Gastrointestinal Manifestations of Immunodeficiency

Introduction

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 (IL)-10 receptor mutation, X-linked inhibitor of apoptosis (XIAP) mutation, ICOS mutation, and TTC-7 mutation. In addition, it is now recognized that “idiopathic inflammatory bowel disease” (a.k.a. Crohn 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 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 will first give an overview of the immunologic pathways that can be affected in primary immune deficiency and then will review the gastrointestinal manifestations and complications of the more common primary immunodeficiency syndromes ( Table 40.1 ). We have also incorporated a discussion of the diagnosis of very early onset inflammatory bowel disease (IBD) into this chapter. A more detailed discussion of the systemic complications of each specific syndrome can be found elsewhere.

Innate Versus Adaptive Immunity

The immune response is a complex process and 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. 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). This initial interaction between the PAMPs and PRRs is the initiation of the innate immune response. The former are structurally diverse and include bacterial end products and proteins such as lipopolysaccharides, glycolipids, peptidoglycans, lipoproteins, flagellins, nucleotides, and nucleic acids. The latter PRRs detect these various families of PAMPs through the use of ligand recognition domains, which include C-type lectins and nucleic acid domains, as well as leucine rich repeating (LRR) domains. The difference between these PRRs and classic T- and B-cell receptors (BCRs) found on lymphocytes is that their recognition is germ-line coded and evolves from selection of the former pathogens (PAMPs). These receptors can be observed on the cell surface or in the intracellular compartments (i.e., cytosol or endosomes). Those found on the surface include Toll-like receptors (TLRs) and C-type lectin receptors (CLRs) and within the cytoplasm include nucleotide-binding oligomerization domain (NOD)–like receptors (NLR), AIM2-like receptors, cyclic GMP-AMP synthase (cGAS), and RIG-I-like receptors (RLR).

TLRs are the best known of the PRRs and date back to discovery of these same type of receptors in Drosophila. There are 11 functional receptors that each sense different microbial components of bacteria, fungi, or virus. In each case, depending on which TLR is activated, specific adaptor molecules can be recruited (i.e., MyD88 dependent or TRAF3 dependent), and it is this adapter molecule recruitment that leads to specific TLR end signaling pathway activation (i.e., NFkB or IRF3, respectively). There is another equally important class of pattern recognition molecules, namely the NLR, which comprise a PRR family of proteins that are cytosolic located and sense a variety of microbial structures, such as peptidoglycan, and other microbial components, such as flagellin. NLRs consist of three domains: a C-terminal LRR domain, a central NOD oligomerization domain, and an N-terminal Caspase recruitment domain (CARD).

The NLR family can be divided into additional subsets related to function: in particular, related to inflammasome activation, autophagy (cell death), antigen presentation with signal propagation, and finally transcription activation. The N-terminus CARD (caspase recruitment) domain mediates protein–protein interactions and mediates the pyrin domain binding of the NLRP subfamily and subsequent activation of the inflammasome, which in turn leads to increased IL-1B secretion. Furthermore, the CARD domain of the NLR can also mediate the binding and activation of RIPK2, the upstream activating molecule of nuclear factor-kappa B (NF-κB), and MAPK signaling pathways. The C Terminus LRR domain is necessary for the binding and detection of bacterial end-product molecules such as muramyl dipeptide (MDP) ligands; it consists of leucine-rich amino acid strands, forming a peptide loop receptor.

These molecules can be recognized by the cytosolic-located PRRs NOD1 and NOD2, and other NLRs that detect bacterial and viral PAMPs (i.e., peptidoglycan, flagellin, viruses). These NLRs detect the presented bacterial or viral components and can then induce the inflammasome complex, which leads to, as mentioned above, caspase-1-mediated activation of the inflammasome and subsequent IL-1B and IL-18 release. The latter may influence the occurrence of tissue inflammation.

