Combined Immunodeficiencies

Severe Combined Immunodeficiency

The term severe combined immunodeficiency (SCID) designates a genetically heterogeneous group of PIDDs characterized by impaired development and function of T lymphocytes. In some cases, development of B or natural killer (NK) lymphocytes (or both) is also affected ( Fig. 24-1 ). However, because T cells play a critical role also in most B-cell responses, serious T-cell dysfunction precludes effective humoral immunity even in patients in whom the genetic defect does not affect B-cell development. Complete absence of specific cellular and humoral immunity in patients with SCID leads to an extreme infectious diathesis early in life. Mucocutaneous candidiasis is a common finding. Infections with common viral pathogens (e.g., varicella, herpes simplex, measles, adenoviruses, respiratory syncytial virus, influenza, and parainfluenza) are often fatal. Patients are also susceptible to opportunistic infections with commensal organisms that are normally nonpathogenic, such as Pneumocystis jiroveci. Even attenuated vaccine organisms such as oral polio vaccine virus, rotavirus vaccine, varicella vaccine, and bacille Calmette-Guérin (BCG) can cause severe or fatal infection. Transfusion of blood products containing viable lymphocytes may lead to fatal graft-versus-host disease. Autoimmunity and other manifestations of immune dysregulation (e.g., skin rash) are frequently observed, especially in patients with residual development of T lymphocytes (“leaky” SCID). Patients with SCID are also at increased risk of malignancies, including lymphoproliferative disorders caused by Epstein-Barr virus (EBV) and other tumors.

Diagram of lymphocyte development. Pluripotent stem cells give rise to all cellular blood elements. The common lymphoid progenitor gives rise to the three principal lineages of lymphocytes: T cells, B cells, and natural killer (NK) cells. Most peripheral T cells express the αβ form of the T-cell antigen receptor (TCR) and develop through distinct stages in the thymus. Mature helper T cells express the CD3 antigen coreceptor complex along with the major histocompatibility complex (MHC) class II receptor CD4, whereas cytotoxic cells express the MHC class I receptor CD8. A minority (1% to 5%) of peripheral T cells express the γδ form of the TCR along with CD3, but without CD4 or CD8; less is known about their development. B cells develop initially in the bone marrow and pass through several stages before exiting to complete development in the spleen. Mature B cells express distinct markers (CD19 and CD20) along with surface immunoglobulin M (IgM) and IgD. B cells are activated in germinal centers to undergo class switching and become either memory B cells expressing IgG, IgA, or IgE or Ig-secreting plasma cells. Most IgG-producing plasma cells reside in the bone marrow. NK cells are a distinct lineage of cytotoxic cells; little is known regarding their development from lymphoid precursors.

Typical symptoms of SCID are recurrent severe infections, chronic diarrhea, and failure to thrive. Symptoms are often seen in the first weeks of life but may be delayed by several months. Antibodies derived from the mother by transfer across the placenta may provide some early protection. Physical examination may reveal foci of infection (e.g., thrush) and the absence of discernible lymphoid tissue. Hypogammaglobulinemia is often present but is not universal. Specific antibody responses are almost always severely impaired.

SCID is most often classified according to the peripheral blood lymphocyte phenotype—that is, absence or presence of the major lymphocyte types. T cells are absent (or very low) and nonfunctional in all classic forms of SCID, a phenotype designated “T ⁻ .” The presence or absence of B cells is indicated by adding “B ⁺ ” or “B ⁻ ,” respectively. The same pattern applies for NK cells. Table 24-2 lists the various lymphocyte phenotypes of SCID and the molecular defects associated with them. In as many as 40% of patients with SCID, maternal T cells may have engrafted in the fetus during gestation, and this situation may occasionally confuse the diagnostic picture. Maternally derived T cells tend to be anergic, but they may also be associated with clinical manifestations similar to those of graft-versus-host disease, such as eczematous rash, eosinophilia, and splenomegaly. In rare circumstances, maternal engraftment may lead to even more unusual clinical findings, such as IgA monoclonal gammopathy, autoimmune cytopenias, and allograft rejection.

TABLE 24-2

Lymphocyte Phenotype Classification of Severe Combined Immunodeficiency and Associated Gene Defects

Lymphocyte Phenotype	Genes
T − B − NK −	ADA, AK2, NP *
T − B − NK +	DCLRE1C , LIG4, NHEJ1 , PRKDC, RAG1 , RAG2
T − B + NK −	IL2RG , JAK3
T − B + NK +	CD3D, CD3E, CD3G, † CD3Z, IL7R, PTPRC

 

* B-cell development is variably affected in nucleoside phosphorylase (NP) deficiency.

† CD3G mutations are rarely associated with a severe T-cell deficiency.

T ⁻ B ⁻ NK ⁻ Severe Combined Immunodeficiency

Adenosine Deaminase and Purine Nucleoside Phosphorylase Deficiencies.

Figure 24-2 shows the salvage pathway of purine nucleotide synthesis. Deficiencies of the enzymes adenosine deaminase (ADA) and purine nucleoside phosphorylase (PNP) are associated with immunodeficiency. ADA deficiency accounts for approximately 10% to 15% of all patients with SCID, or approximately a third of SCID cases with autosomal recessive inheritance. PNP deficiency is quite rare, with approximately 70 cases reported. Although PNP deficiency is mainly expressed as a somewhat selective defect in cellular immunity, it is discussed here because of similarities in their biochemical pathophysiology with ADA deficiency. The absence of ADA or PNP leads to intracellular accumulation of deoxy­adenosine and deoxyguanosine, respectively. These molecules are not themselves toxic to lymphocytes. However, when they are converted to their 5′-triphosphates (dATP and dGTP), they inhibit ribonucleotide reductase and prevent de novo synthesis of deoxynucleotides. Without building blocks for the replication and repair of DNA, the cells cease to divide. Lymphocytes die to a much greater extent than other cell types do. In both ADA and PNP deficiency, T-cell precursors in the thymus appear to be especially sensitive to death by apoptosis (programmed cell death). B cells are more often depleted in ADA deficiency than in PNP deficiency. In the latter the B-cell phenotype is more variable.

Salvage pathway of purine nucleotide biosynthesis. d, Deoxy; dATP, deoxyadenosine triphosphatase; dGTP, deoxyguanosine triphosphatase.

Approximately 85% of individuals with ADA deficiency will display a SCID phenotype with markedly reduced numbers of both T and B cells and low serum antibody levels. NK cells are only rarely found in patients with ADA deficiency. Additional clinical manifestations may include radiographic alterations of the ribs, vertebral bodies, and iliac crests as well as sensorineural deafness, liver dysfunction, lung disease resembling alveolar proteinosis, and cognitive impairment and other neurologic abnormalities. Immune dysregulation is common in patients with ADA deficiency ; it may manifest with allergy (eczema, asthma) and autoimmunity (cytopenias, hypothyroidism, diabetes) and is associated with loss of regulatory T-cell function. Rarely, ADA deficiency may present with generalized erythroderma and infiltration of skin by activated autologous T cells, resembling Omenn syndrome (OS). Bone marrow hypocellularity is frequently observed in ADA deficiency; myelodysplasia also has been reported. Finally, patients with ADA deficiency are at increased risk for multicentric dermatofibrosarcoma protuberans, a very rare tumor with a characteristic chromosomal translocation (t[17;22][q22;q13]) resulting in the COL1A1 -platelet-derived growth factor β (PDGFB) fusion gene. Between 10% and 15% of patients with ADA deficiency may have a delayed or late-onset form that may be manifested in late infancy or early childhood. These patients initially may have variable numbers of circulating lymphocytes and some humoral immunity that quickly wanes. The severity of the phenotype appears to correlate to some degree with the amount of residual ADA activity. Autoimmunity is particularly common in patients with residual ADA enzymatic activity.

Patients with PNP deficiency are very susceptible to viral and fungal infections. They have decreased numbers of circulating T cells, often initially with normal numbers of B cells and normal serum immunoglobulin (Ig) levels. With time, humoral immunity usually deteriorates. Approximately 50% of children with PNP deficiency have neurologic complications such as spasticity, diplegia, paresis, and other motor disorders, as well as cognitive impairment. Autoimmune manifestations, especially cytopenias, are also very common.

