | Increased IgA and IgE levels, decreased IgM and normal IgG levels | Vomiting, diarrhea, CMV colitis, giardiasis | Features of hypohidrotic ectodermal dysplasia, growth delay |
| X-linked inhibitor of apoptosis | Multifunctional protein, which regulates caspase and apoptosis molecules resulting in regulation of cell death, modulation of inflammatory signaling, immune homeostasis, cell proliferation, and cell invasion | XIAP protein inhibits two members of the cell-death caspase proteases, caspase-3 and caspase-7 | Enterocolitis in children, diarrhea, intestinal malformations (atresia) | Carcinoma, neurodegenerative disorders, (i.e., amyotrophic lateral sclerosis (ALS), Parkinson’s, and Huntington’s), autoimmunity |
| IPEX | FoxP3 mutation leads to impaired T-cell development | Decreased suppressor regulatory FoxP3 cells, eosinophilia, may have increased IgE and IgA levels | Severe enteropathy with watery/bloody diarrhea, gastritis | Eczema, atopy, lymphadenopathy, diabetes mellitus, thyroiditis |
Innate Versus Adaptive Immunity
The immune response is a complex process that can be divided into innate and adaptive responses. This distinction is somewhat arbitrary, as the innate immune response can initiate the adaptive immune response. The differences between these two arms of the immune system are summarized in Table 40-2 . The innate immune system is the first line of defense against invading microorganisms, and involves a response to a limited number of microbial products, including lipopolysaccharides, peptidoglycans, and flagellins. The microbial products that activate the innate immune system are called pathogen-associated molecular patterns (PAMPs), and the cellular receptors that bind these products are called pattern-recognition receptors (PRRs). The innate system serves a prominent protective function in all tissues and organs, especially the intestinal tract, genitourinary tract, respiratory tract, and the skin, where there is greater exposure to the external environment and foreign antigens. Components of the innate immune system include epithelial surfaces that form physical barriers (e.g., the skin, lung, or gut epithelia), antimicrobial peptides (defensins and cathelicidins), complement, intraepithelial lymphocytes, dendritic cells, macrophages, and neutrophils.
| Innate Immunity | Adaptive Immunity | |
|---|---|---|
| Response | Immediate | Delayed (days to weeks) |
| Stimuli | Limited (bacterial LPS, HSP, etc.) | Variable |
| Receptors | Toll-like receptors | MHC–TCR |
| Cells | Dendritic cells, macrophages, NK cells, intraepithelial | T and B lymphocytes of the gut |
| Mechanisms | Variety | Cellular and humoral immune responses |
| Mechanical barriers—epithelial cells, cytotoxic (defensins and other secretory enzymes), gastric acid, mucins, commensal intestinal flora, intestinal motility |
The initiation of an innate immune response involves the interaction of a PAMP microbial substance (protein, lipopeptide, or lipopolysaccharide) with a PRR on a cell (e.g., a dendritic cells or a macrophage). The PRR may be either on the surface of a cell (e.g., Toll-like receptors [TLRs]) or an intracellular molecule (e.g., an intracellular nucleotide-binding oligomerization domain [NOD] protein). The interaction of an organism’s PAMP product with a cell’s PRR triggers a signaling cascade involving mitogen-activated protein (MAP) kinases and Inhibitor of kappa B (IkB) kinases, ultimately resulting in transcription of NF-κB responsive cytokine-producing genes. The end result is cytokine (e.g., IL-1β, IL-6, tumor necrosis factor [TNF]) production. The cytokines can in turn produce a rapid but limited immune response. The initial immune response generated by the innate immune system may include the production of additional cytokines by dendritic cells (IL-12, IL-23), the phagocytosis of a microbe by a macrophage or neutrophil, or the killing of bacteria and infected cells by natural killer (NK) cells ( Figure 40-1 ).
The innate immune system is limited in its repertoire. It can respond only to a small number of bacterial molecules, and bacteria have evolved proteins (e.g., virulence factors) that are not recognized by innate immune receptors. In contrast, the adaptive immune system has the ability to generate receptors and antibodies that recognize a much wider array of microbial pathogens. The principal effector cell components of the adaptive immune system are antibody-producing B cells, phagocytes, and cytotoxic T cells (CD8+ and NK T cells (NK T). To activate the adaptive immune system, macrophages and dendritic cells take up and digest antigens, and process and present the antigen to T cells. Activated helper T cells in turn stimulate the production of antibody-producing B cells and cytotoxic cells.
Thus, the human immune system can generate new antibodies and new cellular receptors to allow it to recognize pathogens and fight infections more efficiently. However, these responses often take days to weeks to achieve maximal activity and require a somatic gene rearrangement, which results in immunologic memory. The majority of immunodeficiency syndromes described in this chapter represent defects in adaptive immunity.
Components of the Adaptive Immune Response
To trigger the cascade of immunologic events summarized in Box 40-1, an exogenous antigen must penetrate the physical barriers at epithelial surfaces. In certain specialized regions of gut epithelium termed follicle-associated epithelium (dome epithelium), modified epithelial cells (M cells) preferentially bind bacteria and viruses. These M cells are located over lymphoid nodules and Peyer’s patches in the gut. They provide a portal of entry that directly exposes potential pathogens to the systemic and mucosal components of the adaptive immune system.