NOD2 is expressed in multiple cell types that reside within the gastrointestinal tract. These include Paneth cells, intestinal epithelial cells, stem cells, and stromal cells. NOD2 can also be expressed in innate cell types, such as monocyte, macrophage, and dendritic cells. More recently there has arisen controversy as to the role of this PRR in the occurrence of Crohn disease. In initial reports, it was thought that deficiencies in NOD2 lead to decreased bacterial clearance with subsequent increased NF-κB activity due to this activity. ^, In further studies, it has been demonstrated that NOD2 acts a regulatory molecule with its function to decrease IL-12 generation and NF-κB activity. NOD2 can also recruit the autophagy protein autophagy-related 16-like 1 (ATG16L1) to the plasma membrane at the site of bacterial entry to drive autophagy. In a similar vein, NOD1 signaling has been linked to regulatory activity through the activation and generation of interferon-α.

Thus the innate system serves a prominent protective function in all tissues and organs, especially the intestinal tract, genitourinary tract, respiratory tract, and 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, cathelicidins); complement, intraepithelial lymphocytes, dendritic cells, macrophages, and neutrophils. ^,

In summary, the PRR may be on the surface of either a cell (e.g., a TLR) or an intracellular molecule (e.g., an intracellular NOD protein). The interaction of an organism’s PAMP product with a cell’s PRR triggers a signaling cascade involving MAP kinases and IκB kinases, ultimately resulting in transcription of NF-κB responsive cytokine producing genes. The end result is cytokine (e.g., IL-1B, IL-6, tumor necrosis factor) 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 ( Fig. 40.1 ). ^,

The innate immune system is limited in its repertoire. It can only respond 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 natural killer T cells [NKT]). To activate the adaptive immune system, macrophages and dendritic cells take up and digest antigens and process and present the antigens 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 adapt with the generation of 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. Therefore, the immune system requires other types of cells that can respond acutely. Innate lymphoid cells (ILCs) are a recently identified family of cell types to be added to the quite complex immunologic system. Although ILCs provide significant defense at barrier sites, they can be located in tissues throughout the body.

In contrast to adaptive cells discussed in this chapter, ILCs do not express somatic rearranged antigen determined receptors that recognize self versus nonself antigens, as found on conventional lymphocytes. They do, however, display a functional responsivity that in ways is similar to that of adaptive T cells. Counterparts for each adaptive T-cell response, with the exception of the FOXP3 ⁺ T-regulatory cell, occur as shown in Fig. 40.2 and discussed in additional reviews. ILCs depend on various transcription factors that control their development and corresponding cytokine production (see Fig. 40.2 ). In looking at each of the subsets that can be generated, conventional NK (cNK) cells are the counterpart to conventional CD8 ⁺ T cells, as both have functions such as cytotoxicity and interferon-γ (IFN-γ) secretion. Whereas ILC1s express T-bet and produce IFN-γ, GATA-3 transcription factor is required for ILC2 generation and the secretion of Th2-like cytokines such as IL-5, IL-13, and the epidermal-growth-factor molecule amphiregulin. ^, ILC3s require the expression of RORγc ⁺ , the transcription factor, and correspond to Th17 cells with the secretion of IL-17. In humans, subsets of ILC3s exist which can be defined by expression of the marker NKp44 and CCR6 ⁺ . ^, The CCR6 ⁺ ILC3 population comprises lymphoid-tissue-inducer (LTi) cells that can also secrete IL-22 and are essential for formation of lymphoid organs and respond to fungal infections. ^, It has been demonstrated that ILCs can have plasticity in that the upregulation of the transcription factor T-bet in ILC3s can downmodulate the transcription factor retinoic acid receptor-related orphan nuclear receptor gamma (RORγt) and skew toward the generation of ILC1s, defined by ability of these cells to secrete IFN-γ. ILC cells, similar to adaptive conventional T cells, can also express integrin molecules that direct their migration. They can express α ₄ β ₇ , the corresponding counterpart of the adhesion molecule MadCAM-1, which is expressed reciprocally by endothelial venules of mucosal lymphoid tissue. In addition, ILCs express the chemokine receptor CXCR6—both of these integrins allow for migration to the intestine. ^, Of note, studies have demonstrated that ILCs rarely are replenished from the bone marrow at times of systemic depletion, in contrast to adaptive lymphocytes, which are constantly replaced. Whether ILCs play a role in human IBD remains uncertain. Several studies have demonstrated a change in either number or function of ILCs in Crohn disease. These reports have shown both increased IL-17 production by ILC3s as well as decreased numbers of ILC3 with increased ILC1 population. ^, Moreover, major histocompatibility complex (MHC) class II expression on ILC3s was found to be decreased in studies of pediatric patients with Crohn disease. In correlative studies, reduced expression of MHC class II was found to correlate with increased numbers of Th17 cells, and thus this report suggests that ILC3s might limit pathogenic T cells through reduced MHC class II.