After clinical suspicion is aroused, diagnosis of ADA or PNP deficiency is not difficult. Both ADA and PNP activity is readily measurable in red blood cell or leukocyte lysates. In symptomatic patients, activity is usually 1% or less of that in normal subjects. These methods may be applied also for prenatal diagnosis on cultured amniotic or chorionic villus cells or on fetal blood sampling. PNP is required for the production of hypoxanthine, a precursor of uric acid (see Fig. 24-2 ). Thus individuals with PNP deficiency will have reduced serum and urine urate levels.

Several therapeutic options are available to patients with ADA deficiency, including hematopoietic stem cell transplantation (HSCT), enzyme replacement therapy (ERT) and gene therapy. Excellent results (survival >85%) have been reported after HSCT from matched sibling donors, but results of HSCT from haploidentical or unrelated donors are much less satisfactory (43% and 66% survival, respectively). Moreover, patients with ADA deficiency surviving after HSCT remain at high risk of neurologic complications. ERT with weekly intramuscular injections of polyethylene glycol–conjugated bovine ADA (PEG-ADA) is usually well tolerated and is effective to normalize levels of toxic phosphorylated (deoxy)adenosine derivatives and to improve immune function. However, immune reconstitution is often incomplete. Encouraging results have been obtained with gene therapy, associated with nonmyeloablative cytoreduction. This represents a very important option for patients who lack a human leukocyte antigen (HLA)-identical related donor. HSCT is the only curative therapeutic option for patients with PNP deficiency.

Reticular Dysgenesis Caused by Adenylate Kinase 2 Deficiency.

Reticular dysgenesis caused by adenylate kinase 2 (AK2) deficiency is a very rare autosomal recessive form of SCID, associated with agranulocytosis (with a block at the promyelocyte stage of differentiation in the bone marrow) and sensorineural deafness. AK2 regulates levels of ADP in mitochondria. Deficiency of this enzyme is associated with abnormalities of energy metabolism in granulocytes and lymphocytes (especially T cells), resulting in apoptosis. The number of circulating B and NK lymphocytes can be variably affected, and NK cell differentiation is usually preserved. Therefore, these patients most often exhibit a phenotype other than T- B- NK- SCID; however, we describe this disorder here because it also affects purine metabolism, similar to ADA and PNP deficiencies. OS with oligoclonal expansion of T cells has been described in a patient with AK2 hypomorphic (partially functional) mutations. Patients are at increased risk of myelodysplasia. Sensorineural deafness reflects a role of AK2 in the stria vascularis of the inner ear. Treatment is based on HSCT, but results are less satisfactory than in other forms of SCID, and use of myeloablative conditioning is required for engraftment.

T ⁻ B ⁻ NK ⁺ Severe Combined Immunodeficiency

Defects of Recombinase-Activating Genes (RAG) 1 and 2.

RAG1 and RAG2 encode for DNA-binding proteins that bind to specific recognition sequences flanking coding gene elements of the Ig and T cell receptor (TCR) loci. RAG1 and RAG2 initiate the VDJ recombination process by inducing DNA double-strand breaks at these loci. Proteins of the nonhomologous end-joining (NHEJ) complex ultimately join coding Ig and TCR elements, allowing expression of Ig and TCR molecules ( Fig. 24-3 ). In patients with RAG defects, B- and T-cell differentiation is arrested at an early stage of development. Therefore patients with functionally null mutations of the RAG1 and RAG2 genes have very low numbers of T and B lymphocytes, but NK cell differentiation is preserved. Some patients with hypomorphic RAG1 or RAG2 mutations may sustain differentiation of a limited number of T and (less frequently) B lymphocytes, a condition that is also referred to as “leaky” or “atypical” SCID. In these patients, T lymphocytes often undergo homeostatic proliferation in the periphery and acquire an activated (CD45RO+) phenotype. Oligoclonal expansion of T lymphocytes that infiltrate target tissues causing damage is observed in patients with OS. Patients with OS present with clinical features suggestive of acute graft-versus-host disease. Symptoms include recurrent severe infections, failure to thrive, chronic severe diarrhea, and erythroderma with exfoliation and exudation. Examination may reveal hepatosplenomegaly and lymphadenopathy. Laboratory studies show anemia, hypogammaglobulinemia with an elevated IgE level, a decrease in the number of peripheral B cells, and presence of activated (CD45RO+) circulating T lymphocytes with a restricted (oligoclonal) T cell repertoire. In vitro proliferation of T lymphocytes to antigens and to anti-CD3 is abrogated, whereas proliferation to phytohemagglutinin (PHA) may be variably affected. Although hypomorphic RAG1 and RAG2 mutations are the most common form of OS, the same phenotype may be observed in patients with hypomorphic mutations in other SCID-causing genes. Some evidence suggests that expansion of oligoclonal, tissue-infiltrating T lymphocytes in patients with OS may reflect defects of T-cell tolerance. The study of thymic biopsies from patients with OS has shown abnormalities of medullary epithelial cells, with impaired expression of AIRE (autoimmune regulator, discussed later), a transcription factor that promotes expression of self-antigens, thereby permitting intrathymic deletion of autoreactive T cells or their diversion to FOXP3 ⁺ regulatory T (Treg) cells. Consistent with this, absence of FOXP3 ⁺ cells has also been demonstrated in thymic biopsies from patients with OS.

Gene defects affecting lymphocyte antigen receptor gene rearrangement and causing T ⁻ B ⁻ NK ⁺ severe combined immunodeficiency. The genes that encode immunoglobulin and T-cell antigen receptors are assembled from subunit segments that are separated in the germline and undergo assembly or somatic rearrangement during lymphocyte development. In the figure, a TCR or Ig heavy-chain locus is shown. The heavy chains are composed of four distinct segments: V, variable; D, diversity; J, joining; and C, constant. Some of the segments are flanked by recombination signal sequences (RSS) . RAG1 and RAG2 initiate the process that leads to double-strand breaks (DSB) in DNA. The DNA between coding segments is looped out and forms circles, with the coding sequences joining to one another. In the case of T cells, the larger DNA circle is referred to as a T-cell receptor excision circle. All these DNA joins are made by a group of molecules that together subserve the function of nonhomologous end joining (NHEJ) .

Environmental triggers may modify the disease phenotype in patients with RAG gene defects. In at least one case, progression to OS was observed in a patient with a RAG2 mutation after infection with parainfluenza virus type 3. Cytomegalovirus (CMV) infection has been associated with in vivo expansion of TCRγδ ⁺ T cells and autoimmune manifestations. Finally, somatic mutations may become superimposed on null or “amorphic” mutations and yield mosaicism with revertant or hypomorphic populations of lymphocytes and resultant OS.

Hypomorphic RAG mutations that result in production of mutated proteins with more robust (although subnormal) recombination activity have been identified in patients with delayed presentation characterized by granulomatous lesions and autoimmunity. Occasionally, autoimmunity in patients with RAG defects is associated with preserved number of circulating B cells and normal or increased Ig serum levels. One patient with compound heterozygous missense RAG1 mutations presented with idiopathic CD4 lymphopenia.

Mutations of DCLRE1C (Artemis).

A form of autosomal recessive SCID with the classic T ⁻ B ⁻ NK ⁺ phenotype has an associated feature of general radiation sensitivity not seen with RAG1 or RAG2 mutations and is caused by mutations in the gene DCLRE1C (DNA cross-link repair enzyme 1C), whose protein product is called Artemis. Artemis has a critical role in the function of NHEJ, or the repair of double-stranded DNA breaks (see Fig. 24-3 ). During VDJ recombination, it opens the hairpins sealing the coding ends at V, D, and J elements that have been targeted by the RAG proteins. Absence or impaired function of Artemis blocks T and B lymphocyte development at an early stage, similar to RAG1 and RAG2 mutations. Artemis is ubiquitously expressed, and loss of its function in nonhemopoietic tissues may account for nonimmunologic problems (oral and genital ulcers, dental abnormalities, and malabsorption) and for the increased cellular radiation sensitivity that these patients exhibit. OS has been observed in some patients with Artemis defects. A partial form of the disease, with residual expression and function of the protein, is characterized by reduced number of circulating T and B lymphocytes and increased risk of lymphoma.

DNA Ligase IV Deficiency.

DNA ligase IV (LIG4) is also required for NHEJ. Mutations in the LIG4 gene are associated with microcephaly, cognitive impairment, bone marrow failure, and cellular immunodeficiency that may manifest as T ⁻ B ⁻ NK ⁺ SCID, “leaky” SCID, or OS. There is profound cellular radiosensitivity. Patients are at increased risk of myelodysplasia and leukemia.