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Antigen uptake by antigen-presenting cells (dendritic cells, macrophages)
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Antigen processing
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Antigen presentation to T cells
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T-lymphocyte activation
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B-cell activation, switching, and immunoglobulin production
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Leukocyte homing and adhesion to tissues
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Effector cell recruitment
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Release of inflammatory mediators (e.g., prostaglandin, leukotriene, and complement)
The adaptive immune system has different methods of responding to microbial proteins. The “classical pathway” of antigen presentation involves endocytosis of a microbial protein or peptide by antigen-presenting cells (APCs; including macrophages and dendritic cells). APCs are characterized by their ability to phagocytose proteins or peptides, degrade them intracellularly, complex these peptides with proteins of the major histocompatibility complex (MHC), and transport the peptide–MHC protein to the APC surface. Antigen presentation to a CD4 (helper) T lymphocyte occurs when a peptide complexed to an MHC class II protein on the surface of an APC comes in contact with the T-cell receptor complex on the surface of the lymphocyte. Binding to the T-cell receptor alone is not sufficient to promote T-lymphocyte activation, however. The CD4 molecule on the surface of the T lymphocyte stabilizes the T cell–APC interaction. In addition, to propagate the signaling pathway that leads to T-cell activation, a second costimulatory signal must be delivered to another molecule on the surface of the T cell. The costimulatory signal can be delivered in a number of ways (e.g., macrophage CD80 and CD86 binding to T-cell CD28, the latter association necessary for regulation and intercellular association and interaction of CD86 with cytotoxic T lymphocyte associated protein 4 (CTLA-4) for attenuation of regulation and cellular disassociation, or macrophage lymphocyte function associated antigen 3 (LFA-3) binding to T-cell CD2). Failure to deliver the second signal may result in a clone of T cells that do not respond to antigen, and may be a mechanism by which the host develops tolerance to certain antigens.
If antigenic stimulation and costimulation occur, a signal is transduced through the CD3 complex, characterized by phosphorylation of tyrosine molecules in the CD3 and zeta chains ( Figure 40-2 ). Subsequently, tyrosine kinases, including Lck, Syk, and zeta-associated protein 70 (ZAP-70), are activated and induce phosphorylation of phospholipase Cγ1 , which in turn converts inositol 4,5-biphosphate to inositol 1,4,5-triphosphate (IP 3 ). IP 3 formation results in increased cytosolic free calcium from intracellular stores, and activation of the molecule calcineurin. A second intracellular signal transduction pathway initiated by phospholipase Cγ1 involves the molecules diacylglycerol and protein kinase C (PKC; see Figure 40-2 ). These pathways are separate but synergistic, and inhibition of one or the other may abrogate T-cell activation.
Calcineurin and PKC enzymes in turn promote increased transcription of cytokine gene products mediated by nuclear-binding factors, including the nuclear factor of activated T cells (NF-AT) and NF-κB. NF-κB essential modifier (NEMO), also known as inhibitor of NF-κB kinase γ (IKK-γ), is required for the activation and subsequent translocation to the nucleus of the transcription factor NF-κB, where NF-κB activates multiple target genes. Mutations in this signaling cascade can result in a unique form of immunodeficiency called ectodermal dysplasia with immune deficiency (EDI), a syndrome associated with a variety of skin, facial, and ental abnormalities, but most significantly with abnormalities in host defense cytokine production (i.e., IL-12). A third T-cell activation pathway triggered by antigen recognition involves a group of kinases termed mitogen-activated protein (MAP) kinases, which in turn activate the transcription factor activator protein 1 (AP-1), an important pathway necessary for cellular proliferation.
Based on studies performed with murine T-lymphocyte clones, helper (CD4) T lymphocytes have been categorized into broad types: Th1, Th2, and Th17. These functional T-cell subtypes mature from naive CD4 helper T cells depending on the presence of a specific cytokine milieu. Cytokines secreted by dendritic cells and other APCs are essential in determining whether Th1, Th2, or Th17 cells are generated; release of interferon γ (IFN-γ) and IL-12 preferentially promote differentiation of Th1 cells, and because release of IL-4 promotes Th2 cell formation. IL-1β (in humans and IL-6 in murine models) with transforming growth factor β (TGF-β) is necessary for Th17-cell induction. Dendritic cell activation and cytokine production have also played important roles in the formation of these Th17 cells. IL-23 released by activated dendritic (APCs) initially thought to be important in the induction of IL-17–producing cells has more recently been reported to be important in maturation and stability of Th17 cells.
