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Primary Immune Deficiency Diseases Alain Fischer

INTRODUCTION Immunity is intrinsic to life and an important tool in the fight for survival against pathogenic microorganisms. The human immune system can be divided into two major components: the innate immune system and the adaptive immune system (see Chap. 314). The innate immune system provides the rapid triggering of inflam-matory responses based on the recognition (at the cell surface or within cells) of either molecules expressed by microorganisms or molecules that serve as “danger signals” released by cells under attack. These receptor/ligand interactions trigger signaling events that ultimately lead to inflammation. Virtually all cell lineages (not just immune cells) are involved in innate immune responses; how-ever, myeloid cells (i.e., neutrophils and macrophages) play a major role because of their phagocytic capacity. The adaptive immune system operates by clonal recognition of antigens followed by a dramatic expansion of antigen-reactive cells and execution of an immune effector program. Most of the effector cells die off rapidly, whereas memory cells persist. Although both T and B lymphocytes recognize distinct chemical moieties and execute distinct adaptive immune responses, the latter is largely dependent on the former in generating long-lived humoral immunity. Adaptive responses utilize components of the innate immune system; for example, the antigen-presentation capabilities of dendritic cells help to determine the type of effector response. Not surprisingly, immune responses are controlled by a series of regulatory mechanisms.

Hundreds of gene products have been characterized as effectors or mediators of the immune system (see Chap. 314). Whenever the expression or function of one of these products is genetically impaired (provided the function is nonredundant), a primary immunodeficiency (PID) occurs.

Primary immunodeficiencies are genetic diseases with primarily Mendelian inheritance. More than 200 conditions have now been described and deleterious mutations in approximately 150 genes have been identified. The overall prevalence of PIDs has been esti-mated in various countries at 5 per 100,000 individuals; however, given the difficulty in diagnosing these rare and complex diseases, this figure is probably an underestimate. Primary immunodeficien-cies can involve all possible aspects of immune responses, from innate through adaptive, cell differentiation, effector function and regulation. For the sake of clarity, PIDs should be classified according to (1) the arm of the immune system that is defective and (2) the mechanism of the defect (when known). Table 316-1 classifies the most prevalent PIDs according to this manner of clas-sification; however, one should bear in mind that the classification of PIDs sometimes involves arbitrary decisions because of overlap and, in some cases, lack of data.

The consequences of PIDs vary widely as a function of the mol-ecules that are defective. This concept translates into multiple levels of vulnerability to infection by pathogenic and opportunistic micro-organisms, ranging from extremely broad [as in severe combined immunodeficiency (SCID)] to narrowly restricted to a single micro-organism [as in Mendelian susceptibility to mycobacterial disease

(MSMD)]. The locations of the sites of infection and the causal microorganisms involved will thus help physicians arrive at proper diagnoses. Primary immunodeficiencies can also lead to immu-nopathological responses such as allergy (as in Wiskott Aldrich syndrome), lymphoproliferation, and autoimmunity. A combina-tion of recurrent infections, inflammation and autoimmunity can be observed in a number of PIDs, thus creating obvious therapeutic challenges. Finally, some PIDs increase the risk of cancer, notably but not exclusively lymphocytic cancers, e.g. lymphoma.

DIAGNOSIS OF PRIMARY IMMUNODEFICIENCIES The most frequent symptom prompting the diagnosis of a PID is the presence of recurrent or unusually severe infections. As men-tioned above, recurrent allergic or autoimmune manifestations may also alert the physician to a possible diagnosis of PID. In such cases, a detailed account of the subject’s personal and family medi-cal history should be obtained. It is of the utmost importance to gather as much medical information as possible on relatives and up to several generations of ancestors. In addition to the obvious focus on primary symptoms, the clinical examination should evaluate the size of lymphoid organs and, when appropriate, look for the characteristic signs of a number of complex syndromes that may be associated with a PID.

The performance of laboratory tests should be guided to some extent by the clinical findings. Infections of the respiratory tract (bronchi, sinuses) mostly suggest a defective antibody response. In general, invasive bacterial infections can result from comple-ment deficiencies, signaling defects of innate immune responses, asplenia, or defective antibody responses. Viral infections, recur-rent Candida infections, and opportunistic infections are generally suggestive of impaired T cell immunity. Skin infections and deep-seated abscesses primarily reflect innate immune defects (such as chronic granulomatous disease); however, they may also appear in the autosomal dominant hyper IgE syndrome. Table 316-2 summa-rizes the laboratory tests that are most frequently used to diagnose a PID. More specific tests (notably genetic tests) are then used to make a definitive diagnosis.

The primary immunodeficiencies discussed below have been grouped together according to the affected cells and the mecha-nisms involved ( Table 316-1 , Fig. 316-1 ).

PRIMARY IMMUNODEFICIENCIES OF THE INNATE IMMUNE SYSTEM

Primary immunodeficiencies of the innate immune system are rela-tively rare and account for approximately 10% of all PIDs.

SEVERE CONGENITAL NEUTROPENIA m

Severe congenital neutropenia (SCN) consists of a group of inher-ited diseases that are characterized by severely impaired neutrophil counts (<500 polymorphonuclear leukocytes (PMN)/μL of blood). The condition is usually manifested from birth. Severe congenital neutropenia may also be cyclic (with a 3-week periodicity), and other neutropenia syndromes can also be intermittent. Although the most frequent inheritance pattern for SCN is autosomal domi-nant, autosomal recessive and X-linked recessive conditions also exist. Bacterial infections at the interface between the body and the external milieu (e.g., the orifices, wounds, and the respiratory tract) are common manifestations. Bacterial infections can rapidly progress through soft tissue and are followed by dissemination in the bloodstream. Severe visceral fungal infections can also ensue. The absence of pus is a hallmark of this condition.

Diagnosis of SCN requires examination of the bone marrow. Most SCNs are associated with a block in granulopoiesis at the

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promyelocytic stage ( Fig. 316-1 ). Severe congenital neutropenia has multiple etiologies, and to date mutations in 11 different genes have been identified. Most of these mutations result in isolated SCN, whereas others are syndromic (see Chap. 60). The most frequent forms of SCN are caused by the premature cell death of granulocyte precursors, as observed in deficiencies of GFI1, HAX1, and elastase 2 (ELA2), with the latter accounting for 50% of SCN sufferers. Certain ELA2 mutations cause cyclic neutropenia syndrome. A gain-of-function mutation in the WASP gene (see the section on WAS below) causes X-linked SCN, which is also associated with monocytopenia.

As mentioned above, SCN exposes the patient to life-threatening, disseminated bacterial and fungal infections. Treatment requires

careful hygiene measures, notably in infants. Later in life, special oral and dental care is essential, along with the prevention of bacterial infection by prophylactic admin-istration of sulfamethoxazole/trimethoprim. Subcutaneous injection of the cytokine granu-locyte colony-stimulating factor (G-CSF) usu-ally improves neutrophil development and thus prevents infection in most SCN diseases. However, there are two caveats: (1) a few cases of SCN with ELA2 mutation are refractory to G-CSF and may require curative treat-ment via allogeneic hematopoietic stem cell transplantation (HSCT) and (2) a subset of G-CSF-treated patients carrying ELA2 muta-tions are at a greater risk of developing acute myelogenous leukemia associated (in most cases) with somatic gain-of-function muta-tions of the G-CSF receptor gene.

ASPLENIA m

Primary failure of the development of a spleen is an extremely rare disease that can be either syndromic (in Ivemark syndrome) or isolated with an autosomal dominant expression; in the latter case, the gene remains to be identi-fied. Due to the absence of natural filtration of microbes in the blood, asplenia predisposes affected individuals to fulminant infections by encapsulated bacteria. Although most infec-tions occur in the first years of life, cases may also arise in adulthood. The diagnosis is confirmed by abdominal ultrasonography and the detection of Howell-Jolly bodies in red blood cells. Effective prophylactic mea-sures (twice-daily oral penicillin and appro-priate vaccination programs) usually prevent fatal outcomes. The genetic causes of asplenia remain unknown.

