The gastrointestinal (GI) tract is the largest lymphoid organ, and dysfunction of the GI tract is one of the most common manifestations of immunodeficiency. Some studies have suggested that 50–90% of patients with secondary (acquired) immunodeficiency syndromes, such as full-blown AIDS, develop significant GI symptoms. The most common GI manifestations of immunodeficiency are infection and malignancy, which correlate with the progressive deterioration of host defense systems. Patients often develop diarrhea, abdominal pain, dysphagia, and odynophagia, as well as nausea, vomiting, weight loss, and GI bleeding. The overall goal of evaluation is, therefore, to identify treatable causes of the symptoms and to preserve the function of the GI tract.

The impaired host immune system results from either primary inherited defects or secondary acquired deficiencies resulting from infectious agents (eg, HIV) or pathologic insults, including nutritional deficiencies or the iatrogenic effects of medical interventions (eg, immunosuppressive therapies). In addition, the chronic disease burden associated with advanced age and, to a lesser degree, the poorly understood physiologic decline of host defense systems associated with aging play an important role in the development of GI symptoms in geriatric populations. A detailed description of the nature and mechanisms of the GI manifestations of each individual primary and acquired (secondary) immunodeficiency is beyond the scope of this chapter. However, a comprehensive understanding of the composition and development of the immune defense systems of the GI tract and their alterations in pathologic conditions is essential for the clinical management of GI problems associated with immunodeficiency patients.

A. Pathophysiology of Gastrointestinal Defense Systems

The intestinal epithelium serves as the major frontier of self-protection from exogenous injurious events. To defend against the vast quantity of infectious agents and toxins, and to ensure homeostasis of the gut epithelium for nutritional absorption, the body relies on the proper development and maintenance of the intestinal mucosal immune systems, including both innate and adaptive immunity. Abnormalities originated from abnormal development of the GI defense systems or inability to maintain the function of these systems, stemming from congenital abnormalities, nutritional defects, or insults from toxins (eg, immunosuppressives) or infections, can lead to disturbances of mucosal defense and homeostasis. These disturbances, in turn, can produce a variety of GI symptoms, including chronic diarrhea, abdominal pain, and bleeding.

Innate immunity is characterized by a rapid response to specific general structures associated with microbes of all classes (bacteria, mycobacteria, viruses, and fungi). Innate immunity is initiated by so-called pattern recognition receptors such as the toll-like receptors (TLRs). The TLR4, for example, recognizes bacterial lipopolysaccharides, and are expressed on a wide variety of cell types, including natural killer (NK) cells, NK-T cells (a subclass of T cells), mast cells, epithelial cells and, most importantly macrophages and dendritic cells, the central conductor of the immune orchestra. Innate immunity functions as part of a first line of defense to ward off pathogenic invasions and to recruit other components of the defense system to protect the host. For example, in response to pathogenic bacteria, phagocytes engulf microorganisms (by phagocytosis), NK cells remove damaged cells (from either pathogen or malignant transformation) by secretion of lytic enzymes such as granzymes and perforins, and NK and NK-T cells alarm other immune defense cells against the microbial invasion by secreting cytokines, such as interferon-γ.

The molecular mechanisms that underlie host interactions with microbes reflect the nature of the innate immune response and, as noted, are mediated by specific pattern recognition receptors that recognize the commonly conserved features of microbes. These pathogen-associated molecular patterns, such as the lipopolysaccharides recognized by TLR4, peptidoglycans recognized by TLR2, and double-stranded RNA recognized by TLR3, are not expressed by host cells. Recognition of these microbial products by the host immune cell receptors triggers signal transduction pathways that initiate acute phase inflammatory reactions, which typically occur within a few hours of exposure. For example, the recognition of a common pathogen-associated molecule, lipopolysaccharide, by the TLR4 leads to activation of nuclear factor-κB (NF-κB) (by destroying the inhibitory factor IKKα) which initiates an acute phase inflammatory response. Macrophage and dendritic cells are the central regulator of innate immune response. Aberrant activation of macrophage and dendritic cells has been implicated in mucosal damage in autoimmune-inflammatory disorders (such as the IBD), and has been related to aberrant expression of VentX, a homeobox transcriptional factor implicated in proliferation and differentiation of hematopoietic and immune cells. In addition to the cellular components of innate immunity, noncellular components of innate immunity—such as normal peristalsis, gastric acid, bile secretion, pancreatic enzymes, mucus, epithelial cellular tight junctions, and the indigenous microbial flora—also play an important role in protecting the host from adverse reactions associated with pathogenic infection.