Type 1 helper T cells (Th1) promote cellular immune responses and delayed-type hypersensitivity by secreting IL-2, IFN-γ and tumor necrosis factor β (TNF-β). In contrast, type 2 helper T cells (Th2) promote B-lymphocyte differentiation into plasma cells and antibody formation by secreting IL-4, IL-5, IL-10, and IL-13. Thus, a Th1 cytokine pattern promotes macrophage activation with the aim of eliminating intracellular microbes, whereas a Th2 response results in mast cell activation, clearing of parasites, and allergic reactions. A third type of CD4 cell, called Th17, has recently been identified, and it functions in host defense by elimination of extracellular pathogens. This is achieved through recruitment of leukocytes (neutrophils but not eosinophils) to areas of inflammation via IL-17 and mediating the release of proinflammatory molecules (i.e., IL-6, granulocyte-colony stimulating factor [G-CSF], granulocyte macrophage -colony stimulating factor [GM-CSF], IL-1β, TNF-α) and factors that affect the aforementioned recruitment of cells (i.e., IL-8, Growth regulated protein alpha 13 [GRO-α]). Although all of these cell types are involved in host defense, dysregulation of these pathways with increased cytokine secretion can result in pathogenesis. Th1 and Th17 cells have been implicated in the pathogenesis of Crohn’s disease, whereas Th2 cells have been implicated in the pathogenesis of ulcerative colitis and allergic disorders. Furthermore, abnormalities resulting in decreased secretion of these host defense molecules also can clearly have implications. Thus, it has been shown that abnormalities in regulators of inflammation can result in diseases that affect host defense. Recent discoveries in the regulation of the inflammatory pathway have demonstrated that signal transducer and activator of transcription 3 (STAT3) and NF-κβ and NFkB are important in mediating the immune response. In relation to the latter, an additional downstream molecule, suppressor of cytokine secretion 3 (SOC3), plays a significant role in IL-17 production, in that in its absence, IL-23–induced STAT3 phosphorylation is enhanced, leading to increased IL-17 activation. However, in impaired regulation of these important host defense inflammatory pathways, in particular Job’s syndrome (hyper-IgE syndrome) it has been shown that an underlying defect in STAT3 gene encoding results in decreased IL-17 response to extracellular pathogens with occurrence of pneumonias and a host of other abnormalities (i.e., eczema, abscess formation, and mucocutaneous candidiasis).
Another group of T cells termed regulatory T cells serves to downregulate the immune response and promote immunologic tolerance. The best-characterized regulatory T-cell subset is the CD4+CD25+ T cell, which secretes anti-inflammatory cytokines, such as IL-10 and TGF-β, or can express latent TGF-β on its surface and effects through cell–cell contact. The IL-10–producing cell (or TR1 cell ) inhibits macrophage activation and antagonizes the proinflammatory Th1 cytokine IFN-γ, whereas TGF-β inhibits B- and T-cell proliferation or affects NF-κB cytokine transcription. The TGF-β secreting regulatory T cells are characterized by a transcription factor called FoxP3, and mutations in this gene in humans results in IPEX (immune dysfunction, polyendocrinopathy, enteropathy, X-linked) a rare cause of infantile autoimmunity (discussed later in this chapter).
Humoral immunity is generated by B lymphocytes, which, on exposure to antigen, proliferate and differentiate into plasma cells ( Figure 40-3 ). All B cells are initially programmed to synthesize IgD or IgM (see Figure 40-3 ). For a B cell to switch its class of antibody produced to IgG or IgA (isotype switching), several other molecular stimuli need to occur (see Figure 40-3 ). The CD40 ligand (gp39, CD154) is a molecule on the surface of the T cell that binds to CD40 on B cells. This interaction promotes B-cell activation and differentiation, and isotype switching from IgM to IgG, IgA, or IgE. Conversely, the CD40–CD154 interaction also promotes activation of CD4+ T cells. Deficiency of this molecule results in an unusual form of immunodeficiency termed the hyper-IgM syndrome. Another T-cell protein termed inducible costimulatory (or ICOS) is also important in B-cell differentiation, and ICOS mutations have been associated with common variable immune deficiencies. Subsequent differentiation to immunoglobulin-producing plasma cells depends on a number of B-cell genes and receptors, including the transmembrane activator and CAML interactor (TACI) gene and CD19, the loss of which results in decreased B-cell numbers or maturation of B-cell phenotype. Cytokines, such as IL-4, are responsible for switching B cells from IgM to IgE production, and TGF-β has been shown to play a role in B-cell switching to IgA production. Thus, humoral immunodeficiencies may arise from either direct mutations in B-cell genes (e.g., TACI, which results in selective IgA or common variable immune deficiency), or mutations in T-cell genes (e.g., CD40 ligand) that are essential for B-cell differentiation. Furthermore, abnormalities involved in cellular activation of B cells via costimulation from T cells such as ICOS, a member of the CD28 family, can also lead to decreased B-cell maturation and immunoglobulin production.
The result of the immune response is the recruitment of activated effector cells (cytotoxic lymphocytes, macrophages, neutrophils, eosinophils, and mast cells) to an infected or inflamed tissue. In bacterial infections, neutrophils can phagocytose and degrade microorganisms; this process is facilitated by opsonization of bacteria by immunoglobulin and complement. In viral infections, infected cells are typically lysed by CD8 (cytotoxic) T cells, which have two distinct mechanisms of cytotoxicity: perforin and Fas ligand. Perforin is a membrane pore-forming molecule, which allows release of granular enzymes (e.g., granzymes) directly into the cytosol of the target cells. Granzyme B induces rapid apoptosis of the target cell in caspase-dependent and caspase-independent manners.