LEUKOCYTE ADHESION m

DEFICIENCY (LAD) Leukocyte adhesion deficiency consists of three autosomal recessive conditions (LAD I, II and III) (see Chap. 60). The most frequent condition (LAD I) is caused by mutations in the β2 integrin gene; following leukocyte activation, β2 integrins mediate adhesion to inflamed endothelium expressing cognate ligands. LAD III results from a defect in a regu-latory protein (kindlin, also known as Fermt 3) involved in activating the ligand affinity of β2

integrins. The extremely rare LAD II condition is the end result of a defect in selectin-mediated leukocyte rolling that occurs prior to β2 integrin binding. There is a primary defect in fucose transporter such that oligosaccharide selectin ligands are missing in this syn-dromic condition.

Given that neutrophils are not able to reach infected tissues, LAD renders the individual susceptible to bacterial and fungal infec-tions in a way that is similar to that of patients with SCN. LAD also causes impaired wound healing and delayed loss of the umbilical cord. A diagnosis can be suspected in cases of pus-free skin/tissue infections and massive hyperleukocytosis (>30,000/μL) in the blood (mostly granulocytes). Patients with LAD III also develop bleed-ing because the β2 integrin in platelets is not functional. Use of

TABLE 316-1 Classification of Primary Immune Deficiency Diseases

Deficiencies of the Innate Immune System

Phagocytic cells:

Impaired production: severe congenital neutropenia (SCN) -

Asplenia -

Impaired adhesion: leukocyte adhesion deficiency (LAD) -

Impaired killing: chronic granulomatous disease (CGD) -

Innate immunity receptors and signal transduction:

Defects in Toll-like receptor signaling -

Mendelian susceptibility to mycobacterial disease -

Complement deficiencies:

Classical, alternative, and lectin pathways -

Lytic phase -

Deficiencies of the Adaptive Immune System

T lymphocytes:

Impaired development - Severe combined immune deficiencies (SCIDs) Di George syndrome

Impaired survival, migration, function - Severe combined immunodeficiencies

Hyper IgE syndrome (autosomal dominant)

CD40 ligand deficiency

Wiskott Aldrich syndrome

Ataxia telangiectasia and other DNA repair deficiencies

B lymphocytes:

Impaired development -

Impaired function -

XL and AR agammaglobulinemia

Hyper IgM syndrome

Common variable immunodeficiency (CVID)

IgA deficiency

Regulatory Defects

Innate immunity Autoinflammatory syndromes (outside the scope of this chapter)

Severe colitis

Adaptive immunity Hemophagocytic lymphohistiocytosis (HLH)

Autoimmune lymphoproliferation syndrome (ALPS)

Autoimmunity and inflammatory diseases

(IPEX, APECED)

Abbreviations: APECED, autoimmune polyendocrinopathy candidiasis ectodermal dysplasia; AR, autosomal recessive; IPEX, immunodysregulation polyendocrinopathy enteropathy X-linked syndrome; XL, X-linked.

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TABLE 316-2 Test Most Frequently Used to Diagnose a Primary Immune Deficiency (PID)Test Information PID Disease

Blood cell counts and cell morphology Neutrophil counts

Lymphocyte counts*

Eosinophilia

Howell-Jolly bodies

¯Severe congenital neutropenia, LAD

T cell ID

WAS, Hyper IgE syndrome

Asplenia

Chest x-ray Thymic shadow

Costochondral junctions

SCID, Di George syndrome

Adenosine deaminase deficiency

Bone x-ray Metaphyseal ends Cartilage hair hypoplasia

Immunoglobulin serum levels IgG, IgA, IgM

IgE

B cell ID

Hyper IgE syndrome, WAS, T cell ID

Lymphocyte phenotype T, B lymphocyte counts T cell ID, agammaglobulinemia

Dihydrorhodamine fluorescence (DHA) assay

Nitro blue tetrazolium (NBT) assay

Reactive oxygen species

Production by PMN

Chronic granulomatous disease

CH50, AP50 Classic and alternative complement pathways Complement deficiencies

Ultrasonography of the abdomen Spleen size Asplenia

*Normal counts vary with age. For example, the lymphocyte count is between 3000 and 9000/µL of blood below the age of 3 months and between 1500 and 2500/µL in adults.Abbreviations: ID, immunodeficiency; LAD, leukocyte adhesion deficiency; PMNs, polymorphonuclear leukocytes; SCID, severe combined immunodeficiency; WAS, Wiskott Aldrich syndrome.

NeutrophilPhagocytosis

Phagocytosis

KillingROS production

KillingROS production

Adhesion

Migration

HSC CMP

MB

SCN WHIM LAD CGD

CGD

MSMD

GMprog.

Monoblast

Promono

Promyelo. myelo.

Monocyte

Dendritic cells

Tissue macrophages

Bone Marrow Blood Tissue

Figure 316-1 Differentiation of phagocytic cells and related primary immunodeficiencies (PIDs). Hematopoietic stem cells (HSCs) differentiate into common myeloid pro-genitors (CMPs) and then granulocyte-monocyte progenitors (GM-prog.) which, in turn, differentiate into neutrophils (mb: myeloblasts; promyelo: promyelocytes; myelo: myelocytes) or monocytes (monoblasts and promonocytes). Upon activation, neutrophils adhere to the vascular endothelium, transmigrate, and phagocytose the targets. Reactive oxygen species (ROS) are delivered to the microorganism-containing phagosomes.

Macrophages in tissues kill using the same mechanism. Following activation by interferon γ (not shown here), mac-rophages can be armed to kill intracellular pathogens such as mycobacteria. For sake of simplicity, not all cell differentiation stages are shown. The abbreviations for PIDs are contained in boxes placed at corresponding stages of the pathway. SCN, severe congenital neutropenia; WHIM, warts, hypogamma-globulinemia, immunodeficiency myelokathexis; LAD, leukocyte adhesion deficiencies; CGD, chronic granulomatous diseases; MSMD, Mendelian susceptibility to mycobacterial disease.

[AU: Figure was redrawn. Please review.]

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immunofluorescence and functional assays to detect β2 integrin can help form a diagnosis. Severe forms of LAD may require hematopoi-etic stem cell transplantation (HSCT), although gene therapy is also now being considered. Neutrophil-specific granule deficiency (a very rare condition caused by a mutation in the gene for transcrip-tion factor C/EBPα) results in a condition that is clinically similar to LAD.

CHRONIC GRANULOMATOUS DISEASES m

Chronic granulomatous diseases (CGDs) are characterized by impaired phagocytic killing of microorganisms by neutrophils and macrophages (see Chap. 30). The incidence is approximately 1 per 200,000 live births. About 70% of cases are associated with X-linked recessive inheritance versus autosomal inheritance in the remain-ing 30%. CGD causes deep-tissue bacterial and fungal abscesses in macrophage-rich organs such as the lymph nodes, liver, and lungs. Recurrent skin infections (such as folliculitis) are common and can prompt an early diagnosis of CGD. The infectious agents are typi-cally catalase-positive bacteria (such as Staphylococcus aureus and Serratia marcescens ) but also include Burkholderia cepacia , patho-genic mycobacteria (in certain regions of the world), and fungi (mainly filamentous molds, such as Aspergillus ).

CGD is caused by defective production of reactive oxygen species (ROS) in the phagolysosome membrane following phagocytosis of microorganisms. It results from the lack of a component of NADPH oxidase (gp91phox or p22phox) or of the associated adapter/activating proteins (p47phox, p67phox or p40phox) that mediate the transport of electrons into the phagolysosome for creating ROS by interaction with O 2 . Under normal circumstances, these ROS either directly kill engulfed microorganisms or enable the rise in pH needed to activate the phagosomal proteases that contribute to microbial killing. Diagnosis of CGD is based on assays of ROS production in neutrophils and monocytes (see Table 316-2 ). As its name suggests, CGD is also a granulomatous disease. Macrophage-rich granulomas can often arise in the liver, spleen, and other organs. These are sterile granulomas that cause disease by obstruction (bladder, pylorus, etc.) or inflammation (colitis, restrictive lung disease).

The management of infections in patients with CGD can be a complex process. The treatment of bacterial infections is generally based on combination therapy with antibiotics that are able to pen-etrate into cells. The treatment of fungal infections requires aggres-sive, long-term use of antifungals. Inflammatory/granulomatous lesions are usually steroid-sensitive; however, glucocorticoids often contribute to the spread of infections. Hence, there is strong need for new therapeutic options in what is still a poorly understood disease.

