Key Points
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Defects of T cell development and/or function cause increased susceptibility to infections of bacterial, viral and fungal origin, and are often associated with autoimmune manifestations and malignancies.
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The most severe forms of these disorders, severe combined immunodeficiency (SCID), are fatal unless immune reconstitution is attained, typically with hematopoietic stem cell transplantation (HSCT) or in selected cases with gene therapy or enzyme replacement therapy.
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Newborn screening based on enumeration of T cell receptor excision circles (TRECs) permits early identification of SCID and thereby allows adoption of therapeutic interventions aimed to reduce the risk of infection while preparing for HSCT, resulting in improved overall survival.
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Several forms of T cell immunodeficiency are associated with other hematopoietic and non-hematopoietic defects, whose severity may have a significant impact on prognosis and outcome.
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Hygiene measures, antimicrobial prophylaxis, regular immunoglobulin replacement therapy and nutritional support are cardinal aspects of treatment for patients with T cell deficiencies, along with HSCT.
T lymphocytes are an essential component of adaptive immunity. Through cytolytic activity and secretion of T H 1 (interferon [IFN]-γ) and T H 17 (interleukin [IL]-17, -22) cytokines they mediate resistance to viruses, mycobacteria and fungi. In addition, interaction of T H 2 cells with B lymphocytes and antigen-presenting cells, and release of soluble mediators such as IL-4 and IL-10 promote T-dependent antibody responses and contribute to defense against extracellular pathogens. Consequently, defects in T cell development and/or function result in severe combined immunodeficiency (SCID), with increased susceptibility to severe infections from early in life.
In addition, impaired development and/or function of regulatory T (T REG ) lymphocytes, which play a crucial role in immune homeostasis, causes autoimmunity. This chapter will discuss the etiology, clinical presentation, diagnostic approach and main principles of treatment for congenital T cell disorders. For a more detailed discussion of hematopoietic stem cell transplantation (HSCT) and gene therapy the reader is referred to Chapter 16 .
Severe Combined Immunodeficiency
Etiology
SCID is a heterogeneous group of disorders that present with a distinct immunologic phenotype ( Table 9-1 ). Molecular and cellular mechanisms responsible for SCID include:
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Defects of lymphocyte survival : adenosine deaminase (ADA) deficiency, reticular dysgenesis
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Signaling defects : X-linked SCID, JAK3 deficiency, IL-7R deficiency, CD45 deficiency
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Defects of expression and signaling through the pre-T cell receptor (pre-TCR) and the TCR : defects of RAG1, RAG2, Artemis, Cernunnos, DNA ligase IV (LIG4), DNA protein kinase catalytic subunit (DNA-PKcs), defects of CD3 chains (CD3δ, CD3ε, CD3ζ), defect of TCR α constant (TRAC) chain, CD45 deficiency.
| Disease | Gene | Inheritance | CIRCULATING LYMPHOCYTES | ||
|---|---|---|---|---|---|
| T | B | NK | |||
| B − SCID | |||||
| Reticular dysgenesis | AK2 | AR | ↓↓ | ↓ | ↓↓ |
| RAG deficiency | RAG1, RAG2 | AR | ↓↓ | ↓↓ | N |
| Radiation-sensitive SCID | DCLRE1C (Artemis) | AR | ↓↓ | ↓↓ | N |
| PRKDC | AR | ↓↓ | ↓↓ | N | |
| LIG4 | AR | ↓↓ | ↓↓ | N | |
| NHEJ1 | AR | ↓↓ | ↓ | N | |
| T − B + SCID | |||||