Derangements at any point in this complex pathway may result in three principal types of clinical disorder in immunodeficient patients:
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Susceptibility to infection may be increased.
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Autoimmune disease, including enteropathy, colitis, and hepatitis, may occur because of untoward activation of immune mononuclear cells with inability to suppress these unwanted immune responses properly.
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Increased long-term risk of malignancy.
Humoral Immunodeficiencies
Selective IgA Deficiency
Selective IgA deficiency is the most common primary immunodeficiency, with a prevalence of approximately one in 500. It has a male predominance, and in patients with IgA deficiency, the serum IgA levels are significantly higher in winter than in other seasons. The decreased IgA production may result from a wide variety of potential immunologic derangements including alterations in B-cell switching. Individuals with this disorder have extremely low levels (less than 5 mg/dL) of serum and mucosal IgA. In addition, 15% to 20% of patients with selective IgA deficiency also have low levels of IgG subclasses IgG 2 and IgG 4 . A compensatory increase in biologically active secretory IgM frequently protects against infection. The pathogenesis of IgA deficiency is not known, although mutations in the TACI gene have been identified in a small number of patients. In addition, certain human leukocyte antigen (HLA) haplotypes, including B8 and DR-3 are associated with selective IgA deficiency. Studies of T-cell function have been normal in most patients with selective IgA deficiency.
Most persons with selective IgA deficiency are asymptomatic. The precise mechanism of this lack of disease in IgA deficiency is unclear and is thought to be due in part to a compensatory increase in secretory IgM, and possibly in IgG as well. However, patients with IgA deficiency are at increased risk for infections, gastrointestinal disease, and autoimmune disease ( Box 40-2 ). Children with selective IgA deficiency have been shown to be at an increased risk of developing dental caries. Adult patients with IgA deficiency are at an increased risk of developing oral mucosal infections, including pharyngitis, stomatitis, and herpes labialis. Recurrent giardiasis refractory to antibiotic therapy may result in partial villus atrophy and secondary malabsorption. Chronic Strongyloides infection, poorly responsive to antihelminthic therapy, has also been reported. Of interest, individuals with selective IgA deficiency are able to resolve rotavirus disease and actually show higher total IgG and IgG 1 subclass antibody titers to rotavirus than people with normal IgA levels. This suggests that IgA is not needed to clear rotavirus in humans.
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Upper respiratory infections
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Otitis media
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Sinusitis
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Bronchiectasis
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Allergic disorders (including food allergies, asthma, eczema)
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Anaphylaxis to intravenous immunoglobulin
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Giardiasis
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Strongyloidiasis
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Nodular lymphoid hyperplasia
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Celiac disease (with false-negative antiendomysial antibody)
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Achlorhydria
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Malabsorption villus atrophy
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Cholelithiasis
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Inflammatory bowel disease
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Primary biliary cirrhosis
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Gastrointestinal carcinoma and lymphoma
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Henoch-Schönlein purpura
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Hepatitis C
The most common noninfectious complication of selective IgA deficiency is celiac disease, which is estimated to occur in approximately 5% to 15% of patients with selective IgA deficiency. Antigliadin IgA, antiendomysial IgA, and anti-tissue transglutaminase IgA antibodies commonly yield false-negative results and are unreliable screening tools in this population; the tissue transglutaminase IgG antibody may be a better screening test but has not been well validated. Heneghan et al. found that of 604 subjects with celiac sprue, 14 (2.3%) had IgA deficiency. In a prospective study in which jejunal biopsy was performed in 65 consecutive children with selective IgA deficiency, 7.7% showed diagnostic features of celiac disease. Additional gastrointestinal complications reported in selective IgA deficiency have included ulcerative colitis, Crohn’s disease, and nodular lymphoid hyperplasia. However, it is unclear whether these are true associations, or simply represent two conditions that occur coincidentally.
Patients with IgA deficiency have also been found to be at an increased risk for multiple autoimmune disorders other than celiac disease, including Graves’ disease, systemic lupus erythematosus, type 1 diabetes, myasthenia gravis, and rheumatoid arthritis. These diseases and IgA deficiency are both associated with the MHC genes and non-MHC genes including interferon-induced helicase 1 and c-type lectin domain family 16, member A. Allergic diseases also seem to be more prevalent in patients with IgA deficiency. In a study of 32 adults with IgA deficiency, 84.4% were found to have allergic and/or autoimmune disorders, compared to only 47.6% of 63 age- and gender-matched controls.
Antibiotic therapy with metronidazole or nitazoxanide should be administered to patients with selective IgA deficiency and giardiasis. If diarrhea persists and biopsy demonstrates villous atrophy, a gluten-free diet may be therapeutic. Intravenous immunoglobulin (IVIG) should be avoided in patients with selective IgA deficiency, because it does not cross the mucosal surfaces and may result in systemic anaphylaxis. Finally, a small number of patients with selective IgA deficiency may develop common variable immunodeficiency (CVID), which has a much higher prevalence of gastrointestinal complications.