The treatment of CGD mostly relies on preventing infections. It has been unambiguously demonstrated that prophylactic usage of sulfamethoxazole/trimethoprim is both well tolerated and highly effective in reducing the risk of bacterial infection. Daily adminis-tration of azole derivatives (notably intraconazole) also reduces the frequency of fungal complications. It has long been suggested that interferon-γ administration is helpful, although medical experts continue to disagree over this controversial issue. Most patients do reasonably well with prophylaxis and careful management. However, some patients develop severe and persistent fungal infec-tions and/or chronic inflammatory complications that ultimately require hematopoietic stem cell transplantation (HSCT). The latter is an established curative approach for CGD; however, the benefit/risk ratio must be carefully assessed on a case-by-case basis. Gene therapy approaches are also being evaluated.

MENDELIAN SUSCEPTIBILITY TO MYCOBACTERIAL m

DISEASE (MSMD) This group of diseases is characterized by a defect in the IL-12-interferon (IFN)-γ axis (including IL12p40, IL12 receptor (R) β 1 ,

interferon-γ R 1 and R 2 and STAT1 deficiencies), which ultimately leads to impaired IFN-γ-dependent macrophage activation. Both recessive and dominant inheritance modes have been observed. The hallmark of this PID is a specific and narrow vulnerability to tuberculous and nontuberculous mycobacteria. The most severe phenotype (as observed in complete IFN-γ receptor deficiency) is characterized by disseminated infection that can be fatal even when aggressive and appropriate antimycobacterial therapy is applied. In addition to mycobacterial infections, MSMD patients (and particu-larly those with an IL-12/IL-12 R deficiency) are prone to develop-ing Salmonella infections. Although MSMDs are very rare, they should be considered in any patient with persistent mycobacterial infection. Treatment with interferon-γ may efficiently bypass an IL-12/IL-12 R deficiency.

TOLL-LIKE RECEPTOR (TLR) PATHWAY DEFICIENCIES m

In a certain group of patients with early-onset, invasive Streptococcus pneumoniae infections or (less frequently) Staphylococcus aureus or other pyogenic infections, conventional screening for PIDs does not identify the cause of the defect in host defense. It has been estab-lished that these patients carry recessive mutations in genes that encode essential adaptor molecules (IRAK4 and MYD88) involved in the signaling pathways of the majority of known Toll-like recep-tors (TLRs) (see Chap. 314). Remarkably, susceptibility to infec-tion appears to decrease after the first few years of life—perhaps an indication that adaptive immunity (once triggered by an initial microbial challenge) is then able to prevent recurrent infections.

Certain TLRs (TLR3, 7, 8 and 9) are involved in the recognition of RNA and DNA and usually become engaged during viral infec-tions. Very specific susceptibility to herpes simplex encephalitis has been described in patients with a deficiency in Unc93b (a molecule associated with TLR-3, -7, -8 and -9 and probably required for correct subcellular localization) or TLR3. The fact that no other TLR deficiencies have been found—despite extensive screening of patients with unexplained, recurrent infections—strongly suggests that these receptors are functionally redundant. Hypomorphic mutations in NEMO/IKK-γ (a member of the NF-KB complex, which is activated downstream of TLR receptors) lead to a complex, variable immunodeficiency and a number of associated features. Susceptibility to both invasive, pyogenic infections and mycobacte-ria may be observed in this particular setting.

COMPLEMENT DEFICIENCY m

The complement system is composed of a complex cascade of plasma proteins (see Chap. 314) that leads to the deposition of C3b fragments on the surface of particles and the formation of immune complexes that can culminate in the activation of a lytic complex at the bacterial surface. C3 cleavage can be mediated via three path-ways: the classic, alternate, and lectin pathways. C3b coats particles as part of the opsonization process that facilitates phagocytosis following binding to cognate receptors. A deficiency in any com-ponent of the classic pathway (C1q, C1r, C1s, C4, and C2) can pre-dispose an individual to bacterial infections that are tissue-invasive or that occur in the respiratory tract. Likewise, a C3 deficiency or a deficiency in factor I (a protein that regulates C3 consumption, thus leading to a C3 deficiency due to its absence) also results in the same type of vulnerability to infection. It has recently been reported that a very rare deficiency in Ficolin-3 predisposes affected individuals to bacterial infections. Deficiencies in the alternative pathway (factors D and properdin) are associated with the occurrence of invasive Neisseria infections.

Lastly, deficiencies of any complement component involved in the lytic phase (C5, C6, C7, C8 and, to a lesser extent, C9) predis-pose affected individuals to systemic infection by Neisseria . This is explained by the critical role of complement in the lysis of the

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thick cell wall possessed by this class of bacteria.

Diagnosis of a complement deficiency relies primarily on testing the status of the classic and alternate pathway via func-tional assays, i.e., the CH50 and AP50 tests, respectively. When either pathway is profoundly impaired, determination of the status of the relevant compo-nents in that pathway enables a precise diagnosis. Appropriate vaccinations and daily administration of oral penicillin are efficient means of preventing recurrent infections. It is noteworthy that several complement deficiencies (in the classic pathway and the lytic phase) may also predispose affected individuals to auto-immune diseases (notably systemic lupus erythematosus; see Chap. 319).

PRIMARY IMMUNODEFICIENCIES OF THE ADAPTIVE IMMUNE SYSTEM

m T LYMPHOCYTE DEFICIENCIES ( TABLE 316-1 , FIGS. 316-2 AND 316-3)

Given the central role of T lymphocytes in adaptive immune responses (see Chap. 314), PIDs involving T cells generally have severe pathological consequences; this explains the poor overall progno-sis and the need for early diagnosis and the early intervention with appropriate therapy. Several differentiation pathways of T cell effectors have been described, one or all of which may be affected by a given PID ( Fig. 316-2 ). Follicular helper CD4+ T cells in germinal centers are required for T-dependent antibody pro-duction, including the generation of Ig class switched, high-affinity antibodies. CD4+ T H1 cells provide cytokine-dependent (mostly interferon-γ-dependent) help to mac-rophages for intracellular killing of various microorganisms, includ-ing mycobacteria and salmonella . CD4+ T H2 cells produce IL-4, IL-5, and IL-13 and thus recruit and activate eosinophils and other cells required to fight helminth infections. CD4+ T H17 cells produce IL-17 and IL-22 cytokines that recruit neutrophils to the skin and lungs to fight bacterial and fungal infections. Cytotoxic CD8+ T cells can kill infected cells, notably in the context of viral infections. In addition, certain T cell deficiencies predispose affected individuals to Pneumocystis jiroveci lung infections early in life and to chronic gut/biliary duct/liver infections by Cryptosporidia and related gen-era later on in life. Lastly, naturally occuring or induced regulatory T cells are essential for controlling inflammation (notably reactivity to commensal bacteria in the gut) and autoimmunity. The role of other T cell subsets with limited T cell receptor (TCR) diversity [such as γδTCR T cells or natural killer T (NKT) cells] in PIDs is less well known; however, these subsets can be defective in certain PIDs and this finding can sometimes contribute to the diagnosis (e.g., NKT cell deficiency in X-linked proliferative syndrome). T cell deficiencies account for approximately 20% of all cases of PID.

Severe Combined Immunodeficiencies Severe combined immunodeficiencies (SCIDs) constitute a group of rare PIDs characterized by a profound block in T cell development

and thus the complete absence of these cells. The developmental block is always the consequence of an intrinsic deficiency. The inci-dence of SCID is estimated to be 1 in 50,000 to 100,000 live births. Given the severity of the T cell deficiency, clinical consequences occur early in life (usually within 3 to 6 months of birth). The most frequent clinical manifestations are recurrent oral candidiasis, fail-ure to thrive, and protracted diarrhea and/or acute interstitial pneu-monitis caused by Pneumocystis jiroveci (although the latter can also be observed in the first year of life in children with B cell deficien-cies). Severe viral infections or invasive bacterial infections can also occur. Patients may also experience complications related to infec-tions caused by live vaccines (notably BCG) that may lead not only to local and regional infection but also to disseminated infection manifested by fever, splenomegaly, and skin and lytic bone lesions. A scaly skin eruption can be observed in a context of maternal T cell engraftment (see below). A diagnosis of SCID can be suspected on the basis of the patient’s clinical history and, possibly, a family his-tory of deaths in very young children (suggestive of either X-linked or recessive inheritance). Lymphocytopenia is strongly suggestive of SCID in more than 90% of cases ( Table 316-2 ). The absence of a thymic shadow on a chest x-ray can also be suggestive of SCID. An accurate diagnosis relies on precise determination of the number of circulating T, B, and NK lymphocytes and their subsets. T cell lym-phopenia may be masked in some patients by the presence of mater-nal T cells (derived from maternal-fetal blood transfers) that cannot

ZAP-70

MHCII

STIM1

SCID

CLP

CD4

CD40LSAPICOS

Th

B cells

Myeloid

NK cells

HSC

Orai1 HLH

γIFN, etc...