| X-linked SCID | IL2RG | XL | ↓↓ | N | ↓↓ |
| JAK-3 deficiency | Jak-3 | AR | ↓↓ | N | ↓↓ |
| IL-7Rα deficiency | IL7RA | AR | ↓↓ | N | N |
| CD45 deficiency | CD45 | AR | ↓↓ | N/↓ | ↓ |
| CD3δ, CD3ε, or CD3ζ deficiency | CD3D, CD3E, CD3Z | AR | ↓↓ | N | N |
| Coronin-1A deficiency | CORO1A | AR | ↓↓naïve | N | N |
| Purine metabolism deficiency | |||||
| Adenosine deaminase deficiency | ADA | AR | ↓↓ | ↓ | ↓ |
| Nucleoside phosphorylase deficiency | PNP | AR | ↓↓ | ↓/N | ↓/N |
| Omenn syndrome | RAG1, RAG2, DCLRE1C, LIG4, ADA, AK2 | AR | ↓/N | ↓↓ | N |
| IL7R, RMRP | AR | ↓/N | N | N | |
| IL2RG | XL | ↓/N | N | ↓↓ | |
| ZAP70 | AR | ↓ (↓↓ CD8) | N | N | |
| TCRα constant chain deficiency | TRAC | AR | ↓(almost all T cells are TCRγδ + ) | N | N |
| ZAP-70 deficiency | ZAP70 | AR | ↓ (↓↓ CD8) | N | N |
| LCK deficiency | LCK | AR | N (↓↓ CD4 naïve) | N | N |
| RHOH deficiency | RHOH | AR | ↓↓ naïve T cells | N | N |
| MST1 deficiency | STK4 | AR | ↓↓ naïve T cells, ↑ T EMRA and Teff | N | N |
| ITK deficiency | ITK | AR | Progressive ↓ | N | N |
| DOCK8 deficiency | DOCK8 | AR | ↓ | N, ↓memory B cells | N |
| Calcium flux defects | |||||
| Stim1 deficiency | STIM1 | AR | N | N | N |
| Orai1 deficiency | ORAI1 | AR | N | N | N |
| Mg 2+ flux deficiency | MAGT1 | XL | ↓CD4 | N | N (impaired function) |
| CD25 deficiency | IL2RA | AR | ↓ | N | N |
| STAT5b deficiency | STAT5B | AR | ↓ | N | N |
| Human ‘nude’ phenotype | FOXN1 | AR | ↓↓ | N | N |
| MALT1 deficiency | MALT1 | AR | N | N | N |
| CARD11 deficiency | CARD11 | AR | N(↓memory T) | N (mostly transitional) | N |
| IKBKB deficiency | IKBKB | AR | N(↓memory T) | N (↓↓memory B) | N |
| Activated PI3K-δ | PI3KCD | AD | ↓CD4, ↑ T EMRA | ↓ | N |
| IL-21R deficiency | IL21R | AR | N | N (↓memory B) | N |
| CD27 deficiency | CD27 | AR | N | N (↓↓memory B) | N |
| MHC class I deficiency | TAP1, TAP2, TAPBP | AR | ↓ (↓↓CD8) | N | N |
| MHC class II deficiency | CIITA, RFXANK, RFX5, RFXAP | AR | ↓ (↓↓CD4) | N | N |
| CTPS1 deficiency | CTPS1 | AR | ↓CD4 | N (↓memory B) | N |
| X-linked hyper-IgM syndrome | CD40LG | XL | N | N | N |
| ID with multiple intestinal atresia | TTC7A | AR | ↓ | ↓ | N |
| Cartilage hair hypoplasia | RMRP | AR | ↓/N | N | N |
| Schimke syndrome | SMARCAL1 | AR | ↓ | N | N |
Hypomorphic mutations in these genes may allow for residual T cell development, with or without immune dysregulation. These conditions, and other defects at later stages in T cell development, will be discussed separately in this chapter (see ‘Other Combined Immunodeficiencies’).
SCID Caused by Adenosine Deaminase Deficiency
Adenosine deaminase (ADA) mediates conversion of adenosine into inosine, and of deoxyadenosine into deoxyinosine. Deficiency of ADA, inherited as an autosomal recessive trait, accounts for 5% to 10% of all cases of SCID. Lack of ADA results in intracellular accumulation of deoxyadenosine and of its phosphorylated metabolites, among which dATP is particularly toxic to lymphoid precursors. Consequently, complete ADA deficiency is characterized by extreme lymphopenia (T − B − NK − SCID) and extra-immune manifestations (reflecting the housekeeping nature of the ADA gene) from early in life. However, partial defects of the enzyme may result in less severe clinical presentation (delayed or late-onset forms) that may even present in adulthood.
Reticular Dysgenesis
This rare form of autosomal recessive SCID is characterized by severe lymphopenia and agranulocytosis, associated with sensorineural deafness. The disease is caused by mutations of the AK2 gene, encoding for adenylate kinase 2 that controls intramitochondrial levels of ADP. AK2 deficiency results in increased cell death in lymphoid progenitors and in myeloid precursors committed to neutrophil differentiation.