X-linked agammaglobulinemia
X-linked (Bruton’s) agammaglobulinemia (XLA) manifests with recurrent infections after 9 months of age. In a study by Conley and Howard, the mean age at diagnosis in the 60 patients with sporadic XLA was 35 (median 26, range 2 to 11) months. Affected boys have a paucity of peripheral lymphoid tissue and low serum levels of all classes of immunoglobulin. Humoral responses to specific antigens are markedly depressed or absent. The gene for XLA has been localized to chromosome Xq21.3-q22. B cells from affected persons have different mutations affecting the function of a B-cell–specific tyrosine kinase gene (BtK) . Defects in the Btk gene affect the early stages of B-cell differentiation.
The onset of recurrent bacterial infections is typically during the latter part of the first year of life, when the levels of maternal antibodies acquired passively through the placenta are no longer protective. Recurrent sinusitis, otitis media, pneumonia, and bronchitis are the most common reported illnesses in persons with XLA. Autoimmune disease (including arthritis and dermatomyosis) may also develop. Chronic enteritis develops in 10%; identifiable causes of the enteritis include Giardia, Salmonella, Campylobacter, Cryptosporidium, rotavirus, coxsackievirus, and poliovirus. In a multicenter survey, gastrointestinal infections with recurrent diarrhea were seen in 13% of patients with XLA. In certain instances of gastrointestinal infection resistance, antibiotic treatment may require coadministration of high-dose IgM, the latter to increase opsonization of resistant organisms. Associations with sclerosing cholangitis and a sprue-like illness have also been noted. Patients with XLA, small bowel strictures, and transmural intestinal fissures resembling Crohn’s disease have been seen. In contrast to Crohn’s disease, however, no granulomas or plasma cells are identified when strictures are resected. In a reported case, the regional enteritis of the terminal ileum in a patient with XLA was thought to be caused by enterovirus infection. Patients with XLA may also be at increased risk for small and large bowel cancers.
Skin and bone infections as well as bacteremia can occur secondary to an organism closely related to Flexispira rappini and thus called a “Flexispira-like organism,” and more distantly related to Helicobacter . This organism, which can be stained with acridine orange, can only be eradicated by prolonged intravenous antibiotic therapy.
Treatment of XLA is aimed at replacing IgG, either intravenously or subcutaneously. In a study of 80 adults and children with either CVID (see below) or XLA, patients were given a liquid IVIG preparation at 3- or 4-week intervals over a 12-month period. This was well tolerated, with only six episodes of acute serious bacterial infections occurring, corresponding to an annual rate of 0.08. The annual rate for all infections was 3.55. Neither IgA nor IgM can be replaced. Antibiotic treatment of recurrent infections is necessary. Vaccinations containing live viruses are contraindicated. A recent study suggests that children with XLA have a quality of life that is superior to children with rheumatic disease.
Hyper-IgM Syndrome
Hyper-IgM syndrome is a rare humoral immune disorder that affects mainly boys (55% to 65%) and is characterized by severe recurrent bacterial infections with decreased serum levels of IgG, IgA, and IgE, but increased IgM levels. The molecular basis for the X-linked form of immunodeficiency with hyper-IgM (HIGM) has been identified as a T-cell defect, in which mutations in the gene that encodes the CD40 ligand molecule are present. The CD40 ligand of the T cell cannot interact with the CD40 molecule on the B-cell surface, resulting in impaired isotype switching from IgM to IgG or IgA, and reduced functional antibody. In a recently published study of 23 patients with HIGM, six different CD40L mutations were identified. An underlying genetic defect was not identified in 6 of 14 patients analyzed. An autosomal recessive form of hyper-IgM syndrome has also been reported, which involves a mutation in the gene that encodes activation-induced cytidine deaminase (AICD).
Boys with hyper-IgM syndrome present between 1 month and 10 years of age with opportunistic infections. Chronic encephalitis and idiopathic neurologic deterioration may occur. Reported gastrointestinal complications include histoplasmosis of the esophagus, cryptosporidiosis, giardiasis, hepatosplenomegaly, intestinal lymphoid hyperplasia, and recurrent large painful oral ulcerations ( Figures 40-4 and 40-5 ). Protracted or recurrent diarrhea is common, occurring in about one-third of the patients, and Cryptosporidium is the most frequently isolated pathogen. Patients with hyper-IgM syndrome are also at increased risk for intestinal lymphoma.
Liver disease and other autoimmune disorders are frequently seen in hyper-IgM syndrome. Abnormal transaminase and alkaline phosphatase levels are seen in 50% of patients. Two separate series have suggested that sclerosing cholangitis and cirrhosis occur in up to 35% of patients older than 10 years of age. Pancreatic and hepatobiliary malignancies have been reported in patients as young as 7 years of age.