Cernunnos Deficiency.

Cernunnos (also known as XLF) is another component of the NHEJ pathway and is encoded by the NHEJ1 (nonhomologous end-joining 1) gene. Mutations of this gene cause lymphopenia, radiation sensitivity, growth retardation, microcephaly and developmental delay, bone marrow failure, and an increased risk of myelodysplasia. The T-and B-cell immunodeficiency of Cernunnos deficiency is less severe than in patients with RAG or LIG4 defects; however, there are quantitative and qualitative alterations of the T-cell repertoire, a severe reduction in the number of invariant NK T cells and mucosa-associated invariant T lymphocytes, and abnormalities of class-switch recombination in B lymphocytes (see section on class-switch defects).

DNA Protein Kinase Catalytic Subunit (DNA-PKcs) Deficiency.

A homozygous missense mutation in the PRKDC (protein kinase, DNA-activated, catalytic polypeptide) gene, encoding for DNA-PKcs was identified in a patient with T ⁻ B ⁻ NK ⁺ SCID and cellular radiosensitivity, but without microcephaly or mental retardation.

T ⁻ B ⁺ NK ⁻ Severe Combined Immunodeficiency

X-Linked Severe Combined Immunodeficiency, Mutations of the Cytokine Receptor Common γ Chain.

In Western countries, approximately 40% of all patients with SCID are males with an X-linked form of the disease, (XSCID), caused by mutations of the IL2RG (interleukin-2 receptor γ) gene, that encodes for the common γ chain (γ _c ), shared by cytokine receptors for interleukin-2 (IL-2), IL-4, IL-7, IL-9, IL-15, and IL-21 ( Fig. 24-4 ). Thus a defect in a single molecule interrupts several cytokine pathways, thereby severely disrupting immune function. Typically, patients with XSCID lack T and NK lymphocytes; these defects reflect defective signaling via IL-7R and IL-15R, respectively. However, some patients with XSCID may have variable numbers of their own T or NK cells and may retain partial immune function, reflecting some preservation of γ _c expression and of cytokine-mediated signaling. B lymphocytes are typically present, but they are nonfunctional as a result of impaired IL-21–mediated signaling. Patients with γ _c deficiency have typical clinical features of SCID. In addition, they are unusually susceptible to chronic and severe human papillomavirus (HPV) infections, and this phenotype may not be corrected after HSCT. Delayed presentations have been reported in association with hypomorphic mutations or with somatic mutations in T-cell progenitor cells, allowing generation of a diversified pool of functional T lymphocytes that may persist for years. Gene revertant T cells undergoing in vivo expansion may also cause a phenotype resembling OS.

Cytokine receptors and signaling via γ _c and Jak3. The γ _c chain participates in signaling by way of all these cytokine receptors; it associates with the Jak3 kinase in every case. The α chains of each receptor are distinct; receptors for IL-2 and IL-15 also share a β chain. The α or β chains or both associate with Jak1. After cytokine binding, Jak kinases recruit STAT (signal transducer and activator of transcription) proteins. These molecules dimerize and then translocate to the nucleus, where they associate with other transcriptional regulators and alter gene expression.

JAK3 Deficiency.

A form of T ⁻ B ⁺ NK ⁺ SCID phenotypically very similar to XSCID is associated with defects in the tyrosine kinase JAK3. The similarity with XSCID is easily understood because JAK3 is a critical signal-transducing molecule associated with the γ _c chain (see Fig. 24-4 ). Hypomorphic mutations that allow residual JAK3 protein expression and function may associate with partial preservation of circulating T cells and delayed clinical onset, with lymphoproliferation and susceptibility to warts and other viral infections.

T ⁻ B ⁺ NK ⁺ Severe Combined Immunodeficiency

Defects of the Interleukin-7 Receptor α Chain.

Signaling through the IL-7 receptor (IL-7R) is required for proliferation of early T-cell progenitors and survival of T lymphocytes. The IL-7R is composed of an α chain (IL-7Rα), encoded by the IL7R gene, and γ _c (see Fig. 24-4 ). Mutations of the IL7R gene in humans cause T ⁻ B ⁺ NK ⁺ SCID. One case of OS caused by a homozygous missense mutation, permissive for IL-7Rα expression, has been reported.

Mutations Affecting Components of the T-Cell Antigen Receptor Complex

The TCR/CD3 complex is made up of the TCRα and TCRβ (or TCRγ and TCRδ) chains of the receptor making contact with major histocompatibility antigen-peptide complexes, as well as components of the CD3 signal-transducing complex: CD3γ, CD3δ, CD3ε, and CD3ζ ( Fig. 24-5 ).

Components of the T-cell antigen receptor. The actual receptor making contact with a major histocompatibility complex (MHC)-peptide complex is a heterodimer of α and β (or γ and δ) chains. This heterodimer sits in the cell membrane in association with the signal-transducing CD3 complex. This complex contains two heterodimers, one γε and one δε, and one ζ ₂ homodimer. Also shown is the MHC class II coreceptor molecule CD4. Tyrosine kinases Lck, Fyn, and ZAP-70 associate with components of the receptor complex via immunoreceptor tyrosine-based activating motifs (ITAMs) and transduce signals after interaction of the receptor with peptide/MHC.

Defects in the CD3δ (gene CD3D ) lead to a T ⁻ B ⁺ NK ⁺ SCID phenotype. Patients have varying degrees of panhypogammaglobulinemia and are susceptible to disseminated viral infections. In some cases, a normal-sized thymus was visualized, in marked contrast to almost all other forms of SCID, in which the thymus is absent or extremely hypoplastic. In one case, CD3δ deficiency was associated with OS. A multicenter study of 13 patients with CD3δ deficiency treated by HSCT has shown superior immune reconstitution after transplantation from HLA-matched donors: use of conditioning chemotherapy may be needed to achieve engraftment.

Deficiency of CD3ε (gene CD3E ) and of CD3ζ (gene CD3Z ) are associated with a similar phenotype and markedly reduced levels of the TCR/CD3 complex on the surface of circulating T lymphocytes. In one patient with CD3ζ deficiency, some of the circulating T cells were found to express normal levels of the TCR/CD3 complex as the result of somatic mutations on one of the CD3Z alleles, allowing expression of poorly functioning TCR/CD3 complexes.

In contrast, the phenotype of CD3γ (gene CD3G ) deficiency is heterogeneous. One of two genotypically affected siblings presented with clinical features of SCID and autoimmunity associated with severe T-cell lymphopenia, whereas the other one had a milder immunologic phenotype and remained asymptomatic until 12 years of age, when he developed autoimmunity and recurrent infections. This variability of clinical and immunologic phenotype has been confirmed in other patients.

A homozygous splice-site mutation in the TCRα constant region gene has been identified in two patients with a history of recurrent infections and autoimmunity. Development of T cells expressing TCRγδ was not affected. In vitro proliferative responses to mitogens and antigens were decreased, but specific antibody production was preserved.

CD45 Deficiency

A few patients have been found to have a form of SCID resulting from mutations in the gene encoding the protein tyrosine phosphatase CD45 (gene PTPRC ), which plays an important role in T-cell activation. These patients have a SCID phenotype with diminished numbers of poorly functional T cells, normal or increased numbers of B cells, and variable number of NK cells.

Other Combined Immunodeficiencies (with T Cells Present)

Table 24-3 lists disorders of combined immunodeficiency with variable lymphocyte phenotypes.

TABLE 24-3

Combined Immunodeficiencies with T Cells Present and Associated Gene Defects

Syndrome	Gene
Variable T cell lymphopenia	CORO1A, MST1
Relative CD4+ T cell deficiency	LCK, MHCIITA , RFX5 , RFXANK , RFXAP, RHOH
Relative CD8+ T cell deficiency	CD8A, TAP1 , TAP2 , TAPBP , ZAP70
Hyper IgE syndrome type 2	DOCK8
Veno-occlusive disease with immunodeficiency	SP110
Ion (Ca ++ and Mg ++ ) transport defects	MAGT1, ORAI1, STIM1
Other	CARD11, IL21R

 

Relative Deficiency of CD4+ T Cells

Lck Deficiency.