X-Linked Severe Combined Immunodeficiency (SCIDX1, γc Deficiency)
SCIDX1 is the most common form of SCID in humans, with an estimated incidence of 1 : 100,000 to 1 : 150,000 live births. Inherited as an X-linked trait, it is characterized by complete absence of both T and NK lymphocytes, with preserved number of B lymphocytes (T − B + NK − SCID). The disease is caused by mutations in the IL2RG gene that encodes for the IL2 receptor common gamma chain (IL-2Rγ c , γ c ). The γ c chain is constitutively expressed by T, B and NK cells, as well as myeloid cells and other cell types, including keratinocytes. The γ c protein is an integral component of various cytokine receptors, namely IL-2R, IL-4R, IL-7R, IL-9R, IL-15R and IL-21R. In all of these receptors, the γ c is coupled with the intracellular tyrosine kinase Janus-associated kinase (JAK)-3, that mediates signal transduction. Lack of circulating T and NK cells in SCIDX1 males reflects defective signaling through IL-7R and IL-15R, respectively.
JAK-3 Deficiency
JAK-3 is a cytoplasmic tyrosine kinase that is physically and functionally associated with the γ c in all of the γ c -containing cytokine receptors. Mutations of the JAK3 gene result in a clinical and immunologic phenotype (i.e. T − B + NK − SCID) that is undistinguishable from SCIDX1, but has an autosomal pattern of inheritance.
IL-7Rα Deficiency
IL-7Rα deficiency results in an autosomal recessive form of SCID characterized by lack of circulating T lymphocytes, with preserved number of B and NK cells (T − B + NK + SCID). IL-7 is produced by stromal cells in bone marrow and in the thymus, and provides survival and proliferative signals to IL-7R + lymphoid progenitor cells.
T − B − SCID Caused by Defective VDJ Recombination
B and T lymphocytes recognize foreign antigen through specialized receptors, the immunoglobulin (Ig) and the T cell receptor (TCR), respectively. These receptors are encoded by variable/diversity/joining (VDJ) gene segments that undergo somatic rearrangement through a mechanism known as VDJ recombination. This process is initiated when the lymphoid-specific recombinase activating gene 1 (RAG1) and RAG2 proteins recognize specific recombination signal sequences (RSS) that flank each of the V, D and J gene elements and introduce a DNA double-strand break in this region. Subsequently, a series of ubiquitously expressed proteins (including Ku70, Ku80, DNA-PKcs, XRCC4, DNA ligase IV, Artemis and Cernunnos/XLF) involved in recognition and repair of DNA damage mediate the final steps of the VDJ recombination process.
Defects of V(D)J recombination cause complete absence of both T and B lymphocytes, with preserved presence of NK cells (T − B − NK + SCID). RAG1 and RAG2 mutations do not affect mechanisms of DNA double-strand break (dsb) repair and hence are not associated with increased cellular radiosensitivity. By contrast, defects of Artemis, LIG4, Cernunnos/XLF or DNA-PKcs cause increased radiosensitivity, reflecting impaired dsb repair. Of note, hypomorphic mutations in the RAG1/2 genes and in the Artemis-encoding DCLRE1C gene have been associated with variable clinical and immunologic phenotypes, ranging from Omenn syndrome to expansion of TCRγδ + T cells to delayed onset immunodeficiency with granuloma and/or autoimmunity.
CD3/TCR Deficiencies
The CD3 complex consists of CD3γ, δ, ε and ζ chains and is required to mediate signaling through the pre-TCR and the TCR. In humans, defects of the CD3 δ, ε or ζ chains cause autosomal recessive T − B + NK + SCID. In contrast, CD3γ deficiency is associated with a partial T cell lymphopenia and a variable clinical phenotype.
CD45 Deficiency
Two unrelated patients have been reported in whom SCID was caused by the complete absence of the CD45 protein, a phosphatase that modulates signaling through the TCR/CD3 complex. The immunologic phenotype is characterized by complete lack of T cells, with normal to increased B cell counts.
Other Combined Immunodeficiencies
Omenn Syndrome and Other Conditions Associated with Hypomorphic RAG Mutations
Omenn syndrome (OS) is a combined immunodeficiency characterized by generalized erythroderma, lymphadenopathy, hepatosplenomegaly, respiratory infections, diarrhea, failure to thrive, hypoproteinemia with edema, and eosinophilia ( Figure 9-1 ). IgE serum levels are often elevated, and T lymphocytes have an oligoclonal repertoire.