γIFN, etc...

IL4, etc...

DOCK 8

IL17, etc...

IL21, etc...

IL10, TGFβ, etc...

IL4, cytotoxicityγIFN, etc...

CytotoxicityγIFN, TNF, etc...

Tc

TH1

CD8

TH2

TFh

Treg

NKT

TH17Orai1

STIM1

γδ

Thymus

MSMD

Tyk2STAT3

ZAP-70

TAP

IPEX(Foxp3)

XLP(SAP, XIAP)

Figure 316-2 T cell differentiation, effector pathways, and related primary immunodeficiencies (PIDs). Hematopoietic stem cells (HSCs) differentiate into common lymphoid progenitors (CLPs), which, in turn, give rise to the T cell precursors that migrate to the thymus. The development of CD4+ and CD8+ T cells is shown. Known T cell effector pathways are indicated, i.e., γδ cells, cytotoxic T cells (Tc), TH1, TH2, TH17, TFh (follicular helper) CD4 effector T cells, regulatory T cells (Treg), and natural killer T cells (NKTs); abbreviations for PIDs are contained in boxes. Vertical bars indicate a complete deficiency; broken bars a partial deficiency. SCID, severe combined immunodeficiency; ZAP 70, zeta-associated protein de-ficiency, MHCII, major histocompatibility complex class II deficiency; TAP, TAP1 and 2 deficiencies; Orai1, Stim-deficiencies; HLH, hematopoietic lymphohistiocytosis; MSMD, Mendelian susceptibility to mycobacterial disease; Tyk2, DOCK8, autosomal recessive form of hyper IgE syndrome; STAT3, autosomal dominant form of hyper IgE syndrome, CD40L, ICOS, SAP deficiencies; IPEX, immunodysregulation polyendocrinopathy enteropathy X-linked syndrome; XLP, X-linked proliferative syndromes.

[AU: Figure was redrawn. Please review.]

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be eliminated. Although counts are usually low (<500/μL of blood), higher maternal T cell counts may, under some circumstances, ini-tially mask the presence of SCID. Thus, screening for maternal cells by using adequate genetic markers should be performed whenever necessary. Inheritance pattern analysis and lymphocyte phenotyp-ing can discriminate between various forms of SCID and provide guidance in the choice of accurate molecular diagnostic tests (see below). To date, six distinct causative mechanisms for SCID ( Fig. 316-3 ) have been identified:

Severe combined immunodeficiency caused by a cytokine-signaling defi-ciency The most frequent SCID phenotype (accounting for 40–50% of all cases) is the absence of both T and NK cells. This outcome results from a deficiency in either the common γ chain receptor (γc) that is shared by several cytokine receptors (the IL-2, 4, 7, 9, 15 and 21 receptors) or Jak-associated kinase (JAK) 3 that binds to the cytoplas-mic portion of the γc chain receptor and induces signal transduction following cytokine binding. The former form of SCID (γc deficiency) has an X-linked inheritance mode, while the second is autosomal recessive. A lack of the IL-7Rα chain (which, together with γc, forms the IL-7 receptor) induces a selective T cell deficiency.

Purine metabolism deficiency Ten to 20% of SCID patients exhibit a deficiency in adenosine deaminase (ADA), an enzyme of purine metabolism that deaminates adenosine (ado) and deoxyadenosine (dAdo). An ADA deficiency results in the accumulation of ado and dAdo metabolites that induce premature cell death of lymphocyte progenitors. The condition results in the absence of B and NK lymphocytes as well as T cells. The clinical expression of complete ADA deficiency typically occurs very early in life. Since ADA is a ubiquitous enzyme, its deficiency can also cause bone dysplasia with abnormal costochondral junctions and metaphyses (found in 50% of cases) and neurologic defects. The very rare purine nucleo-side phosphorylase (PNP) deficiency causes a profound although incomplete T cell deficiency that is often associated with severe neurologic impairments.

Defective rearrangements of T and B cell receptors A series of SCID condi-tions are characterized by a selective deficiency in T and B lymphocytes with autosomal recessive inheritance. These conditions account for 20–30% of SCID cases and result from muta-tions in genes encoding proteins that mediate the recombination of V(D)J gene elements in T and B cell antigen receptor genes (required for the generation of diversity in antigen recognition). The main defi-ciencies involve RAG-1, RAG-2, DNA-dependent protein kinase and Artemis. A less severe (albeit vari-able) immunologic phenotype can result from other deficiencies in the same pathway, i.e., DNA ligase 4 and Cernunnos deficiencies. Given that these latter factors are involved in DNA repair, these deficiencies also cause developmental defects.

Defective (pre-)T cell receptor signal-ing in the thymus A selective T cell defect can be caused by a series of rare deficiencies in molecules involved in signaling via the pre-TCR or the TCR. These include deficiencies in

CD3 subunits associated with the (pre)TCR (i.e., CD3 δ, e, and ζ) and CD45.

Reticular dysgenesis Reticular dysgenesis is an extremely rare from of SCID that causes T and NK deficiencies with severe neutropenia and sensorineural deafness. It results from an adenylate kinase 2 deficiency.

Defective egress of lymphocytes Defective egress of lymphocytes from the thymus has been found in a patient with very low T cell counts but a normal thymic shadow. This condition was found to result from a deficiency in coronin-1A.

Patients with SCID require appropriate care with aggressive anti-infective therapies, immunoglobulin replacement, and (when necessary) parenteral nutrition support. In most cases, curative treatment relies on HSCT. Today, HSCT provides a very high cura-tive potential for SCID patients who are otherwise in reasonably good condition. In this regard, the feasibility of neonatal screening is now being evaluated. Gene therapy has been found to be suc-cessful for cases of X-linked SCID (γc deficiency) and SCID caused by an ADA deficiency, although toxicity has become an issue in the treatment of the former disease. Lastly, a third option for the treatment of ADA deficiency consists in enzyme substitution with a pegylated enzyme.

Thymic Defects A profound T cell defect can also result from faulty development of the thymus, as is most often observed in rare cases of Di George syndrome—a relatively common condition leading to a constel-lation of multiple developmental defects. In approximately 1% of such cases, the thymus is completely absent, leading to virtually no mature T cells. However, expansion of oligoclonal T cells can occur and is associated with skin lesions. Diagnosis (using fluorescence in situ hybridization) is based on the identification of a hemizygous deletion in the long arm of chromosome 22. To recover the capa-bility for T cell differentiation, these cases require a thymic graft.

Prevention of cell apoptosisDNA replication (purin metabolism)ADA

γc cytokine-dependent signals γcJAK-3, IL7Rα

Pre TCR/TCR signallingCD45, CD3δ, ε, ζ

V(D)J recombinationRag-1/-2, Artemis,DNA PKcs, DNA L4,Cernunnos

Myeloidcompartment

Cell survivalAdenylate kinase 2

EgressCronin 1A

Thymus

NK

CD8

CD4

B

CLPHSC

Figure 316-3 T cell differentiation and severe combined immunodeficiencies (SCIDs). The vertical bars indicate the six mechanisms currently known to lead to SCID. The names of deficient proteins are indicated in the boxes adjacent to the vertical bars. A broken line means that deficiency is partial or involves only some of the indicated immunodeficiencies. HSCs: hematopoietic stem cells; CLPs: common lymphoid progenitors; ADA: adenosine deaminase deficiency; DNAL4: DNA ligase 4.

[AU: Figure was redrawn. Please review.]

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CHARGE syndrome (CHD7 deficiency) is a less frequent cause of impaired thymus development. Lastly, the very rare “nude” defect is characterized by the absence of both hair and the thymus.