The lymphocyte-specific protein tyrosine kinase (Lck) associates with CD4 and CD8 molecules and plays a critical role in T-cell signaling by mediating phosphorylation of immunoreceptor tyrosine activation motifs in the intracytoplasmic domains of CD3 subunits and of the ζ chain–associated protein of 70 kDa (ZAP70). Homozygosity for a missense LCK mutation was identified in a child with recurrent respiratory infections, protracted diarrhea, failure to thrive, skin nodules, vasculitis, arthritis, and autoimmune thrombocytopenia. There was a severe defect in the number of circulating CD4+ lymphocytes, and the density of both CD4 and CD8 molecules on the surface of CD3+ cells was markedly reduced. T lymphocytes showed a restricted TCR repertoire. Proliferative responses to anti-CD3 were profoundly impaired.

RhoH Deficiency.

The Ras homology family member H (RhoH) is a small GTPase that is phosphorylated in response to TCR stimulation, allowing recruitment of Lck and ZAP-70 to the TCR-associated signaling complex. Mutations of the RHOH gene have been identified in two siblings with warts, variably associated with granulomatous lung disease, psoriasiform skin changes, and molluscum contagiosum. One of the affected individuals developed Burkitt lymphoma in childhood. Immunologic abnormalities included reduced number of naïve CD4+ lymphocytes and oligoclonal T cell repertoire, with accumulation of CD8+ effector memory CD45RA+ lymphocytes (TEMRA cells) with an “exhausted” (CD45RA+CCR7−) phenotype. The reduced number of lymphocytes expressing skin-homing receptors (cutaneous lymphocyte antigen, CCR4, CCR6, CCR10, β7-integrin) may impair defense against cutaneous viral infections and contribute to development of warts.

Major Histocompatibility Complex Class II Deficiency.

The major histocompatibility complex (MHC) in humans is called the HLA complex. The class I and class II HLA molecules expressed on cell surfaces are critical for practically all mechanisms of specific immune activation. Class I molecules are present on most cells of the body. They present antigenic peptides derived principally from intracellular sources to the antigen receptors of T cells expressing CD8. HLA class II molecules are generally restricted to specialized antigen-presenting cells (APCs), including monocytes and macrophages, dendritic cells, and B cells, but are also expressed by thymic epithelial cells. HLA class II molecules mainly present peptides imported from outside the cell to antigen receptors of T cells bearing CD4. Defects in the synthesis, expression, or function of HLA molecules may be expected to have profound consequences on lymphocyte development and on immune competence. In particular, defective expression of HLA class II molecules on the surface of thymic epithelial cells impairs development of CD4+ lymphocytes by impairing their positive selection.

Most patients with MHC class II deficiency present early in life with recurrent and severe infections, chronic diarrhea, and failure to thrive. Chronic opportunistic infections of the gastrointestinal tract caused by Cryptosporidium or CMV organisms may lead to severe liver disease with sclerosing cholangitis. The number of circulating CD4+ cells is markedly decreased, and delayed hypersensitivity responses are impaired. All forms of MHC class II molecules (DP, DQ, and DR) are not expressed. Most patients have profound hypogammaglobulinemia; however, some patients have normal serum Ig levels, yet specific antibody responses are not elicited. As a rule, these children do not survive without HSCT. However, bone marrow transplantation in these patients has not been consistently successful, probably reflecting inability to correct defective expression of MHC class II molecules on the surface of thymic epithelial cells.

MHC class II deficiency results from defective regulation of gene transcription as a result of mutations in any of four different genes (CIITA, RFXANK, RFX5, RFXAP) encoding for components of HLA class II transcription complex. Without a complete transcription complex, no HLA class II mRNA is produced, and class II proteins cannot be synthesized. The same complex activates transcription at all HLA class II gene promoters. RFXANK mutations are the main cause of the disease, which is more common in Northern Africa and in the Middle East.

Relative Deficiency of CD8+ T Cells

Defective Expression of HLA Class I.

Several patients with defective expression of HLA class I molecules have been described. These patients have mutations in one of two genes encoding either TAP1 or TAP2 (transporter associated with antigen processing 1 or 2) or in the gene encoding tapasin, a TAP-binding protein molecular chaperone. The TAP1/TAP2 heterodimer is required for shuttling of cytosolic peptides across the endoplasmic reticulum to load onto nascent HLA class I molecules for eventual expression at the cell surface and presentation to TCRs ( Fig. 24-6 ). HLA class I molecules are highly unstable without a peptide in their binding cleft, and they are not transported to the cell surface. Patients with defective expression of HLA class I molecules suffer mainly from upper and lower respiratory tract bacterial infections, bronchiectasis, and granulomatous skin inflammation. Occasional asymptomatic individuals have also been described. The main immunologic abnormality is low peripheral blood CD8+ T cells; antibody responses may be normal.

Synthesis and assembly of major histocompatibility complex (MHC) class I molecules. ER, Endoplasmic reticulum; β2m, β2-microglobulin; TAP, transporter associated with antigen processing.

ZAP-70 Deficiency.

The ZAP-70 tyrosine kinase has a critical role in TCR-mediated signaling by inducing phosphorylation of the linker of activated T cells and SH2 domain-containing leukocyte phosphoprotein of 76 kDa (SLP-76) (see Fig. 24-5 ). Mutations of the ZAP70 gene in humans are typically associated with severe, early onset infections. Patients have almost complete absence of CD8+ T cells. Although circulating CD4+ cells appear normal, they fail to respond to signals delivered by way of the TCR. In a few cases, hypomorphic ZAP70 mutations have been associated with delayed onset of the disease and manifestations of immune dysregulation (skin rash, wheezing, eosinophilia). Treatment is based on HSCT.

CD8α Deficiency.

CD8 molecules are expressed on the cell surface as either a CD8α ₂ homodimer or a CD8αβ heterodimer. CD8α (gene CD8A ) deficiency is a rare autosomal recessive disorder characterized by lack of circulating CD8+ lymphocytes and by an increased number of CD3+CD4−CD8− cells that express markers of effector cytotoxic T lymphocytes (CD11b, CD57). The disease is reported here because of some phenotypic similarities (reduced number of CD8+ cells) with ZAP-70 deficiency; however, clinical manifestations are distinct and more similar to MHC class I deficiency, with recurrent respiratory infections and delayed diagnosis.

Management of Combined Immunodeficiency

Immunodeficiency Syndromes

The term syndromic immunodeficiencies has been coined to describe the occurrence of abnormal development or function of the immune system leading to susceptibility to infection, autoimmunity, or malignancy in the setting of a genetically determined disorder with characteristic features of altered development or function of other organ systems or the body as a whole. Here we will review several disorders with prominent immune dysfunction. These diseases and their associated genes are listed in Table 24-4 . Space does not permit a detailed description of the tremendous variety of syndromes that have been associated with immunodeficiency. Interested readers are referred to an excellent review on this topic.

Other Immunodeficiencies Associated with Defective Mechanisms of DNA Repair

The Nijmegen breakage syndrome is a disorder of chromosome fragility with autosomal recessive inheritance. The phenotype is similar to that of AT and consists of growth retardation, microcephaly, immunodeficiency, sensitivity to radiation, and a high rate of lymphoma. The affected gene is designated NBS1 . Nibrin, its protein product, is another substrate of ATM in the cellular response to ionizing radiation. Absence of nibrin function leads to disruption of mechanisms of DNA repair, but it does not appear to result in abnormal function of cell cycle checkpoints. Another similar syndrome, AT-like disorder, results from mutations of the gene MRE11A , which encodes another ATM substrate.

Postmeiotic segregation 2 (PMS2) and MutS homologue 6 (MSH6) are components of the DNA mismatch repair pathway. PMS2 deficiency is associated with increased occurrence of malignancies, café-au-lait spots, and defective CSR. MSH6 deficiency is also associated with increased risk of cancer and defective maturation of antibody responses, with impairment of CSR and a skewed pattern (higher rate of transitions) of somatic hypermutation.

Immunodeficiencies with Chromosomal Instability

Bloom syndrome is characterized by chromosomal instability with increased sister chromatid exchange and homologous chromosome translocations and is associated with increased frequency of infections, low levels of IgM, and impaired delayed-type hypersensitivity responses. The disease is caused by mutations of the BLM gene, encoding for a helicase.

The immunodeficiency-centromeric instability facial anomalies syndrome is characterized by hypogam­maglobulinemia, facial dysmorphisms, and branching of chromosomes 1, 9, and 16. The disease may be caused by mutations in the DNA methyl transferase 3B (DNMT3B) or in the zinc-finger- and-BTB (bric-a-brac, tramtrack, broad complex)-domain-containing 24 (ZBTB24) genes.