In most cases, OS is due to hypomorphic mutations in RAG1 and RAG2 genes, however it may be caused also by hypomorphic defects in other genes, including DCLRE1C , IL7R , LIG4 , RMRP , IL2RG , ADA , ZAP70 and AK2 . Impaired thymic expression of AIRE, a transcription factor involved in expression and presentation of self-antigens, has been reported in patients with OS, and may favor survival of autoreactive T cell clones.
Patients with hypomorphic mutations in the RAG1/2 genes may also present with other clinical and immunologic phenotypes. Expansion of TCRγδ + T cells has been frequently reported after cytomegalovirus (CMV) infection and may associate with autoimmunity (especially cytopenias). In other cases, RAG deficiency may present with granulomatous lesions and/or autoimmunity. The severity of the clinical phenotype of RAG deficiency correlates, at least in part, with the residual levels of recombination activity of the mutant protein. However, environmental factors are also important, because patients with similarly severe mutations may present with distinct phenotypes.
Nucleoside Phosphorylase Deficiency
Purine nucleoside phosphorylase (PNP) converts guanosine into guanine and deoxyguanosine to deoxyguanine. Autosomal recessive PNP deficiency causes accumulation of phosphorylated deoxyguanosine metabolites (and of dGTP in particular) that inhibit ribonucleotide reductase, whose activity is essential to DNA synthesis. PNP deficiency is particularly deleterious to developing T lymphocytes and to central nervous system cells, causing severe T cell lymphopenia and neurologic deterioration.
TCRα Constant Chain ( TRAC ) Gene Defect
A homozygous splice-site mutation of the TCRα constant ( TRAC ) gene, causing loss of the transmembrane and intracytoplasmic domain, has been reported in two patients. All T cells expressing CD3 at normal density coexpressed TCRγδ; an unusual population of CD3 low T cells expressed TCRαβ. In vitro lymphocyte proliferation to mitogens and antigens was decreased.
Defects of TCR Signaling
Stimulation of T cells through TCR results in activation of the p56lck kinase, which mediates tyrosine phosphorylation of immunoreceptor tyrosine-based activation motifs (ITAMs) in the CD3-γ, -δ, -ε and -ζ chains. The Zeta-associated protein of 70 kDa (ZAP-70) is then recruited to the CD3/TCR complex, allowing activation of downstream signaling molecules such as linker for activation of T cells (LATs) and SLP-76. Autosomal recessive ZAP-70 deficiency is characterized by lack of CD8 + T cells; CD4 + T lymphocytes are present but nonfunctional.
Deficiency of p56lck has been demonstrated in a child with recurrent infections and autoimmunity, associated with CD4 + T cell lymphopenia, oligoclonal T cell repertoire and impaired T cell proliferation.
The Ras homolog family member H (RHOH) is a small GTPase that plays an important role in T cell activation. A homozygous nonsense mutation of the RHOH gene in two young adult siblings was associated with marked reduction of naïve CD4 + T cells, restricted T cell repertoire, expansion of memory T cells, including T EMRA (CD8 + CD45RA + CCR7 − CD244 + ) cells, and impaired in vitro T cell proliferation. The clinical phenotype was characterized by warts, Burkitt’s lymphoma, psoriatic-like skin rash and lung granulomatous disease.
The macrophage stimulating 1 (MST1) molecule is involved in intracellular signaling. Patients with MST1 deficiency show increased susceptibility to recurrent bacterial and viral infections (including warts and molluscum contagiosum), as well as autoimmunity, associated with severe reduction of naïve T cells, increased proportion of CD8 + T EMRA cells, restricted T cell repertoire, impaired proliferation to mitogens, increased apoptosis of T lymphocytes and reduced number of memory B cells.
The interleukin-2-inducible T cell kinase (ITK) is activated in response to TCR stimulation and participates in intracellular signaling. ITK deficiency is characterized by increased risk of infections (especially due to herpesviruses) and prominent immune dysregulation, associated with a reduced number of naïve CD4 + cells, defective T cell proliferation and progressive hypogammaglobulinemia. There is an increased risk of Epstein-Barr virus (EBV)-driven lymphoproliferative disease, with frequent pulmonary involvement.