Omenn Syndrome Omenn syndrome consists of a subset of T cell deficiencies that present with a unique phenotype, including early-onset erythro-dermia, alopecia, hepatosplenomegaly, and failure to thrive. These patients usually display T cell lymphocytosis, eosinophilia, and low B cell counts. It has been found that the T cells of these patients exhibit a low TCR heterogeneity. This peculiar syndrome is the consequence of hypomorphic mutations in genes usually associ-ated with SCID, i.e., RAG-1, RAG-2, or (less frequently) Artemis or IL-7Rα. The impaired homeostasis of differentiating T cells thus causes this immune system–associated disease. These patients are very fragile, thus requiring simultaneous anti-infective therapy, nutritional support, and immunosuppression. HSCT provides a curative approach.

Functional T Cell Defects ( Fig. 316-2 ) A subset of T cell PIDs with autosomal inheritance is characterized by partially preserved T cell differentiation but defective activation resulting in abnormal effector function. There are many causes of these defects, but all lead to susceptibility to viral and opportunistic infections, chronic diarrhea, and failure to thrive, with onset during childhood. Careful phenotyping and in vitro functional assays are required to identify these diseases, the best characterized of which are the following.

Zeta-associated protein 70 (ZAP 70) deficiency Zeta-associated pro-tein 70 is recruited to the TCR following antigen recognition. A ZAP 70 deficiency leads typically to an almost complete absence of CD8+ T cells; CD4+ T cells are present but cannot be activated in vitro by TCR stimulation.

Calcium signaling defects A small number of patients have been reported who exhibit a profound defect in in vitro T and B cell activation as a result of defective antigen-receptor mediated Ca 2+ influx. This defect is caused by a mutation in the calcium chan-nel gene (ORAI-) or its activator (STIM-1). It is noteworthy that these patients are also prone to autoimmune manifestations (blood cytopenias) and exhibit a nonprogressing muscle disease.

HLA class II deficiency Defective expression of HLA class II molecules is the hallmark of a group of four recessive genetic defects all of which affect molecules (RFX5, RFXAP, RFXANK, and CIITA) involved in the transactivation of the genes coding for HLA class II. As a result, low but variable CD4+ T cell counts are observed in addition to defective antigen-specific T and B cell responses. These patients are particularly susceptible to herpesvirus, adenovirus, and enterovirus infections and chronic gut/liver Cryptosporidium infections.

HLA class I deficiency Defective expression of molecules involved in antigen presentation by HLA class I molecules (i.e., TAP-1, TAP-2, and Tapasin) leads to reduced CD8+ T cell counts, loss of HLA class I antigen expression, and a particular phenotype consist-ing of chronic obstructive pulmonary disease and severe vasculitis.

Other defects A variety of other T cell PIDs have been described, some of which are associated with a precise molecular defect [e.g., IL-2-inducible T cell kinase (ITK) deficiency]. These conditions are also characterized by profound vulnerability to infections, such as severe Epstein-Barr virus (EBV)–induced B cell proliferation and autoimmune disorders in ITK deficiency. Milder phenotypes are associated with CD8 and CD3Δ deficiencies.

HSCT is indicated for most of these diseases, although the prog-nosis is worse than in SCID because many patients are chronically

infected at the time of diagnosis. Fairly aggressive immunosuppres-sion and myeloablation may be necessary to achieve engraftment of allogeneic stem cells.

T Cell Primary Immunodeficiencies with DNA Repair Defects This is a group of PIDs characterized by a combination of T and B cell defects of variable intensity, together with a number of non-immunologic features resulting from DNA fragility. The autosomal recessive disorder ataxia telangiectasia (AT) is the most frequently encountered condition in this group. It has an incidence of 1:40,000 live births and causes B cell defects (low IgA, IgG2 deficiency, and low antibody production), which often require immunoglobulin replacement. Ataxia telangiectasia is associated with a progressive T cell immunodeficiency. As the name suggests, the hallmark fea-tures of AT are telangiectasia and cerebellar ataxia. The latter mani-festations may not be detectable before the age of 3–4 years, so that AT should be considered in young children with IgA deficiency and recurrent and problematic infections. Diagnosis is based on a cyto-genetic analysis showing excessive chromosomal rearrangements (mostly affecting chromosomes 7 and 14) in lymphocytes. Ataxia telangiectasia is caused by a mutation in the gene encoding the ATM protein—a kinase that plays an important role in the detec-tion and repair of DNA lesions (or cell death if the lesions are too numerous) by triggering several different pathways. Overall, AT is a progressive disease that carries a very high risk of lymphoma, leuke-mia, and (during adulthood) carcinomas. A variant of AT (“AT-like disease”) is caused by mutation in the MRE11 gene.

Nijmegen breakage syndrome (NBS) is a less common condition that also results from chromosome instability (with the same cyto-genetic abnormalities as in AT). NBS is characterized by a severe T and B cell combined immune deficiency with autosomal reces-sive inheritance. Individuals with NBS exhibit microcephaly and a bird-like face, but have neither ataxia nor telangiectasia. The risk of malignancies is very high. Nijmegen breakage syndrome results from a deficiency in Nibrin (NBSI, a protein associated with MRE11 and Rad50 that is involved in checking DNA lesions) caused by hypomorphic mutations.

Severe forms of dyskeratosis congenita (also known as Hoyeraal-Hreidersson syndrome) combine a progressive immunodeficiency that can also include an absence of B and NK lymphocytes, progres-sive bone marrow failure, microcephaly, in utero growth retarda-tion, and gastrointestinal disease. The disease can be X-linked or, more rarely, autosomal recessive. It is caused by the mutation of genes encoding telomere maintenance proteins, including dyskerin (DKC1).

Finally, the immunodeficiency with centromeric and facial anom-alies (ICF) is a complex syndrome of autosomal recessive inheri-tance that variably combines a mild T cell immune deficiency, a more severe B cell immune deficiency, with a coarse face, a digestive disease, and mild mental retardation. A diagnostic feature is the detection by cytogenetic analysis of multiradial aspects in multiple chromosomes (most frequently 1, 9, and 16) corresponding to an abnormal DNA structure secondary to defective DNA methylation. It is the consequence of a deficiency in the DNA methyltransferase DNMT3B.

T Cell Primary Immunodeficiencies with Hyper IgE Several T cell PIDs are associated with elevated serum IgE levels (as in Omenn syndrome). A condition sometimes referred to as autosomal recessive hyper IgE syndrome is notably characterized by recurrent bacterial infections in the skin and respiratory tract and severe skin and mucosal infections by pox viruses and human pap-illomaviruses, together with severe allergic manifestations. T and B lymphocytes counts are low. Mutations in the DOCK8 gene have been found in a subset of these patients.

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A very rare, related condition with autosomal recessive inheri-tance that causes a similar susceptibility to infection with various microbes (see above), including mycobacteria, reportedly results from a deficiency in Tyk-2, a JAK family kinase involved in the signaling of many different cytokine receptors.

Autosomal Dominant Hyper IgE Syndrome (HIES) This unique condition, the autosomal dominant hyper IgE syn-drome , is usually diagnosed by the combination of recurrent skin and lung infections that can be complicated by pneumatoceles. Infections are caused by pyogenic bacteria and fungi. Several other manifestations characterize HIES, including facial dysmorphy, defective loss of primary teeth, hyperextensibility, scoliosis, and osteoporosis. Elevated serum IgE levels are typical of this syn-drome. Recently, defective TH17 effector responses have been shown to account at least in part for the specific patterns of sus-ceptibility to particular microbes. This condition is caused by a heterozygous (dominant) mutation in the gene encoding the tran-scription factor STAT3 that is required in a number of signaling pathways following binding of cytokine to cytokine receptors (such as that of IL-6 and the IL-6 receptor).

Cartilage Hair Hypoplasia The autosomal recessive cartilage hair hypoplasia (CHH) disease is characterized by short-limb dwarfism, metaphyseal dysostosis, and sparse hair, together with a combined T and B cell PID of extremely variable intensity (ranging from quasi-SCID to no clinically signifi-cant immune defects). The condition can predispose to erythroblas-topenia, autoimmunity, and tumors. It is caused by mutations in the RMRP gene for a noncoding ribosome-associated RNA.