Mutations of the mini-chromosome maintenance-deficient 4 (MCM4) gene have been identified in patients with recurrent and severe viral infections (in particular, caused by herpes simplex virus 1 [HSV-1], varicella zoster virus [VZV] and CMV), growth retardation, adrenal insufficiency, and selective NK cell deficiency with lack of the CD56 ^dim NK subset. The disease is inherited as autosomal recessive trait. MCM4 is a component of a multiprotein complex required for both initiation and elongation of eukaryotic DNA replication. MCM4 mutations were shown to cause abnormalities of cell cycle, with increased proportion of fibroblasts in G2/M and S phases of cell cycle and an aberrant (>4n) DNA content, and genomic instability.

Pigmentary Dilution Disorders

Pigmentary dilution disorders include diseases in which abnormalities in melanosome trafficking within cells lead to characteristic pale skin and silvery-gray or ashen hair. Several forms of pigmentary dilution disorders are also characterized by a variable degree of immune deficiency, in particular impaired cell-mediated cytotoxicity. In these conditions inability to clear virus-infected cells leads to persistent and exaggerated inflammatory responses with macrophage activation, release of proinflammatory cytokines, and continuous activation of infiltrating CD8 ⁺ T cells that secrete high amounts of IFN-γ and cause tissue damage. Fever, hepatosplenomegaly, lymphadenopathy, and cytopenia caused by impaired hematopoiesis in the bone marrow and hemophagocytosis are typical manifestations of immune activation during the so-called accelerated phase of the disease. Impaired cytotoxicity of virus-infected cells reflects defective trafficking, docking or release of cytolytic granules in NK cells, and cytotoxic T cells. This defect parallels defects of melanosome trafficking.

Chédiak-Higashi syndrome is characterized by partial albinism, peripheral neuropathy, and increased risk of viral infections. Neutropenia is often present and may facilitate bacterial infections. Recognition of “giant” lysosomes in leukocytes facilitates the diagnosis. The disease is caused by mutation of the lysosomal trafficking regulator (LYST) gene. The precise mechanism by which the LYST protein works is not known, although it is thought to regulate trafficking of intracellular vesicles. HSCT is the only definitive treatment, but it does not prevent possible progression of neurologic complications.

Griscelli syndrome (GS) type 2 also associates partial albinism and immunodeficiency with increased susceptibility to infections, fever, and cytopenia. The disease is caused by mutations of the RAB27A gene, which encodes for a protein that permits docking of the cytolytic granules to the cell membrane. In contrast, GS type 1 (caused by mutations of the MYO5A gene, encoding for the myosin Va protein) and GS type 3 (due to mutations of the gene encoding for the melanin chaperone melanophilin) are characterized by hypopigmentation without immunodeficiency.

Hermansky-Pudlak syndrome type 2 (HPS2) is characterized by oculocutaneous albinism, bleeding diathesis, neutropenia, interstitial lung disease, and recurrent infections. Patients are at increased risk of hemophagocytosis. The disease is caused by mutations of the β subunit of the adaptor-related protein complex 3 (gene AP3B1 ) involved in sorting of proteins to the lysosomes. Patients with HPS9, which is caused by mutations of the pallidin (PLDN) gene, present with hypopigmentation and nystagmus; recurrent cutaneous infections also have been reported.

Mutations of the Nuclear Factor κ-B Pathway

NF-κB is a transcription factor that is critical for the activation of numerous genes on leukocyte stimulation. Activity of this factor is regulated by an inhibitor known as IκB. Phosphorylation of IκB by IκB kinase (IKK) leads to IκB degradation and liberates active NF-κB. IKK is composed of three subunits, α, β, and γ; the latter is also known as the NF-κB essential modulator (NEMO). The gene encoding NEMO is on the X chromosome. Null mutations in this gene are incompatible with life for male subjects and lead to the X-linked dominant disease incontinentia pigmenti in females. Certain mutations that allow partial NEMO function are associated with an immunologic phenotype that may have some similarities to hyper-IgM. Along with a combined immunodeficiency, these patients may exhibit hypohidrotic ectodermal dysplasia and lymphedema with osteopetrosis. Distinct hypomorphic mutations define specific disease characteristics, thus establishing genotype-phenotype correlation, albeit imperfectly. Somatic mosaicism in T lymphocytes has been detected in a significant proportion of males with NEMO deficiency, providing evidence for selective advantage for NEMO-expressing T cells in vivo. However, whether this may affect the disease phenotype is not clear.

Patients may suffer opportunistic-type disseminated viral infections and P. jiroveci pneumonia and are also highly susceptible to atypical mycobacterial infections. Inflammatory bowel disease is also frequently seen, reflecting a role of NF-κB in controlling epithelial integrity and the interaction between the mucosal immune system and gut microflora. Finally, lymphedema and osteopetrosis may also be part of the disease phenotype.

Most patients are hypogammaglobulinemic and have impaired vaccine responses (especially to polysaccharide antigens). Peripheral blood lymphocyte subsets and in vitro measures of lymphocyte function may be unremarkable or variably diminished; NK cell cytotoxicity may be impaired. Signaling by way of TLRs is also affected. Therapy with gamma globulin and antibiotic prophylaxis is essential. Despite these measures, infections may still occur. HSCT may cure the immunologic abnormalities and resolve increased susceptibility to infections, but inflammatory bowel disease may persist, along with extra-immune manifestations of the disease.

A few patients have been found to have a similar phenotype as a result of a so-called hypermorphic (gain of function) mutation of the IκBα chain. In this situation the IκBα is resistant to phosphorylation by IKK and cannot be dissociated, degraded, and induced to release NF-κB so that it may translocate to the nucleus to activate transcription.

Defects of Toll-Like Receptor Signaling

IRAK-4 and Myd88 are components of a complex mediating signaling downstream of all TLRs (except TLR3). Patients with IRAK4 or MYD88 mutations have severe, invasive bacterial infections such as meningitis, bacteremia, septic arthritis, deep-tissue abscesses, and osteomyelitis with gram-positive organisms (pre­dominantly Staphylococcus aureus and Staphylococcus pneumoniae . Less severe skin and respiratory infections also occur frequently. Most patients begin to exhibit infections in early childhood, but these wane significantly in frequency and intensity in the second decade of life. Most patients have impaired antibody responses to pneumococcal polysaccharides, but other routine tests of immune function are normal. Many patients have high levels of all Ig isotypes, possibly owing to immune stimulation by repeated bacterial infections. Signaling is impaired through all TLRs other than TLR3. Management is mainly with antibiotic prophylaxis and IgG therapy.

The Syndrome of Warts, Hypogammaglobulinemia, Infections, and Myelokathexis

The syndrome of warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM syndrome) is an autosomal dominant disorder of leukocyte trafficking caused by mutations of the chemokine receptor CXCR4. Patients carry heterozygous mutations in the intracellular tail of CXCR4 that prevent interaction with β-arrestin, thus allowing continuous signaling induced by CXCR4 ligand, CXCL12. This signal retains mature neutrophils in the bone marrow (myelokathexis) and alters trafficking of B and T lymphocytes, causing lymphopenia.

Impairment of cellular immunity and defective number of plasmacytoid dendritic cells (which are the major source of IFN-γ) cause warts, and neutropenia and hypogammaglobulinemia account for recurrent bacterial infections that mostly affect the respiratory tract. The number of switched memory B cells is reduced, and there is oligoclonality of the antibody repertoire. Gamma globulin replacement therapy generally reduces the rate of infection. The CXCR4 antagonist AMD3100 (plerixafor) corrects neutropenia and lymphopenia.