Therapy for hyper-IgM syndrome involves γ-globulin replacement therapy and treatment of specific infectious complications. γ-Globulin administration may reduce the frequency of bacterial infections and the incidence of lymphoid hyperplasia associated with HIGM. Treatment of the autoimmune conditions may include corticosteroids, immune modulating agents, or biologic therapies. Recombinant CD40 ligand (rCD40L) administered subcutaneously improved T-cell immune function in three children with hyper-IgM. Although they were receiving the drug, these patients were able to mount cutaneous delayed-type hypersensitivity reactions, and their T cells developed the ability to respond to T-cell mitogens with synthesis of IFN-γ and TNF-α.
Transient Hypogammaglobulinemia of Infancy
Transient hypogammaglobulinemia of infancy (THI) is a poorly defined condition characterized by low serum immunoglobulin levels in infancy, with attainment of normal levels at a later time. Serum IgG level is typically low, without any subclass specificity; IgA or IgM levels may also be decreased. The prevalence of this condition in infants with recurrent infections ranges from 0.1% to 5% in different studies. Children with THI typically present with recurrent respiratory infections at 6 to 12 months of age. In a multicenter survey of 77 children with this disorder, 91% of patients presented with recurrent infections, 47% had environmental allergies, and 4% had autoimmune disease. The immunoglobulin deficiency and clinical symptoms usually resolve within 24 months. However, a small subset of children initially diagnosed with THI may ultimately be diagnosed with other immune deficiencies, such as common variable immune deficiency.
Chronic diarrhea is the second most common complication in these patients after respiratory illness. Lactose intolerance, Giardia lamblia infestation, or Clostridium difficile infection were found in one-third of 55 children with low serum immunoglobulin levels and chronic diarrhea. Small bowel histology demonstrated enteritis or villus atrophy in up to 50% of these patients. It is unclear whether these patients had THI or enteric protein loss from the intestinal illness. In children with recurrent C. difficile infection unresponsive to antibiotics and low antibody titers to C. difficile, IVIG has resulted in clearance of the infection.
Cellular Immunodeficiencies
DiGeorge Syndrome
DiGeorge syndrome arises from a defect in the differentiation of the third and fourth pharyngeal pouches during embryologic development, usually due to a chromosome 22q11 deletion. The syndrome consists of conotruncal cardiac anomalies, hypoparathyroidism, velopharyngeal insufficiency, craniofacial dysmorphism, and thymic hypoplasia. Patients may have absent T cells or normal T-cell numbers. In addition to immunologic dysfunction, anatomic abnormalities such as bronchomalacia and aspiration can lead to recurrent respiratory tract infections.
Most infants with DiGeorge syndrome experience developmental delay, facial dysmorphia, and palatal dysfunction. Feeding difficulties arise from poor coordination of the tongue, pharyngeal, and esophageal muscles. Infants with cleft palates can have difficulty breastfeeding, and patients with cardiac anomalies can fatigue easily while trying to feed. Two percent to 5% of affected children have delayed eruption of teeth and enamel hypoplasia. Many children experience constipation and gastroesophageal reflux, which may be partially due to hypotonia. Malrotation of the intestines can occur. Treatment involves transplantation of either mature T cells, or thymus tissue for patients with absent T cells. In a worldwide study of 17 patients transplanted with hematopoietic cells, the overall survival rate was 41%, with a median follow-up of 5.8 years. Patients who received cells from HLA-matched siblings showed the best results. The median survival of the deceased patients was only 7 months after transplantation (range 2 to 18 months).
Chronic Mucocutaneous Candidiasis and APECED Syndrome
Chronic mucocutaneous candidiasis is characterized by a diminished T-cell response to candidal antigens. Infants with this disorder present with persistent thrush or candidal dermatitis, failure to thrive, and dystrophic nails. Candidal esophagitis may result in feeding refusal. A subset of children with chronic candidiasis have APECED syndrome (autoimmune polyendocrinopathy, candidiasis, and ectodermal dysplasia). The molecular basis of APECED involves mutations in the AIRE (autoimmune regulator) gene, and perhaps defective regulatory T cells. Patients with APECED have been found to have severely reduced IL-17F and IL-22 responses to Candida albicans antigens and high titers of autoantibodies against IL-17A, IL-17F, and IL-22. These autoantibodies are not present in healthy controls and patients with other autoimmune disorders. Therefore, the aforementioned autoantibodies may cause chronic mucocutaneous candidiasis in patients with APECED. The clinical features of APECED in addition to the candidiasis include hypoparathyroidism, adrenal insufficiency, pernicious anemia, type 1 diabetes, and gonadal failure. Malabsorption secondary to pancreatic insufficiency contributes to poor weight gain in 10% of patients. Therapy includes eradication of Candida with topical antibiotics plus ketoconazole or fluconazole, as well as hormone or pancreatic enzyme replacement when appropriate.
Combined Cellular–Humoral Immunodeficiencies
Common Variable Immunodeficiency
CVID, also called acquired hypogammaglobulinemia, adult-onset hypogammaglobulinemia, or dysgammaglobulinemia, is a rare heterogeneous group of disorders affecting between one in 50,000 and one in 200,000 persons. It is characterized by hypogammaglobulinemia, recurrent infections, enteropathy, autoimmune disease, and malignancy. Up to 45% of cases are diagnosed in childhood. The cause of CVID is unknown, but B-lymphocyte differentiation into plasma cells is impaired, and mutation in the TACI gene has been identified in a subset of patients. The different abnormalities reflect the variability of CVID, and support the concept that more than one gene is probably responsible for the immune abnormalities in CVID.