CD40 Ligand and CD40 Deficiencies Hyper IgM syndrome (HIGM) is a well-known PID that is usually classified as a B-cell immune deficiency (see Fig. 316-4 and below). It results from defective immunoglobulin class switch recombina-tion (CSR) in germinal centers and leads to profound deficiency in production of IgG, IgA, and IgE (although IgM production is maintained). Approximately half of HIGM sufferers are also prone to opportunistic infections, e.g., interstitial pneumonitis caused by Pneumocystis jiroveci (in young children), protracted diarrhea and cholangitis caused by Cryptosporidium , and infection of the brain with Toxoplasma gondii .

In the majority of cases, this condition has an X-linked inheri-tance and is caused by a deficiency in CD40 ligand (L). CD40L induces signaling events in B cells that are necessary for both CSR and adequate activation of other CD40-expressing cells that are involved in innate immune responses against the above-mentioned microorganisms. More rarely, the condition is caused by a defi-ciency in CD40 itself. The poorer prognosis of CD40L and CD40 deficiencies (relative to most other HIGM conditions) implies that (1) thorough investigations have to be performed in all cases of HIGM and (2) potentially curative HSCT should be discussed on a case-by-case basis for this group of patients.

Wiskott Aldrich Syndrome Wiskott Aldrich syndrome (WAS) is a complex, recessive, X-linked disease with an incidence of approximately 1 in 200,000 live births. It is caused by mutations in the WASP gene that affect not only T lymphocytes but also the other lymphocyte subsets, dendritic cells, and platelets. WAS is typically characterized by the following clinical manifestations: recurrent bacterial infections, eczema, and

Bone marrow Blood Lymphoid organs

HSC CLP proB

CD19CD34

CD27IgM

IgG

IgM

CSRSHM

IgA

IgE

CD27IgMG(-)

IgAdeficiency

preBImmature

BMemory

B

MemoryB

preBCR

surfaceIgM

surfaceIgMIgD

B

B

Plasmocyte

Plasmocyte

Agammaglobulinemia

μ heavy chainsλ5

CD79aCD79bBLNKBTK

CD40LCD40IKKγAIDUNGPMS2

ICOSTACI

BAFFRCD19

Hyper IgMsyndrome

CVID

Figure 316-4 B cell differentiation and related primary immunodeficiencies (PIDs). Hematopoietic stem cells (HSCs) differentiate into common lymphoid progenitors (CLPs), which give rise to pre-B cells. The B cell differentiation pathway goes through the pre–B cell stage (expression of the µ heavy chain and surrogate light chain), the immature B cell stage (expres-sion of surface IgM), and the mature B cell stage (expression of surface IgM and IgD). The main phenotypic characteristics

of these cells are indicated. In lymphoid organs, B cells can differentiate into plasma cells and produce IgM or undergo (in germinal centers) Ig class switch recombination (CSR) and somatic mutation of the variable region of V genes (SHM) that enable selection of high-affinity antibodies. These B cells produce antibodies of various isotypes and generate memory B cells. PIDs are indicated in the purple boxes. CVID: common variable immunodeficiency.

[AU: Figure was redrawn. Please review.]

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bleeding caused by thrombocytopenia. However, these manifesta-tions are highly variable—mostly as a consequence of the many different WASP mutations that have been observed. Null mutations predispose affected individuals to invasive and bronchopulmo-nary infections, viral infections, severe eczema, and autoimmune manifestations. The latter include autoantibody-mediated blood cytopenia, glomerulonephritis, skin and visceral vasculitis (includ-ing brain vasculitis), erythema nodosum, and arthritis. Another possible consequence of WAS is lymphoma, which may be virally induced (e.g., by EBV or Kaposi’s sarcoma–associated herpesvirus). Thrombocytopenia can be severe and compounded by the periph-eral destruction of platelets associated with autoimmune disorders. Hypomorphic mutations usually lead to milder outcomes that are generally limited to thrombocytopenia. It is noteworthy that even patients with “isolated” X-linked thrombocytopenia can develop severe autoimmune disease or lymphoma later in life. The immuno-logic workup is not very informative; there can be a relative CD8+ T cell deficiency, and frequently accompanied by low serum IgM levels and decreased antigen-specific antibody responses. A typical feature is reduced-sized platelets on a blood smear. Diagnosis is based on intracellular immunofluorescence analysis of WASP gene expression in blood cells. WASP regulates the actin cytoskeleton and thus plays an important role in many lymphocyte functions, including cell adhesion and migration, and the formation of syn-apses between antigen-presenting and target cells. Predisposition to autoimmune disorders may (at least in part) be related to defective regulatory T cells. The treatment of WASP should match the sever-ity of disease expression. Prophylactic antibiotics, immunoglobulin G (IgG) supplementation, and careful topical treatment of eczema are indicated. Although splenectomy improves platelet counts in a majority of cases, this intervention is associated with a significant risk of infection (both pre- and post-HSCT). Allogeneic HSCT is curative, with fairly good results overall. Gene therapy trials are also under way.

A few other complex PIDs are worth mentioning. Sp110 defi-ciency causes a T cell PID with liver venoocclusive disease and hypogammaglobulinemia. Chronic mucocutaneous candidiasis (CMC) is probably a heterogeneous disease, considering the dif-ferent inheritance patterns that have been observed. In some cases, chronic candidiasis is associated with late-onset bronchopulmonary infections, bronchiectasis, and brain aneurysms. Moderate forms of CMC are related to autoimmunity and AIRE deficiency (see below). Recently, innate immunodeficiencies (CARD9 and Dectin-1) have been found in a few families with CMC.

B LYMPHOCYTE DEFICIENCIES ( TABLE 316-1 , FIG. 316-4 ) m

Deficiencies that predominantly affect B lymphocytes are the most frequent PIDs and account for 60–70% of all cases. B lymphocytes make antibodies. Pentameric IgMs are found in the vascular com-partment and are also secreted at mucosal surfaces. IgG antibodies diffuse freely into extravascular spaces, whereas IgA antibodies are produced and secreted predominantly from mucosa-associated lymphoid tissues. Although Ig isotypes have distinct effector functions, including Fc receptor–mediated and (indirectly) C 3 receptor–dependent phagocytosis of microorganisms, they share the ability to recognize and neutralize a given pathogen. Defective antibody production therefore allows the establishment of inva-sive, pyogenic bacterial infections as well as recurrent sinus and pulmonary infections (mostly caused by Streptococcus pneumo-niae , Hemophilus influenzae , Moraxella catarrhalis , and, less frequently, by gram-negative bacteria). If left untreated, recurrent bronchial infections lead to bronchiectasis and, ultimately, cor pul-monale and death. Parasitic infections such as caused by Giardia lambliasis as well as bacterial infections caused by helicobacter and campylobacter of the gut are also observed. A complete lack

of antibody production (namely agammaglobulinemia) can also predispose affected individuals to severe, chronic, disseminated enteroviral infections causing meningoencephalitis, hepatitis, and a dermatomyositis-like disease.

Even with the most profound of B cell deficiencies, infections rarely occur before the age of 6 months; this is because of transient protection provided by the transplacental passage of immunoglobu-lins during the last trimester of pregnancy. Conversely, a genetically nonimmunodeficient child born to a mother with hypogamma-globulinemia is, in the absence of maternal Ig substitution, usually prone to severe bacterial infections in utero and for several months after birth.

Diagnosis of B cell PIDs relies on the determination of serum Ig levels ( Table 316-2 ). Determination of antibody production follow-ing immunization with tetanus toxoid vaccine or nonconjugated pneumococcal polysaccharide antigens can also help diagnose more subtle deficiencies. Another useful test is B cell phenotype deter-mination in switched γ+ CD27+ and nonswitched memory B cells (γ- CD27+). In agammaglobulinemic patients, examination of bone marrow B cell precursors ( Fig. 316-4 ) can help obtain a precise diagnosis and guide the choice of genetic tests.