Components of the Adaptive Immune Response

To trigger the cascade of immunologic events summarized in Table 40.3 , 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 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 systems. In addition, lamina propria DCs are dependent on the expression of the chemokine receptor CX3CR1 to form transepithelial dendrites, which enable the cells to directly sample luminal antigens.

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 MHC, and transport the peptide–MHC protein to the APC cell 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 (TCR) complex on the surface of the lymphocyte. Binding to the TCR 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. The recognition of specific MHC complexes mediates clonal responses to specific antigens and is under the control of signals received through a second signaling receptor, CD28, which binds to B7 molecules such as CD80/CD86. In the absence of a message through this second signal, CD28, no response occurs and the T cell becomes tolerant. In addition, to propagate the signaling pathway that leads to T-cell activation, this 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 CTLA-4 for attenuation of regulation and cellular disassociation, or macrophage 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 ( Fig. 40.3 ). ^,

Immune homeostasis is a delicate balance between stimulatory signals and those that block these signals and the consequent immune response. One of the major methods of achieving this is by inhibiting CD28-dependent signaling, thus forming a checkpoint regulation of the immune response. This is achieved through the CTLA4 protein, which is expressed predominately on T-regulatory and activated T cells. CTLA4 binds CD80 and CD86 molecules with high affinity, which competitively competes with the CD28 ligand and, therefore, blocks the T-cell signaling response. ^, Given its effects, CTLA4 mutations have been associated with potential risk alleles for a variety of diseases that affect multiple organs, such as Graves disease, celiac disease, diabetes, and systemic lupus erythematosus. ^, Similar to CTLA4 deficiency that occurs in mice, patients with CTLA4 deficiency can develop a T-cell infiltrative disease in several organs, including the intestines, lungs, bone marrow, central nervous system, and kidneys.

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 ( Fig. 40.4 ). 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 (see Fig. 40.4 ). These pathways are separate but synergistic, and inhibition of one or the other may abrogate T-cell activation.

Calcineurin and protein kinase C 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 the 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, EDI (ectodermal dysplasia with immune deficiency), a syndrome associated with a variety of skin, facial, and dental 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 AP-1, an important pathway necessary for cellular proliferation. ^,

Primary immune deficiencies can therefore present with a wide amount of clinical immune phenotypes with both immune and nonimmune features. The variety of causes of PIDs are predominately deleterious to the function of the targeted protein and are usually rare (<0.1%) in nature. This contrasts with other common genetic variants (≥0.1%) that contribute to the development of more general immunological diseases, such as intestinal inflammation or other autoimmune disease states. Concerning T-cell differentiation and mutations that can occur in the various chains that comprise the TCR, TCRα mutations can result in the loss of TCRαβ-expressing T cells and clinical features consistent with both autoimmunity and immunodeficiency. Patients present with recurrent respiratory infections and various viral infections (such as varicella and Epstein-Barr virus [EBV] infections). Other clinical manifestations can include otitis media, fungal infections (candidiasis), diarrhea, failure to thrive, hemolytic anemia, and significant lymphadenopathy. The loss of either CD3ε or CD3δ can also result in the selective loss of T cells. In addition, patients present with diminished class-switched immunoglobulins with subsequent recurrent respiratory infections, along with significant intestinal inflammation. Lastly, loss of CD3γ can result in combined immunodeficiencies and autoimmunity, which include susceptibility to viral, bacterial, and fungal infections; occurrence of hypogammaglobulinemia; hemolytic anemia; and significant intestinal inflammation.