Patients typically present in late childhood and young adulthood with recurrent sinusitis, bronchitis, and pneumonia. Common causes of respiratory infections include Streptococcus pneumoniae , Haemophilus influenzae, and Mycoplasma pneumoniae; mycobacteria, Pneumocystis, and fungi are less frequent pathogens. Diagnosis of CVID is established by demonstration of persistently low antibody levels over time and impaired responses to standard pediatric immunizations. XLA must be excluded in male patients. Patients with CVID are at risk of developing noninfectious pulmonary and hematologic diseases. One such disease is granulomatous and lymphocytic interstitial lung disease, a restrictive lung disease associated with early mortality. Combination chemotherapy with rituximab and azathioprine has been shown to improve pulmonary function and decrease radiographic abnormalities without resulting in chemotherapy-related complications. Rituximab was also shown to be effective for patients with CVID who develop immune thrombocytopenia and/or autoimmune hemolytic anemia (85% response rate in one study of 33 such patients). Patients with CVID are also more likely than their age-matched controls to develop asthma.
Gastrointestinal disease occurs in up to 70% of patients and accounts for much of the morbidity ( Box 40-3 ). Infectious diarrhea caused by a wide variety of pathogens may occur. Nodular lymphoid hyperplasia is detected radiographically or endoscopically in up to 20% of patients, and may predispose to either malabsorption or gastrointestinal bleeding. In one case report, a 40-year-old patient with CVID developed cytomegalovirus infection of the stomach and small bowel with multiple ulcers and strictures, resulting in intestinal obstruction.
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Enteric infections (including Shigella, Salmonella, and dysgonic fermenter 3)
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Giardiasis
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Cryptosporidiosis
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Nodular lymphoid hyperplasia
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Enterocolitis
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Enteropathy, malabsorption, wasting syndrome
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Perirectal abscess
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Short stature
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Zinc deficiency
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Inflammatory bowel disease
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Ménétrier’s disease
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Atrophic gastritis or pernicious anemia
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Gastric adenocarcinoma
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Intestinal lymphoma
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Cecal carcinoma (undifferentiated)
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Hepatitis C with cirrhosis
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Nodular regenerative hyperplasia of the liver
Between 10% and 20% of patients with CVID have an enteropathy characterized by weight loss, abdominal pain, and severe diarrhea in the absence of enteric infection. Small bowel biopsy in these patients demonstrates partial or subtotal villus atrophy, hyperplastic crypts, and apoptotic bodies. Although the diagnosis of CVID is suspected when plasma cells are absent in a gastrointestinal biopsy, this finding is present in only about two-thirds of patients with this disease. Gluten- or lactose-free diets may help a subset of patients, but most improve when treated with an elemental diet, although parenteral nutrition may also be required. The severe malabsorption may result in vitamin B 12 deficiency and/or zinc deficiency. An inflammatory bowel disease-like syndrome, characterized by villous blunting, small intestinal strictures, microscopic colitis with infiltration of the lamina propria by increased numbers of mononuclear and intra-epithelial lymphocytes, may also occur. The gut inflammation seen in patients with CVID has been shown to be mediated primarily by IL-12 and IFN-γ. This is in contrast to the T-helper cytokines that are produced in high numbers in patients with Crohn’s disease, including IL-23, IL-17, and TNF-α.
Patients with CVID are at a 30-fold increased risk for the development of gastric carcinoma or malignant lymphoma. The lymphomas in CVID are extranodal and usually B cell in type. Cunningham-Rundles et al. studied 22 B-cell lymphomas in patients with CVID over a period of 25 years, and found that five lymphomas arose in mucosal sites—mucosa-associated lymphoid tissue (MALT) lymphomas. These MALT lymphomas are low-grade B-cell lymphomas and tend to occur in organs that have acquired lymphoid tissue as a result of long-term infectious or autoimmune stimulation (e.g., chronic gastric Helicobacter pylori infection and chronic hepatitis C infection). H. pylori infection and p53 gene mutation may play a role in the gastric carcinogenesis. The small bowel lymphomas reported may manifest with intestinal malabsorption. In addition, a cecal carcinoma of neuroendocrine origin has been reported in a 16-year-old patient with CVID.
Some 20% of patients with CVID have a persistent mild increase in transaminase levels. The cause is unknown, with liver biopsies demonstrating mild periportal changes or granulomas. Nodular regenerative hyperplasia (NRH) of the liver can also occur in patients with CVID. In one retrospective study, 5% of 261 patients with CVID were found to have NRH, which appeared to have multistage presentation. In early stages, the predominance of patients presented with increased transaminase and alkaline phosphatase levels with/without bilirubinemia. In more progressive patient subgroups, the former was associated with significant portal hypertension resulting in splenic sequestration of immune cells and associated leukopenia and thrombocytopenia. In a more severe population a substantial proportion of patients developed an autoimmune hepatitis-like liver disease concomitant with portal hypertension that resulted in severe liver dysfunction and death due to sepsis. Patients with CVID who develop NRH are more likely to have other disease-related complications of CVID, including nonceliac (gluten insensitive) lymphocytic enteropathy. Hepatitis C is can occur as a complication of IVIG infusion in patients with CVID and may have an aggressive course. Treatment includes IFN and liver transplantation.