Agammaglobulinemia Agammaglobulinemia is characterized by a profound defect in B cell development (<1% of the normal B cell blood count). In most patients, very low residual Ig isotypes can be detected in the serum. In 85% of cases, agammaglobulinemia is caused by a mutation in the BTK gene that is located on the X-chromosome. The BTK gene product is a kinase that participates in (pre) B cell receptor signal-ing. When the kinase is defective, there is a block (albeit a leaky one) at the pre-B to B cell stage ( Fig. 316-4 ). Detection of BTK by intracellular immunofluorescence of monocytes, and lack thereof in patients with X-linked agammaglobulinemia, is a useful diagnostic test. Not all of the mutations in BTK result in agammaglobulinemia, since some patients have a milder form of hypogammaglobulinemia and low but detectable B cell counts. These cases should not be con-fused with common variable immunodeficiency (CVID, see below). About 10% of agammaglobulinemia cases are caused by alterations in genes encoding elements of the pre-B cell receptor, i.e., the μU heavy chain, the λ5 surrogate light chain, Igα or Igβ, and the scaf-fold protein BLNK. In 5% of cases, the defect is unknown. It is noteworthy that agammaglobulinemia can be observed in patients with ICF syndrome, despite the presence of normal peripheral B cell counts. Lastly, agammaglobulinemia can be a manifestation of a myelodysplastic syndrome (associated or not with neutropenia). Treatment of agammaglobulinemic patients is based on immuno-globulin replacement (see below). Profound hypogammaglobuline-mia is also observed in adults, in association with thymoma.

Hyper IgM (HIGM) syndromes Hyper IgM syndrome is a rare B cell PID characterized by defec-tive Ig CSR. It results in very low serum levels of IgG and IgA and elevated or normal serum IgM levels. The clinical severity is similar to that seen in agammaglobulinemia, although chronic lung disease and sinusitis are less frequent and enteroviral infections are uncom-mon. As discussed above, a diagnosis of HIGM involves screening for an X-linked CD40L deficiency and an autosomal recessive CD40 deficiency, which affect both B and T cells. In 50% of cases affecting only B cells, these isolated HIGM syndromes result from mutations in the gene encoding activation-induced deaminase, the protein that induces CSR in B cell germinal centers. These patients usu-ally have enlarged lymphoid organs. In the other 50% of cases, the etiology is unknown (except for rare UNG and PMS2 deficiencies). Furthermore, IgM-mediated autoimmunity and lymphomas can occur in HIGM syndrome. It is noteworthy that HIGM can result

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from fetal rubella syndrome or can be a predominant immunologic feature of other PIDs, such as the immunodeficiency associated with ectodermic anhydrotic hypoplasia X-linked NEMO deficiency and the combined T and B cell PIDs caused by DNA repair defects such as ataxia telangectasia and Cernunnos deficiency.

Common Variable Immunodeficiency (CVID) CVID is an ill-defined condition characterized by low serum levels of one or more Ig isotypes. Its prevalence is estimated to be 1 in 20,000. The condition is recognized predominantly in adults, although clini-cal manifestations can occur earlier in life. Hypogammaglobulinemia is associated with at least partially defective antibody production in response to vaccine antigens. B lymphocyte counts are often normal but can be low. Besides infections, CVID patients may develop lymphoproliferation (splenomegaly), granulomatous lesions, colitis, antibody-mediated autoimmune disease and lymphomas. A family history is found in 10% of cases. A clear-cut dominant inheritance pattern is found in some families, whereas recessive inheritance is observed more rarely. In most cases, no molecular cause can be identified. A small number of patients in Germany were found to carry mutations in the ICOS gene encoding a T cell membrane protein that contributes to B cell activation and survival. In 10% of patients with CVID, monoallelic or biallelic mutations of the gene encoding TACI (a member of the TNF receptor family that is expressed on B cells) have been found. In fact, heterozygous TACI mutations correspond to a genetic susceptibility factor, since similar heterozygous mutations are found in 1% of controls. The BAFF receptor was found to be defective in a kindred with CVID, although not all individuals carrying the mutation have CVID.

A diagnosis of CVID should be made after excluding the presence of hypomorphic mutations associated with agammaglobulinemia or more subtle T cell defects; this is particularly the case in children. It is possible that many cases of CVID result from a constellation of factors, rather than a single genetic defect. Recently, rare cases of hypogammaglobulinemia were found to be associated with CD19 deficiency. These patients have B cells that can be identified by typ-ing for other B cell markers.

Selective Ig Isotype Deficiencies IgA deficiency and CVID represent polar ends of a clinical spectrum due to the same underlying gene defect (s) in a large subset of these patients. IgA deficiency is the most common PID; it can be found in 1 in every 600 individuals. It is asymptomatic in most cases; however, individuals may present with increased numbers of acute and chronic respiratory infections that may lead to bronchiecta-sis. In addition, over their lifetime, these patients experience an increased susceptibility to drug allergies, atopic disorders and auto-immune diseases. Symptomatic IgA deficiency is probably related to CVID, since it can be found in relatives of patients with CVID. Furthermore, IgA deficiency may progress to CVID. It is thus important to assess serum Ig levels in IgA-deficient patients (espe-cially when infections occur frequently), in order to detect changes that should prompt the initiation of immunoglobulin replacement. Selective IgG2 (+G4) deficiency (which in some cases may be asso-ciated with IgA deficiency) can also result in recurrent sinopulmo-nary infections and should thus be specifically sought in this clinical setting. These conditions are ill-defined and a pathophysiologic explanation has not been found.

Selective Antibody Deficiency to Polysaccharide Antigens Some patients with normal serum Ig levels are prone to S. pneumo-niae and H. influenzae infections of the respiratory tract. Defective production of antibodies against polysaccharide antigens (such as those in the S. pneumoniae cell wall) can be observed and is

probably causative. This condition may correspond to a defect in marginal zone B cells, a B cell subpopulation involved in T-independent antibody responses.

Immunoglobulin Replacement IgG antibodies have a half-life of 21–28 days. Thus, injection of plasma-derived polyclonal IgG containing a myriad of high-affinity antibodies can provide protection against disease-causing micro-organisms in patients with defective IgG antibody production. This form of therapy should not be based on laboratory data alone (i.e., IgG and/or antibody deficiency) but should be guided by the occur-rence or not of infections; otherwise, patients might be subjected to unjustified IgG infusions. Immunoglobulin replacement can be performed by IV or subcutaneous routes. In the former case, injec-tions have to be repeated every 3–4 weeks, with a residual target level of 800 mg/mL in patients who had very low IgG levels prior to therapy. Subcutaneous injections are typically performed once a week, although the frequency can be adjusted on a case-by-case basis. A trough level of 800 mg/mL is desirable. Whatever the mode of administration, the main goal is to reduce the frequency of the respiratory tract infections and prevent chronic lung and sinus dis-ease. The two routes appear to be equally safe and efficacious and so the choice should be left to the preference of the patient.

In patients with chronic lung disease, chest physical therapy with good pulmonary toilet and the cyclic use of antibiotics are also needed. Immunoglobulin replacement is well tolerated by most patients, although the selection of the best-tolerated Ig preparation may be necessary in certain cases. Since IgG preparations contain a small proportion of IgAs, caution should be taken in patients with residual antibody production capacity and a complete IgA deficiency, as these subjects may develop anti-IgA antibodies that can trigger anaphylactic shock. These patients should be treated with IgA-free IgG preparations. Immunoglobulin replacement is a lifelong therapy; its rationale and procedures have to be fully under-stood and mastered by the patient and his or her family, in order to guarantee the strict observance required for efficacy.

PRIMARY IMMUNODEFICIENCIES AFFECTING REGULATORY PATHWAYS ( TABLE 316-1 )

An increasing number of PIDs have been found to cause homeo-static dysregulation of the immune system, either alone or in association with increased vulnerability to infections. Defects of this type affecting the innate immune system and autoinflamma-tory syndromes will not be covered in this chapter. However, three specific entities (hemophagocytic lymphohistiocytosis, lymphopro-liferation, and autoimmunity) will be described below.

HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS m

Hemophagocytic lymphohistiocytosis (HLH) is characterized by an unremitting activation of CD8+ T lymphocytes and macrophages that leads to organ damage (notably in the liver, bone marrow, and central nervous system). This syndrome results from a broad set of inherited diseases, all of which impair T and NK lymphocyte cytotoxicity. The manifestations of HLH are often induced by a viral infection. EBV is the most frequent trigger. In severe forms of HLH, disease onset may start during the first year of life or even (in rare cases) at birth.