ZAP-70 is another critical component of T-cell signaling; if deficient, it lends itself to significant T-cell abnormalities. ZAP-70 deficiency can be characterized as a selective deficiency of CD8 ⁺ T cells, ^, and although the number of CD4 ⁺ T cells is normal, their function is defective, as they exhibit abnormal calcium flux in response to TCR engagement, resulting in defective TCR signaling. Clinical features of these patients include recurrent infections (including bacterial and viral lung infections and fungal infections such as candidiasis), hypogammaglobulinemia, and intestinal inflammation. ^,

Inducible T-cell costimulatory (ICOS), another factor critical for T-cell activation, is upregulated on the surface of activated T cells and has structural similarities to CD28 and CTLA-4. ICOS is important for the development of T cell-dependent antibody responses and the formation of germinal center through a stimulation of ICOS-dependent T follicular cells in the germinal center. ^, Furthermore, ICOS deficiency leads to decreased class-switched and memory B cells, and therefore decreased serum immunoglobulins. ^, Thus mutations in ICOS lead to the occurrence of poor humoral antibody generation and the disease common variable immunodeficiency (CVID). Clinical features of the latter include recurrent bacterial infections, sinusitis, bronchiectasis, pneumonia, hepatosplenomegaly, and malignancy (such as B-cell lymphoma and follicular-cell lymphoma). A subset of patients can develop autoimmune liver disease such as nodular regenerative hyperplasia and autoimmune hepatitis. In addition, other subsets of patients can develop an intestinal inflammation reminiscent of Crohn disease, as this disorder and that of liver disease are mediated by an IL-12 IFN-γ process. In each of these cases, disease states can be quite severe with few medical treatment alternatives. ^,

Based on studies performed with murine T-lymphocyte clones, helper (CD4) T lymphocytes have been categorized into broad types—Type 1 helper T cells (Th1), Th2, Th17, and T regulatory (see Fig. 40.3 ). These functional T-cell subtypes mature from naïve CD4 helper T cells, depending upon the presence of specific cytokine milieu. Cytokines secreted by dendritic cells and other antigen-presenting cells are essential in determining whether Th1, Th2, or Th17 cells are generated; release of IFN-γ and IL-12 preferentially promotes differentiation of Th1 cells, and as 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 an important role in the formation of these Th17 cells. IL-23 released by activated dendritic (antigen presenting cells), initially thought to be an important factor in the induction of IL-17 producing cells, has more recently been reported to be important in the maturation and stability of Th17 cells. The primary role of the Th17 subset of helper T cells is the elimination of bacterial and fungal pathogens. ^, The activation of such Th17 cells requires the binding of receptors with the aforementioned PAMPs, such as dectin-1 and dectin-2, which are expressed by DCs and macrophages. ^,

Th1 promote cellular immune responses and delayed-type hypersensitivity by secreting IL-2, INF-γ, and tumor necrosis factor β (TNF-β). In contrast, 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 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, G-CSF, GM-CSF, IL-1β, TNF-α) and factors that affect the aforementioned recruitment of cells (i.e., IL-8, GRO-α). Although all these cell types are involved in host defense, dysregulation of these pathways with increased cytokine secretion can result in disease pathogenesis. Th1 and Th17 cells have been implicated in the pathogenesis of Crohn 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 clearly can have implications. Thus it has been shown that abnormalities in regulators of inflammation can result in diseases affecting host defense. Recent discoveries in the regulation of the inflammatory pathway have demonstrated STAT3 (signal transducer and activator of transcription 3) and NF-κβ. In relation to the latter, an additional downstream molecule, SOC3 (suppressor of cytokine secretion 3), plays a significant role in IL-17 production in that in its absence, IL-23-induced STAT-3 phosphorylation is enhanced, leading to increased IL-17 activation. However, in impaired regulation of these important host defense inflammatory pathways, in particular Job syndrome (Hyper-Ig-E syndrome), it has been shown that an underlying defect in STAT3 gene encoding results in a dominant negative effect leading to decreased IL-17 response to extracellular pathogens. The dominant negative STAT3 mutations specifically impair the development and function of the Th17 subset cells Naïve T cells in patients with Job syndrome are defective in proliferation and differentiation into central memory T cells that can lead to poor suppression of various viruses (i.e., EBV and zoster viruses). Clinical features include the occurrence of pneumonias and a host of other abnormalities (i.e., eczema, abscess formation mucocutaneous candidiasis, Staphylococcus infection, recurrent fungal infections, increased IgE, and eosinophilia-related disorders). ^,