Hyperimmunoglobulin E Syndrome Caused by STAT3 Mutations

Hyper-IgE syndrome (HIES, often designated type 1) was initially described in 1972 in patients with severe sinopulmonary bacterial infections, severe skin superinfections with S. aureus on a chronic eczematous eruption (for which the disease is also known as Job syndrome ), and susceptibility to Aspergillus fumigatus pneumonitis with pneumatocele formation. Additional manifestations include asymmetric or coarse facial features, delayed shedding of primary teeth, bone fragility and fractures, scoliosis, and keratoconjunctivitis. Patients show increased susceptibility to nonfilamentous molds, such as P. jiroveci pneumonia and in particular chronic mucocutaneous candidiasis (CMC). There is an increased rate of malignancies, especially non-Hodgkin lymphoma. Cardiovascular anomalies have been described in recent years and include aneurysms, in particular of the carotids, cerebral arteries, and coronary arteries, and may lead to additional complications such as myocardial infarction. Inheritance of this form of HIES is autosomal dominant, but many cases represent sporadic presentations. The disease is caused by heterozygous dominant-negative mutations of the STAT3 gene that encodes for a transcription factor involved in signaling from a multitude of receptors. In particular, STAT3 is required for the development of T _h 17 cells, which secrete IL-17 and IL-22, two cytokines that play an important role in defense against candida and in promoting secretion of antimicrobial peptides by bronchial epithelial cells.

The major immunologic findings are elevated serum levels of IgE (3000 to >50,000 IU/mL) and eosinophilia. Along with a deficiency of T _h 17 cells, a reduced number of memory (CD27+) B lymphocytes also have been reported. The diagnosis is established on clinical and laboratory grounds; a scoring system has been developed that may be helpful, especially if used in combination with demonstration of lack of T _h 17 cells. Management of HIES caused by STAT3 mutations is mainly by skin care and antimicrobial prophylaxis against S. aureus . The role of antifungal prophylaxis is controversial, but it may be helpful in patients with CMC. HIES patients may lack classical signs and symptoms of infection, such as fever. Therefore careful physical examination, medical history, and imaging studies are needed to evaluate, diagnose, and treat any infections. Controversial results have been obtained after HSCT.

Autosomal Recessive Hyper-Immunoglobulin E Syndrome Caused by TYK2 Mutations

Two distinct forms of autosomal recessive HIES are known. Of these, DOCK8 deficiency has been discussed in the preceding section “Other Combined Immunodeficiencies with Variable Presentation.” Two patients with autosomal recessive HIES caused by mutations of TYK2 , a member of the JAK family of tyrosine kinases involved in intracellular signaling, have been reported. The first patient presented with atopy, elevated serum IgE, and susceptibility to infections sustained by S. aureus , BCG, Salmonella organisms, and viruses. The second patient suffered from disseminated BCG infection, neurobrucellosis, and cutaneous herpes zoster but had normal serum IgE and did not develop atopy.

Chronic Mucocutaneous Candidiasis

CMC affecting the nails, skin, and mucosa is the clinical hallmark of three distinct genetic disorders that affect IL-17–dependent immunity. These include complete, autosomal recessive deficiency of IL-17 receptor α chain (IL17RA), partial autosomal dominant IL-17F deficiency, and heterozygous gain-of-function mutations of signal transducer and activator of transcription 1 (STAT1) . The latter represents the most common cause of isolated CMC. Mutations of caspase recruitment domain-containing protein 9 (CARD9) gene, encoding a cytosolic adaptor molecule involved in intracellular signaling in cells recognizing fungi, also affect development of T _h 17 cells and cause CMC; however, CARD9-deficient patients are also at increased risk of disseminated Candida infections as well as of other fungal infections. Deficiency of T _h 17 cells accounts for CMC also in other forms of primary immunodeficiency, including T-cell deficiencies, HIES, and autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED).

Immunodeficiencies with Skeletal Abnormalities

Cartilage-hair hypoplasia (CHH) is an autosomal recessive disease characterized by short-limbed dwarfism with metaphyseal dysplasia, sparse and fair hair, and joint hypermotility. Dyserythropoietic anemia and a variable degree of immunodeficiency are present in 80% of the patients. A minority of subjects also present with Hirschsprung disease. There is a 6% to 10% rate of malignancies, especially lymphoma and basal cell carcinoma. The disease has a higher prevalence among Finnish and Amish populations and is caused by mutations in the RMRP gene that encodes for the untranslated RNA component of the mitochondrial RNA-processing endoribonuclease that is involved in multiple functions, including ribosomal and messenger RNA processing, mitochondrial DNA replication, and negative regulation of target RNA transcripts on interaction with TERT (telomerase reverse transcriptase).

The immunodeficiency of CHH is characterized by increased frequency of infections. Severe and persistent viral infections (EBV, CMV, HSV, and VZV) and fungal infections may occur, in addition to recurrent respiratory infections. Granulomatous lesions affecting the skin and other tissues have been described in several patients. Laboratory tests reveal a variable degree of immune dysfunction that predominantly affects T cells. In rare cases, immunodeficiency is very severe and may resemble SCID, “leaky” SCID with reduced number of CD8+ lymphocytes, or OS. Irrespective of the severity of the clinical phenotype, thymopoiesis is reduced, and there is T-cell lymphopenia. Moreover, T lymphocytes show abnormalities of cell cycle progression and an increased rate of apoptosis. HSCT is an effective form of treatment for patients with a severe clinical phenotype.

Schimke immuno-osseous dysplasia is an autosomal recessive disease characterized by spondyloepiphyseal dysplasia, focal glomerulosclerosis leading to progressive renal failure, and T-cell immunodeficiency. There is T cell lymphopenia, with an increased proportion of activated/memory T cells and of TCRγδ-expressing T lymphocytes. The disease is caused by mutations of the SMARCAL1 gene, which encodes for a chromatin remodeling protein.

Immunodeficiencies Associated with Disorders of Folate and Cobalamin Metabolism

Inborn errors of folate and cobalamin metabolism may associate with varying degrees of immunodeficiency. In particular, genetically determined defects in vitamin B ₁₂ metabolism are associated with megaloblastic anemia, neutropenia, and neurologic symptoms with seizures and developmental delay. Transcobalamin II (gene TCN2 ) deficiency causes neutropenia leading to recurrent bacterial infections. Severe lymphopenia is observed in patients with deficiency of methionine synthase, causing a SCID-like phenotype with severe viral and bacterial infections. Mutations of proton-coupled folate transporter that impede folate absorption through the gastrointestinal mucosa are also associated with extreme lymphopenia and clinical features of SCID. Mutations of the MTHFD1 gene that encodes for a trifunctional protein essential for processing of single-carbon folate derivatives cause SCID with decreased number of T, B, and NK lymphocytes, which is associated with megaloblastic anemia, leukopenia, atypical hemolytic uremic syndrome, and neurologic abnormalities. Parenteral supplementation therapy is beneficial.

GATA2 Deficiency

In 2010 Vinh and coworkers reported on a series of patients with a distinct clinical phenotype characterized by onset in late childhood or adulthood, susceptibility to disseminated nontuberculous mycobacterial disease, recurrent and severe viral infections (especially those caused by papillomavirus and herpesviruses), and fungal infections. There is increased risk of myelodysplasia and malignancies, including acute myeloid leukemia, squamous cell carcinoma, and EBV-positive leiomyosarcoma. Pulmonary alveolar proteinosis and primary lymphedema have been observed in several patients.

Typical laboratory features include profound monocytopenia, severe reduction in the number of B and NK lymphocytes (in particular, of the CD56 ^bright subset) and dendritic cells and elevated levels of fms-like tyrosine kinase ligand (Flt3L). Depletion of regulatory T cells also has been reported. Examination of the bone marrow reveals hypocellularity, often associated with multilineage dysplasia and cytogenetic abnormalities, including monosomy 7 and trisomy 8. In vitro IL-12 and IFN-γ production in response to stimulation with LPS is markedly reduced, suggesting that disruption of the IL-12/IFN-γ axis may contribute to the increased occurrence of mycobacterial disease.

The disease has been referred to as MonoMAC syndrome (to indicate the monocytopenia and susceptibility to nontuberculous mycobacterial infections) or DCML (dendritic cells, monocytes, B and NK lymphocytes) deficiency and has been shown to be caused by heterozygous, loss-of-function mutations of the GATA2 gene. GATA-2 is a transcription factor that contains two highly conserved zinc finger domains that mediate protein-DNA and protein-protein interactions and is required for stem cell homeostasis, lymphatic vessel development, and the maturation and homeostasis of NK lymphocytes. Disease-causing mutations also include intronic deletions and point mutations in regulatory regions of the gene that affect GATA2 transcript levels. Both autosomal dominant inheritance and sporadic presentation have been reported. If untreated, the disease has a severe prognosis, with death occurring in adulthood as a result of infections or malignancies. Nonmyeloablative HSCT has been successfully performed in several patients, with reconstitution of the number of monocyte, B-cell, and NK-cell populations and reversal of the clinical phenotype.