In comparison to innate immunity, the adaptive (specific or acquired) immune response is characterized by the large number of clonally expanded and distinct B cells and T cells that have been selected to respond to specific foreign antigens and are, at the same time, trained by the host to be tolerant to self-antigens in order to avoid autoimmunity. The selective expansion of the B-cell or T-cell clones is a complex process that involves bone marrow (for B cells) and thymus (for T cells), and requires specific receptors on the lymphocyte cell surface. Moreover, peripheral tissues and organs, such as the intestine, are also involved in the development of adaptive immunity and lymphocyte maturation and, especially, the Peyer patches and mesenteric lymph nodes. The involvement of the intestine in the development and maturation of the immune system characterizes the GI tract as both a site of immune regulation (eg, for the induction of oral tolerance) and a target of immunologic alterations associated with dysregulated immune responses.

As a result of clonal selection, the selected B cells secrete specific classes of immunoglobulins, such as immunoglobulin (Ig) A, IgG, and IgM. Decreased or dysregulated production of immunoglobulins constitutes one of the most common symptomatic forms of immunodeficiency, termed common variable immunodeficiency (CVID). CVID frequently manifests during early adulthood with recurrent respiratory and GI infections, and lymphoid hyperplasia, which is presumably a compensatory response to the immunodeficiency associated with inadequate immunoglobulin production. Although there have been a number of genes that regulate B-cell function (including genes that are expressed by T cells), that have been associated with familial forms of CVID, most cases occur spontaneously and the pathogenesis in these cases is unclear. But given the reduction in immunoglobulin production in all forms of CVID, some of the symptoms associated with this syndrome, at least in part, are amenable to infusions with intravenous immunoglobulin (IVIG). Defects in immunoglobulin class switching or secretion (or transcytosis) can also be associated with immunodeficiency. One such example is selective IgA deficiency, which is the most common primary immune deficiency. Patients with selective IgA deficiency are often asymptomatic and require no treatment (partially due to compensation by secreted IgM and IgG). Recognition of selective IgA deficiency is important because it can obscure the diagnosis of celiac disease and may be associated with unusual chronic infections such as G lamblia.

The other major class of lymphocytes associated with adaptive immunity is the T cell. T cells originate in the bone marrow, like B cells, but receive their final maturation and education within the thymus before trafficking into the systemic circulation and mucosal tissues. Once these so-called naïve T cells leave the thymus, they are instructed by dendritic cells to specific differentiated fates that are either regulatory and inhibit immune responses (so-called T regulatory cells) or effector cells (such as T helper [Th] 1, Th2, or Th17 cells). T cells express an enormous array of specific receptors that are selected within the thymus for recognition of the multitude of antigens to which the host may be exposed within a lifetime. Many rare primary immunodeficiency syndromes are associated with defects in T-cell development that result in susceptibility to infection, malignancy, autoimmunity, or a combination of all three. For example, mutations of the transcription factor FoxP3 lead to a disease called immune-mediated polyendocrinopathy, eczema X-linked (IPEX), in which there is poor formation of T regulatory cells. In addition, mutations of the cell surface molecule CTLA4, which normally inhibits T cells, are associated with autoimmune diseases.

External factors also play an important role in maintaining the normal function of the GI immune system and may form the basis for the development of acquired (secondary) types of immunodeficiency. Nutritional defects, either from malnourishment or protein-loosing enteropathy, or selective nutrient deficiency (eg, vitamin A and zinc deficiency) often lead to impaired host responses to pathogens and the development of recurrent infections. Extensive use of cytotoxic agents in a variety of clinical settings often causes depletion of neutrophils, leading to acute infections that may be associated with inflammation, such as neutropenic enterocolitis or typhlitis. In comparison with the primary immunodeficiencies, the acquired immunodeficiencies are much more common and may be involved in diseases as diverse as severe trauma, burns, cancer, myeloproliferative diseases, and immune-depleting infections such as those associated with HIV and AIDS.

B. Gastrointestinal Immunodeficiency Syndromes

1. Primary GI immunodeficiency syndromes