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 antiinflammatory 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 INF-γ, whereas TGF-β inhibits B- and T-cell proliferation or effects NF-κβ cytokine transcription. The TGF-β secreting regulatory T cells are characterized by a transcription factor called Forkhead box P3 FOXP3, and mutations in this gene in humans results in immune dysfunction, polyendocrinopathy, enteropathy, X-linked (IPEX), a rare cause of infantile autoimmunity (discussed later in this chapter).

In brief, IPEX is an X-linked autoimmune disorder that affects multi-organ systems and results in early-onset severe colitis, candidiasis, eczema, diabetes, hypothyroidism, and autoimmune cytopenias. ^, (FOXP3 is the master transcription factor initiating the development and maintenance of regulatory T cells.) FOXP3-mediated T regulatory cells home to the sites of inflammation and downregulate the immune response through multiple effects, including IL-2 consumption and CTLA-4-mediated inhibition of CD28 ligands. IPEX disease has overlapping clinical similarities, specifically intestinal inflammation, with other immunodeficiency abnormalities that are associated with T-regulatory suppressive deficiencies such as CTLA-4 deficiency, IL-2 signaling defects, and BACH2 deficiency (see below discussion). This further confirms the important role of this cell population in the control of intestinal homeostasis.

Humoral immunity is generated by B lymphocytes, which, on exposure to antigen, proliferate and differentiate into plasma cells ( Fig. 40.5 ). All B cells are initially programmed to synthesize IgD or IgM (see Fig. 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 Fig. 40.5 ). 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 ICOS, is also important in B-cell differentiation, and ICOS mutations have been associated with CVIDs. 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 the B-cell phenotype.

In addition, T cell-dependent antibody responses are also controlled by the innate immune system that utilizes similar molecular pathways. Coengagement of the BCR can occur with the receptor CD21, which recognizes whether an antigen has processed the complement system by attachment of a complement component (specifically C3d) to the aforementioned antigen. Such attachment of C3d to the antigen results in increased recognition within the BCR of B cells. CD21 can then transmit a signal through the signal-transduction receptor CD19 complex to induce signaling via PI3Kinase that coactivates the BCR. Lastly, antibody responses, specifically IgG1 and IgG3 isotypes, can be regulated by TLR signaling through PAMP recognition.

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 either from direct mutations in B-cell genes (e.g., TACI, which results in selective IgA or CVID) or by mutations in T-cell genes (e.g., CD 40 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 (inducible costimulator), a member of the CD28 family, can also lead to decreased B-cell maturation and immunoglobulin production.

The end 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 as observed above in three principal types of clinical disorders in immunodeficient patients: susceptibility to infection may be increased, and 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. Finally, these patients may have increased long-term risk of malignancy.

Humoral Immunodeficiencies

Selective Immunoglobulin A Deficiency

Selective IgA deficiency is the most common primary immunodeficiency, with a prevalence of approximately 1 in 500 (ranging from 1:163 in Spain to 1:965 in Brazil). 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 (<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, and there are multiple genetic mutations that result in low IgA. 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 in part to be due to a compensatory increase in secretory IgM, and possibly in IgG as well. In symptomatic patients, respiratory complications (including pneumonia and sinusitis) and atopic disease are the most commonly reported problems. ^, However, patients with IgA deficiency are at increased risk for infections, gastrointestinal disease, and autoimmune disease ( Table 40.4 ). 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 villous atrophy and secondary malabsorption. Chronic Strongyloides infection, poorly responsive to anthelminthic therapy, has also been reported. Interestingly, individuals with selective IgA deficiency are able to resolve rotavirus disease and actually show higher total IgG and IgG1 subclass antibody titers to rotavirus than people with normal IgA levels. This suggests that IgA is not needed to clear rotavirus in humans.