Immunodeficiencies with Immune Dysregulation

Although autoimmune and inflammatory manifestations may be seen in a large number of primary immunodeficiencies, they represent the main feature in some. The pathophysiology of these disorders may reflect a variety of mechanisms, including impairment of central and peripheral tolerance and chronic immune activation associated with the inability to clear infections. These disorders and their associated genes are listed in Table 24-5 .

Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy Syndrome

APECED syndrome represents the prototypic disorder associated with impairment of central T-cell tolerance. APECED is inherited as an autosomal recessive trait and is characterized by autoimmune hypoparathyroidism, Addison disease, and CMC. Patients are also prone to other autoimmune manifestations, such as hepatitis, alopecia, ovarian failure, and hypothyroidism. There is an increased incidence of oral squamous cell carcinoma, and fulminant autoimmune hepatitis. The disease is caused by mutations in the gene AIRE (autoimmune regulator) encoding a transcription factor expressed by medullary thymic epithelial cells (mTECs). AIRE promotes expression of tissue-specific antigens that are presented by mTECs and thymic dendritic cells to nascent T lymphocytes. High-affinity recognition of self peptides leads to deletion of self-reactive T cells. Therefore mutations of the AIRE gene compromise the mechanism of central tolerance and result in APECED, which is associated with production of multiple autoantibody specificities. Interestingly, autoantibody production in patients with APECED is not restricted to AIRE-dependent self-antigens but also includes antibodies to interferon-α and β as well as IL-17 and IL-22. Defective T _h 17-dependent immune responses may account for chronic mucocutaneous candidiasis in this disease.

Immune Dysregulation Polyendocrinopathy Enteropathy X-Linked Syndrome

Treg cells maintain peripheral T cell tolerance by suppressing self-reactive T lymphocytes that have escaped central tolerance. Generation of Treg cells is controlled by the transcription factor FOXP3. Mutations of the FOXP3 gene cause immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome. IPEX is characterized by severe early-onset autoimmune manifestations that involve the gut (causing intractable diarrhea), pancreas (diabetes), the skin, and other organs. Lymphoproliferation and cytopenias are also very common. Delayed presentations have been also observed. Patients with IPEX require immune suppression, but the only definitive treatment currently available is allogeneic HSCT.

Defects of IL-2–Mediated Signaling

IL-2–mediated signaling is important to maintain immune homeostasis and support the function of Treg lymphocytes. Mutations in the IL2RA gene, which encodes CD25, the α chain of the IL-2R, cause immunodeficiency with IPEX-like immune dysregulation. The clinical phenotype is marked by severe diarrhea, failure to thrive, CMV infection, chronic lung disease, lymphadenopathy, splenomegaly, and autoimmunity (diabetes mellitus, autoimmune hepatitis). Poor in vitro T-cell function that could not be corrected with exogenous IL-2 was demonstrated. The number of FOXP3 ⁺ cells was preserved in patients with CD25 deficiency; however, secretion of IL-10, a cytokine with immunosuppressive activity, was impaired, possibly accounting for the autoimmune manifestations of the disease.

Mutations of the signal transduced and activator of transcription 5B (STAT5B) gene, which encodes a transcription factor activated by IL-2 signaling, cause an autosomal recessive form of immunodeficiency with immune dysregulation. Because STAT5B is also activated in response to growth hormone receptor stimulation, patients with STAT5B deficiency also show growth failure with growth hormone insensitivity.

Autoimmune Lymphoproliferative Syndrome

Apoptosis of self-reactive lymphocytes is another important mechanism to prevent autoimmunity in the periphery and may be induced either through the extrinsic, Fas-dependent pathway or through induction of the mitochondrial pathway in response to cell damage and cytokine (e.g., IL-2) starvation. Both pathways converge on caspase 9 and downstream effector caspases 3 and 7, causing apoptosis. Autoimmune lymphoproliferative syndrome (ALPS) is characterized by lymphadenopathy, splenomegaly, and autoimmune cytopenias and an increased risk of developing lymphoma. Infiltrative lymphoproliferative disease may also cause organ-specific complications (glomerulonephritis, hepatitis, encephalitis, uveitis, interstitial pulmonary disease). There is a characteristic expansion of CD3+TCRαβ+CD4−CD8− double-negative T cells (DNTs).

Most patients are heterozygous for a mutation in the FAS gene; in such families the disease is inherited as an autosomal dominant trait with variable penetrance. Somatic mutations in FAS are another common cause of the disease. More rarely, patients may show biallelic mutations.

Other rare causes of ALPS are represented by mutations of genes encoding Fas ligand (FasL), FADD, caspase 8, and caspase 10, all of which are involved in the Fas-mediated signaling pathway leading to apoptosis. The number of DNTs is only marginally elevated in patients with caspase 8 deficiency.

In addition to an increased proportion of DNTs, other biomarkers that may facilitate the diagnosis of ALPS and that are associated especially with FAS mutations include elevated serum levels of vitamin B ₁₂ , soluble FasL, IL-10, and IL-18. Hypergammaglobulinemia is common. Moreover, patients with ALPS caused by FAS mutation frequently have a reduced number of memory (CD27+) B lymphocytes.

Defects of the “intrinsic” (mitochondrial) pathway of apoptosis leading to ALPS include gain-of-function mutations of NRAS and somatic mutations of KRAS , but these variants do not result in an increased number of DNTs.

Management of ALPS includes use of immunosuppressive drugs (steroids, mycophenolate mofetil, sirolimus) to control autoimmune manifestations and regular monitoring of lymphoproliferation by computed tomography scanning or positron emission tomography for surveillance of lymphoma. Splenectomy may improve the cytopenias but is associated with a marked increase of sepsis. Chronic cytopenias tend to improve over time; HSCT should be reserved for very severe clinical presentations with autoimmune disease refractory to treatment.

ITCH Deficiency

Mutations of the E3 ubiquitin ligase ITCH have been shown to cause multisystem autoimmune disease in affected individuals from a large Amish kindred. Characteristic clinical features include failure to thrive, hepatosplenomegaly, multiorgan autoimmune manifestations (hypothyroidism, hepatitis, diabetes, enteropathy), chronic lung disease, developmental delay, dysmorphic features, and hypotonia. Dysfunction of E3 ubiquitin ligases have been shown to lead to indiscriminate T cell activation, loss of tolerance to self-antigens and accumulation of autoreactive B lymphocytes.

Immunodeficiencies with Impaired Cell-Mediated Cytotoxicity

CD8+ cytotoxic T lymphocytes (CTLs) and NK cells play a critical role in antiviral immune defense through two mechanisms: Fas-mediated apoptosis of virus-infected cells and release of cytolytic granules. In resting CTLs and NK lymphocytes, cytotoxic proteins are contained in endosomal secretory granules. On activation of CTLs and NK lymphocytes, lytic granules polarize toward the immune synapse, dock, and fuse with the cell membrane of the effector cell. Multimers of perforin form pores through which CTLs and NK cells release cytotoxic proteins (granzyme B, granulolysin) into virus-infected target cells, causing activation of caspases and apoptosis of target cells.

Defects in this process are responsible for various forms of familial hemophagocytic lymphohistiocytosis. Defective cell-mediated cytotoxicity is also observed in several forms of pigmentary dilution disorders (discussed previously). Finally, selective susceptibility to EBV infection is at the basis of various forms of lymphoproliferative syndrome. These diseases and their associated genes are listed in Table 24-6 .

Familial Hemophagocytic Lymphohistiocytosis

Familial hemophagocytic lymphohistiocytosis (FHL) includes a heterogeneous group of monogenic disorders characterized by impaired cell-mediated cytotoxicity. In patients with FHL, the inability to clear viral infections causes persistent activation of CD8+ and NK lymphocytes, with production of high amounts of IFN-α and -β and of proinflammatory cytokines (tumor necrosis factor-alpha [TNF-α], IL-6). Clinical features of FHL include recurrent episodes of high fever, pancytopenia, liver and spleen enlargement, and signs of neurologic involvement. The diagnostic criteria were revised in 2007. Elevated serum levels of triglycerides, ferritin, and soluble CD25 and decreased levels of fibrinogen and poor NK function are typical laboratory findings. If left untreated, FHL is rapidly fatal. Severe bacterial and fungal infections and multiple organ failure are the main causes of death. Treatment should be aimed at eradicating the underlying infection while suppressing immune activation at the same time. Corticosteroids, cyclosporine A, etoposide, and antithymocyte globulin are often effective in tempering immune activation. However, relapses are common, and the only curative treatment is represented by HSCT. In particular, reduced intensity conditioning has shown excellent efficacy and limited toxicity.