Therapy for CVID consists of monthly IVIG infusions and symptomatic treatment of infections and malabsorption. Epstein-Barr virus infections in patients with CVID may respond to IFN-α.
Severe Combined Immunodeficiency (SCID)
The term severe combined immunodeficiency (SCID) refers to a group of diseases characterized by molecular defects interfering with T- and/or B-cell differentiation and resulting in an infant with failure to thrive and extreme susceptibility to infections. Approximately 20 defective genes have been associated with SCID; patients are classified according to the specific mutation present, the associated lymphocyte phenotype, and mode of inheritance (see Table 40-1 ). Presenting features include growth impairment, chronic diarrhea, persistent thrush or candidiasis, and overwhelming sepsis. Graft-versus-host disease from transfusions of unirradiated blood, or disseminated illness from live vaccines, may occur if the diagnosis is delayed. Diagnosis is established by the demonstration of low or absent T-lymphocyte numbers in peripheral blood; B-cell and neutrophil counts may also be depressed, depending on the variant of SCID.
Gastrointestinal illness occurs in up to 90% of patients. Organisms frequently associated with illness include rotavirus, Candida , cytomegalovirus, Epstein-Barr virus, and Escherichia coli . Although candidiasis rarely involves the intestine, candidal esophagitis should be suspected in infants with SCID and decreased oral intake. Chronic viral infection is the most frequent cause of enteritis and may be responsible for death in 80% of cases. Chronic rotavirus infection has been reported after administration of the live attenuated rotavirus vaccine. Other less-common causes of enteropathy include Salmonella, Shigella, and Cryptosporidium infections.
Autoimmune manifestations of SCID may include enteropathy, hemolytic anemia, and glomerulonephritis. Boeck et al. found clinically significant gastroesophageal reflux in 20.5% of patients with SCID, much higher than that reported for the normal population (0.1% to 0.3%), but the mechanism is unknown.
Hepatic abnormalities are also common in patients with SCID, and include graft-versus-host disease of the liver, adenovirus and cytomegalovirus hepatitis, rotavirus hepatitis, parenteral nutrition-associated liver disease, and lymphoproliferative disorder. Pancreatic infection by viruses has also been described.
One variant of SCID that seems to render a patient particularly prone to gastrointestinal complications is bare lymphocyte syndrome . Gastrointestinal candidiasis is common in addition to giardiasis, cryptosporidiosis, and other bacterial enteritides. A high incidence of hepatobiliary abnormalities is noted, including sclerosing cholangitis associated with biliary cryptosporidiosis. Bacterial cholangitis secondary to Pseudomonas, Enterococcus, and Streptococcus infections has been described.
The principal therapy for patients with SCID is bone marrow transplantation, ideally from a matched sibling. In a study of 106 patients with adenosine deaminase-deficient SCID who received hematopoietic cell transplantation (HCT), those who received transplants from matched sibling and family donors had significantly better overall survival than those who received matched unrelated transplants (86% and 81%, respectively, vs. 66%; p < 0.05). In patients with SCID with adenosine deaminase deficiency, infusions of a long-acting form of adenosine deaminase correct metabolic abnormalities and provide some restoration of immune function. In addition, gene replacement therapy is also being studied.
NF-κB Essential Modifier Mutations
NF-κB essential modifier (NEMO) mutations have been identified in patients with X-linked hyper-IgM and hypohidrotic ectodermal dysplasia (HED). B-cell switching and APC activation are impaired with NEMO mutations. Certain mutations of NEMO are associated with deficient NK cell cytotoxicity, and dysgammaglobulinemia with very poor specific antibody production. Patients display features of HED with conical teeth and absence (or hypoplasia) of hair, teeth, and sweat glands. Recurrent bacterial and viral infections often occur in infancy.
Gastrointestinal symptoms include persistent vomiting, chronic diarrhea, recurrent cytomegalovirus colitis, and giardiasis. Growth delay is common because of infection and poor nutrition resulting from gastrointestinal symptoms. Parenteral nutrition is often used to provide adequate nutritional support. Patients with NEMO mutations may also develop enterocolitis. The clinical presentation and endoscopic appearance of enterocolitis in patients with NEMO may be similar to that of patients with idiopathic inflammatory bowel disease (e.g., Crohn’s disease) ( Figure 40-6 ). Although IBD causes signs of chronic active enterocolitis (granulomas, deep cryptitis, and lymphocyte predominant inflammation), a relative paucity of lymphocytes and an absence of granulomas is seen in mucosal biopsies taken from patients with NEMO. Although the neutrophil predominant inflammation seen in NEMO is suggestive of acute inflammation, clinical improvement usually requires glucocorticoid therapy. In patients with complications of NEMO, stem cell transplantation has been utilized and may alleviate the intestinal symptoms.