TABLE 40.4

Disorders Associated With Selective Immunoglobulin A Deficiency

Data from Cunningham-Rundles, Leung et al., and Meini et al.

Upper respiratory infections

Otitis media

Sinusitis

Bronchiectasis

Allergic disorders (including food allergies, asthma, eczema)

Anaphylaxis to intravenous immunoglobulin

Giardiasis

Strongyloidiasis

Nodular lymphoid hyperplasia

Celiac disease (with false-negative antiendomysial antibody)

Achlorhydria

Malabsorption villous atrophy

Cholelithiasis

Inflammatory bowel disease

Primary biliary cirrhosis

Gastrointestinal carcinoma and lymphoma

Henoch-Schönlein purpura

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 antitissue 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. ^, 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 GI complications reported in selective IgA deficiency have included ulcerative colitis, Crohn 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 of having 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 with only 47.6% of age- and gender-matched controls.

While there is no cure for selective IgA deficiency, management includes antibiotic therapy for lung disease, supplemental immune globulin for patients with recurrent infection, and prevention of infection by judicious administration of vaccines (including pneumococcal and meningococcal vaccine). 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 used with caution in patients with selective IgA deficiency, because it does not cross mucosal surfaces and may result in systemic anaphylaxis. In such patients, subcutaneous IG or IVIG with low levels of IgA is preferred. Because of the risk of anaphylaxis with blood products, it is recommended that blood products given to an individual with selective IgA deficiency be saline washed. Finally, a small number of patients with selective IgA deficiency may develop CVID, which has a much higher prevalence of gastrointestinal complications.

X-Linked Agammaglobulinemia

X-linked (Bruton) 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 dermatomyositis) may also develop. Gastrointestinal symptoms, including abdominal pain and chronic diarrhea, are reported by approximately 20% of patients with XLA. 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. ^, According to a survey of an immune deficiency network, approximately 4% of patients self-report being diagnosed with Crohn disease. Treatment for such patients includes a combination of intravenous immune globulin and conventional Crohn therapy ( Fig. 40.6 ). ^, Small bowel strictures and transmural intestinal fissures may occur, but no granulomas or plasma cells are identified when strictures are resected. In one reported case, the regional enteritis of the terminal ileum in a patient with XLA was thought to be due to 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 the Helicobacter species. 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 X-linked agammaglobulinemia, patients were given a liquid intravenous immunoglobulin 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 X-linked gammaglobulinemia have a quality of life that is superior to children with rheumatic disease.

Hyper-immunoglobulin M Syndrome

This 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 raised 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 T cell’s CD40 ligand 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 at between 1 month and 10 years of life with opportunistic infections. The most common reported infections are in the respiratory tract, with 30% of patients reporting Pneumocystis jiroveci pneumonia. Chronic encephalitis and idiopathic neurologic deterioration may occur. Gastrointestinal symptoms have been reported in 25% to 30% of patients. Conditions identified include histoplasmosis of the esophagus, cryptosporidiosis, giardiasis, hepatosplenomegaly, intestinal lymphoid hyperplasia, and recurrent large painful oral ulcerations ( Figs. 40.7 and 40.8 ). ^{, ,} 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. Sclerosing cholangitis and cirrhosis occur in up to 35% of patients older than 10 years of age. ^, Often, the sclerosing cholangitis is secondary to Cryptosporidium infection. Pancreatic and hepatobiliary malignancies have been reported in patients as young as 7 years of age. Liver transplantation has been successfully performed in some patients with advanced liver disease.

Therapy of hyper-IgM involves gamma globulin replacement therapy and treatment of specific infectious complications. Gamma 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-IgMWhile 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.

Cellular Immunodeficiencies