The genetic defect has been identified for four forms of FHL so far, and all of them are inherited as autosomal recessive traits. Perforin deficiency accounts for approximately 30% of all cases of FHL. It is caused by mutations of the PRF1 gene that prevent expression or correct assembly of perforin multimers that form pores through which cytolytic enzymes are released into target cells. Mutations of the UNC13D gene, encoding for Munc13-4, impair priming of the cytolytic granules, which is necessary for their fusion with the cell membrane. UNC13D mutations represent the most common form of FHL (30% to 40% of all cases). Defects of the Syntaxin 11 (STX11) gene affect granule exocytosis. Finally, FHL may also be caused by defects of Munc18-2, a protein partner of STX11 encoded by the Syntaxin binding protein 2 (STXBP2) gene.

X-Linked Lymphoproliferative Disease

X-linked lymphoproliferative (XLP) disease is characterized by unique susceptibility to severe complications after EBV infection in male subjects. Two genetically distinct forms are known. In XLP1 the disease is caused by mutations of the SH2 domain containing protein 1 A (SH2D1A) gene, encoding for a small adapter protein (SLAM-associated protein, or SAP) involved in intracellular signaling in T and NK lymphocytes. In particular, SAP binds to CD244 (a SLAM family member) expressed by NK lymphocytes. EBV-infected B cells express high levels of CD48, the CD244 ligand. On CD244/CD48 binding, SAP participates at intracellular signaling and promotes NK cytolytic activity against EBV-infected target cells. In the absence of SAP, NK cytolytic activity is impaired. SAP is also important for the function of follicular helper T cells that promote maturation of antibody responses. XLP2 is caused by mutations of the BIRC4 gene, which encodes for the X-linked inhibitor of apoptosis (XIAP) protein.

XLP1 and XLP2 have partially overlapping clinical features. Hemophagocytic lymphohistiocytosis (HLH) subsequent to primary EBV infection is a prominent sign at clinical presentation in both diseases. XLP1 may manifest with fatal infectious mononucleosis, aplastic anemia, pulmonary lymphoid granulomatosis with vasculitis, and lymphoma. A proportion of XLP1 patients who survive primary EBV infection will develop hypogammaglobulinemia, which in some cases is associated with elevated levels of IgM or IgA. Some patients may have a clinical and laboratory phenotype consistent with common variable immunodeficiency (CVID, discussed later). Functional activity of NK and CTLs is impaired. Finally, patients with XLP1 lack NKT lymphocytes. Without HSCT, 62.5% of the patients survive (and most of them require Ig replacement); however, poor survival rates (less than 20%) have been observed in patients without transplants who have features of HLH. HSCT may cure approximately 80% of XLP1 patients, but poorer outcome (50% survival) has been observed if HLH is present.

In contrast, XLP2 causes recurrent episodes of HLH, with or without EBV infection. Patients with XLP2 are not at increased risk of lymphoma; on the other hand, inflammatory bowel disease is frequently observed. Definitive treatment of XLP2 is also based on HSCT; however, use of a myeloablative conditioning regimen is associated with high mortality.

IL-2 Inducible Tyrosine Kinase Deficiency

Interleukin-2 inducible tyrosine kinase (ITK) is a nonreceptor tyrosine kinase that modulates the strength of intracellular signaling in T lymphocytes on TCR-induced activation. Patients with ITK deficiency are susceptible to EBV-driven lymphoproliferative disease (often involving the lungs as well), Hodgkin lymphoma, hypogammaglobulinemia, autoimmunity, and HLH. The disease is inherited as an autosomal recessive trait. There is a reduced number of naïve CD4+ lymphocytes and of NKT cells. Allogeneic HSCT may cure the disease.

CD27 Deficiency

CD27 is a member of the TNF receptor family and is broadly expressed on the surface of various lymphocyte subsets. By interacting with CD70, it promotes generation and maintenance of T-cell memory. It is also commonly used as a marker of memory B lymphocytes. CD27 deficiency has been identified in some patients presenting with severe EBV infection. Lymphoma and secondary hypogammaglobulinemia have been reported in some of these patients. HSCT represents a curative form of treatment.

CD16 Deficiency

One of the mechanisms by which NK lymphocytes mediate killing of target cells is antibody-dependent cellular cytotoxicity (ADCC), whereby antibody-bound target cells come in contact with NK lymphocytes through binding of the Fc region of IgG molecules to a specific receptor (FcγRIIIa, also known as CD16) expressed on the surface of NK lymphocytes. Homozygosity for the Leu66His amino acid substitution in CD16 causes deficient spontaneous NK cell-mediated cytotoxicity but surprisingly leaves ADCC intact. Expression of CD2, a co-activating NK cell receptor, is decreased, affecting intracellular signaling in NK lymphocytes. Recurrent and severe herpesvirus infections are the clinical hallmark of this condition.

Immunodeficiencies with Selective Predisposition to Pathogens

Most forms of primary immunodeficiencies are characterized by susceptibility to a broad range of pathogens, whose nature (bacteria, viruses, fungi, protozoa) reflects the underlying immune defect. However, in the last two decades it has become clear that certain gene defects that affect the immune system may lead to selective predisposition to a narrow group of pathogens. These findings have supported the genetic theory of infectious diseases, whereby life-threatening infections early in life may in fact be caused by inborn errors of immunity. These disorders and their associated genes are listed in Table 24-7 .

Humoral Immunodeficiency

The humoral immunodeficiencies and their associated gene defects are listed in Table 24-8 . These disorders are characterized by hypogammaglobulinemia or dysgammaglobulinemia, often together with relative deficiency of antibody responses to various forms of antigenic challenge. Cellular immunity is generally intact. Humoral immunodeficiency is most commonly manifested by recurrent bacterial and viral infections of the upper and lower respiratory tract. Pyogenic skin infections, as well as meningitis, osteomyelitis, and other foci of infection, are also seen frequently. These infections are generally caused by the same organisms that are virulent in immunocompetent hosts, predominantly encapsulated bacteria such as Streptococcus pneumoniae , Hemophilus influenzae, S. aureus , and Neisseria meningitidis . Viral infections usually resolve normally in these patients, although a higher rate of recurrence with the same agent may be seen because there is impaired production of neutralizing antibodies or B-cell memory. The results of physical examination are not specific and show only the presence or sequelae of microbial infections. A relative paucity of peripheral lymphoid tissue may be noted in some patients, especially areas rich in B cells (e.g., tonsils). Studies of peripheral blood lymphocyte subsets are often normal; the number of B cells may be reduced in certain syndromes.

The Agammaglobulinemias

X-Linked Agammaglobulinemia

X-Linked agammaglobulinemia (XLA) is also known as Bruton agammaglobulinemia because Bruton provided the classic description of the disease in 1952. Affected male subjects are often asymptomatic during the first months of life while they are protected by transplacentally acquired maternal antibodies. These antibodies fall to low levels by 6 to 9 months of age, and patients begin to experience recurrent bacterial infections. Physical examination at any age often reveals a striking absence of tonsils and palpable lymphoid tissue. Serum Ig is absent or the level is extremely low; in addition, no B cells are found or their numbers are extremely low. Cellular immunity is completely intact. However, these patients are prone to the development of chronic enteroviral meningoencephalitis and vaccine-associated paralytic poliomyelitis, which suggests an important role for humoral immunity in the control of these infections. Moreover, patients may have arthropathy resembling rheumatic disease, which may be due to infection with Mycoplasma or Ureaplasma organisms. Other opportunistic infections, such as P. jiroveci pneumonia, are seen only rarely.

XLA is another example of an immunodeficiency caused by a defect in a signal transduction molecule. In fact, this protein tyrosine kinase is now known as Bruton tyrosine kinase ([Btk], Fig. 24-7 ). It is expressed in B cells at all stages of development, as well as in cell lines derived from monocytes, macrophages, mast cells, and erythroid cells. A variety of BTK gene defects such as point mutations, deletions, and insertions have been described in patients with XLA. In most patients B-cell development is impeded at an early stage (the pro–B-cell to pre–B-cell transition).

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