Diagnosis relies on the identification of the characteristic symp-toms of HLH (fever, hepatosplenomegay, edema, neurologic dis-eases, blood cytopenia, increased liver enzymes, hypofibrinogen-emia, high triglyceride levels, elevated markers of T cell activation, and hemophagocytic features in the bone marrow or cerebrospinal fluid). Functional assays of postactivation cytotoxic granule exo-cytosis (CD107 fluorescence at the cell membrane) can suggest

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genetically determined HLH. The conditions can be classified into three subsets:

Familial HLH with autosomal recessive inheritance, including 1. perforin deficiency (30% of cases) that can be recognized by assessing intracellular perforin expression; Munc13-4 defi-ciency (30% of cases); syntaxin 11 deficiency (10% of cases); Munc18-2 deficiency (10% of cases); and a few residual cases that lack a known molecular defect. HLH with partial albinism. Three conditions combine HLH 2. and abnormal pigmentation, where hair examination can help in the diagnosis: Chediak-Higashi syndrome, Griscelli syndrome, and Hermanski Pudlak syndrome type II. Chediak-Higashi syndrome is also characterized by the presence of giant lysosomes within leukocytes (see Chap. 60), in addition to a primary neurologic disorder with slow progression of symptoms over time. X-linked proliferative syndrome (XLP) is characterized in most 3. patients by the induction of HLH following EBV infection, while other patients develop progressive hypogammaglobu-linemia similar to what is observed in CVID and/or certain lymphomas. XLP is caused by a mutation in the SH2DIA gene that encodes the adaptor protein SAP (associated with a SLAM family receptor). Several immunologic abnormalities have been described, including low 2B4-mediated NK cell cytotox-icity, impaired differentiation of NKT cells, defective antigen-induced T cell death, and defective T cell helper activity for B cells. A related disorder (XLP2) has recently been described. It is also X-linked and induces HLH (frequently after EBV infection), although the clinical manifestation may be less pro-nounced. The condition is associated with a deficiency of the antiapoptotic molecule XIAP. The pathophysiology of XLP2 and its relationship to XLP1 remain unclear.

HLH is a life-threatening complication. The treatment of this condition requires aggressive immunosuppression with either the cytotoxic agent VP-16 or anti-T cell antibodies. Once remission has been achieved, HSCT should be performed, since it provides the only curative form of therapy.

AUTOIMMUNE LYMPHOPROLIFERATIVE SYNDROME m

Autoimmune lymphoproliferative syndrome ( ALPS ) is charac-terized by nonmalignant T and B lymphoproliferation caus-ing splenomegaly and enlarged lymph nodes; 70% of patients also display autoimmune manifestations such as autoimmune cytopenias, Guillain-Barré syndrome, uveitis, and hepatitis (see Chaps. 59 and 314). A hallmark of ALPS is the presence of CD4– CD8– TCRαβ+ T cells (2–50%) in the blood of affected individuals. Hypergammaglobulinemia involving IgG and IgA is also frequently observed. The syndrome is caused by a defect in Fas-mediated apoptosis of lymphocytes, which can thus accumu-late and mediate autoimmunity. Furthermore, ALPS can lead to malignancies.

Most patients carry a heterozygous mutation in the gene encod-ing Fas that is characterized by dominant inheritance and variable penetrance, depending on the nature of the mutation. A rare and severe form of the disease with early onset can be observed in patients carrying a biallelic mutation of Fas, which profoundly impairs the protein’s expression and/or function. Fas-Ligand, cas-pase 10, caspase 8, and neuroblastoma RAS viral oncogene homolog (NRAS) mutations have also been reported in a few cases of ALPS. Many cases of ALPS have not been precisely delineated at the molecular level. Treatment of ALPS is essentially based on the use of proapoptotic drugs, which need to be carefully administered in order to avoid toxicity.

COLITIS, AUTOIMMUNITY, AND PRIMARY m

IMMUNODEFICIENCIES Several PIDs (most of which are T cell related) can cause severe gut inflammation. The prototypic example is immunodysregulation polyendocrinopathy enteropathy X-linked syndrome (IPEX), charac-terized by a widespread inflammatory enteropathy, food intolerance, skin rashes, autoimmune cytopenias, and diabetes. The syndrome is caused by loss-of-function mutations in the gene encoding the transcription factor FOXP3, which is required for the acquisition of effector function by regulatory T cells. In most cases of IPEX, CD4+ CD25+ regulatory T cells are absent from the blood. This condition has a poor prognosis and requires aggressive immunosuppression. The only possible curative approach is allogenic HSCT. IPEX-like syndromes that lack a FOXP3 mutation have also been described. In some cases, a CD25 deficiency has been found. Defective CD25 expression also impairs regulatory cell expansion/function. This functional T cell deficiency means that CD25-deficient patients are also at increased risk of opportunistic infections. It is noteworthy that abnormalities in regulatory T cells have been described in other PID settings, such as in Omenn syndrome, STAT5b deficiency, STIM1 (Ca flux) deficiency, and WAS; these abnormalities may account (at least in part) for the occurrence of inflammation and autoimmunity. The autoimmune features observed in a small frac-tion of patients with Di George syndrome may have the same cause. Recently, severe inflammatory gut disease has been described in patients with a deficiency in the IL-10 receptor.

A distinct autoimmune entity is observed in autoimmune poly-endocrinopathy candidiasis ectodermal dysplasia (APECED) syn-drome, which is characterized by autosomal recessive inheritance. It consists of multiple autoimmune manifestations that can affect solid organs in general and endocrine glands in particular. Mild, chronic Candida infection is often associated with this syndrome. The condition is due to mutations in the autimmune regulator (AIRE) gene and results in impaired thymic expression of self anti-gens by medullary epithelial cells and impaired negative selection of self-reactive T cells that lead to autoimmune manifestations.

CONCLUSION The variety and complexity of the clinical manifestations of the many different PIDs strongly indicate that it is important to raise awareness of these diseases. Indeed, early diagnosis is essential for establishing an appropriate therapeutic regimen. Hence, patients with suspected PIDs must always be referred to experienced clinical centers that are able to perform appropriate molecular and genetic tests. A precise molecular diagnosis is not only necessary for initiat-ing the most suitable treatment but it is also important for genetic counseling and prenatal diagnosis.

One pitfall that may hamper diagnosis is the high variability that is associated with many PIDs. Variable disease expression can result from the differing consequences of various mutations associated with a given condition, as exemplified by WAS and, to a lesser extent, X-linked agammaglobulinemia (XLA). There can also be effects of modifier genes (as also suspected in XLA) and environmental fac-tors such as EBV infection that can be the main trigger of disease in X-linked lymphoproliferative (XLP) conditions. Furthermore, it has recently been established that somatic mutations in an affected gene can attenuate the phenotype of a number of T cell PIDs. This has been described for ADA deficiency, X-linked SCID, RAG deficien-cies, Nemo deficiency and, most prominently, in WAS. In contrast, somatic mutations can create disease states analogous to PID, as reported for ALPS. Lastly, cytokine-neutralizing autoantibodies can mimic a PID, as shown for interferon γ.

Many aspects of the pathophysiology of PIDs are still unknown, and the disease-causing gene mutations have not been identified in

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PART 15

Disorders of Joints and Adjacent Tissues

all cases (as illustrated by CVID and IgA deficiency). However, our medical understanding of PIDs has now reached the stage where scientifically based approaches to the diagnosis and treatment of these diseases can be implemented.

FURTHER READINGS

Boztug K, Klein C: Novel genetic etiologies of severe congenital neutropenia. Curr Opin Immunol 21:472, 2009

Fischer A: Human primary immunodeficiency diseases. Immunity 27:835, 2007

Notarangelo LD, et al: Primary immunodeficiencies: 2009 update. J Clin Investig, in press 2009

[AU/ED: Please add 2010 refer-ence when available and indicate the reference that should be replaced.]

Ochs HD et al: Primary Immunodeficiency Diseases. A Molecular and Genetic Approach 2007 . New York, Oxford University Press, 1999

Seger RA: Modern management of chronic granulomatous dis-ease. Br J Haematol 140:255, 2008

Stiehm ER et al: Immunologic Disorders in Infants and Children . Philadelphia, Elsevier Saunders, 2004

Wood P et al: Recognition, clinical diagnosis and management of patients with primary antibody deficiencies: A systematic review. Clin Exp Immunol 149:410, 2007

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