DOCK8 Deficiency
The dedicator of cytokinesis 8 (DOCK8) protein plays an important role in intracellular signaling and cytoskeleton reorganization. Mutations of the DOCK8 gene cause a severe autosomal recessive immunodeficiency, with increased incidence of skin abscesses, mucocutaneous candidiasis and especially cutaneous viral infections, eczema, severe food allergy and markedly elevated IgE levels and eosinophilia. There is a high risk of human papillomavirus (HPV)-associated squamous cell carcinoma. Vascular thrombosis in the central nervous system, autoimmune cytopenias and other autoimmune manifestations have been also reported. The immunologic phenotype is characterized by multiple abnormalities, with reduced number of naïve T cells, increased proportion of CD8 + T EMRA cells, and defective in vitro T cell proliferation to CD3/CD28 stimulation. Deficiency of T H 17 cells accounts for the increased risk of candidiasis. Migration of T cells and dendritic cells to inflamed/infected tissues is defective. NK and NKT cell function is also compromised. Immunoglobulin levels are variable, although low serum IgM levels are frequently seen. B cell response to TLR9 activation is severely compromised. Antibody responses to T-dependent antigens may be initially normal, but are not sustained over time. The disease has a dismal prognosis, but can be treated by HSCT.
Human ‘Nude’ Phenotype (FOXN1 Defect)
FOXN1 is a transcription factor that controls development of thymic epithelial cells. Mutations of the FOXN1 gene cause a severe T cell immunodeficiency with complete lack of CD8 + T cells, associated with alopecia. Treatment is based on thymus transplantation.
Coronin-1A Deficiency
Coronin-1A is an actin regulator that regulates T cell survival and migration. Mutations of the CORO1A gene cause immunodeficiency with increased risk of EBV lymphoproliferative disease, associated with profound naïve T cell lymphopenia, oligoclonal T cell repertoire and severe reduction of iNKT cells and mucosa-associated invariant T (MAIT) cells.
Major Histocompatibility Complex (MHC) Class II Deficiency
Lack of MHC class II molecules expression on the surface of thymic epithelial cells results in an inability to positively select CD4 + thymocytes and, hence, in the very low number of circulating CD4 + lymphocytes. In addition, the ability to mount antibody responses is also impaired.
MHC class II deficiency has an autosomal recessive pattern of inheritance and may be caused by mutations in the CIITA , RFXANK , RFX5 and RFXAP genes, which encode for transcription factors that govern MHC class II antigen expression.
MHC Class I Deficiency
Human leukocyte antigen (HLA) class I molecules play an essential role in presenting antigenic peptides to cytotoxic T lymphocytes and in modulating the activity of natural killer (NK) cells. HLA class I molecules are composed of a polymorphic heavy chain, associated with β2-microglobulin (β2M). The assembly of HLA class I molecules occurs in the lumen of the endoplasmic reticulum (ER), where they are loaded with peptides derived from the degradation of intracellular organisms. These peptides are transported into the ER via transporter associated with antigen presentation (TAP) proteins. TAP consists of two structurally related subunits (TAP1 and TAP2). In addition, the tapasin protein plays an important role in the loading process. Defects in TAP1, TAP2 or tapasin result in impaired peptide-HLA class I/β2M complex formation with reduced surface expression of HLA class I molecules. Patients with MHC class I deficiency have recurrent sinopulmonary infections and deep skin ulcers, associated with a reduced number of circulating CD8 + T cells.
Deficiency of Calcium-Release Activated Channels (CRAC) and of Magnesium Flux
Lymphocyte activation depends on calcium mobilization. In particular, TCR-induced activation results in release of Ca 2+ from the ER stores. Depletion of these Ca 2+ stores is sensed by the STIM proteins, which oligomerize and bind to the ORAI proteins that form the pore of the Ca 2+ -release activated channels (CRAC) located in the cell membrane, allowing Ca 2+ entry. Mutations of the STIM1 and ORAI1 genes cause an autosomal recessive immunodeficiency with increased risk of infections, hypogammaglobulinemia, impaired antibody responses and profoundly reduced in vitro T cell proliferation. Autoimmune manifestations (especially cytopenias) are common, in particular in patients with STIM1 deficiency. Extra-immune manifestations include nonprogressive myopathy and ectodermal dysplasia.
The magnesium transporter 1 (MAGT1) protein conducts Mg 2+ across the cell membrane, allowing downstream signaling. Mutations of the X-linked MAGT1 gene in humans cause immunodeficiency with increased susceptibility to viral and bacterial infections, and to EBV-driven lymphoproliferative disease. CD4 + T cell lymphopenia has been frequently observed. NK cytolytic activity in response to NKG2D engagement is reduced.
Immunodeficiency with Immune Dysregulation due to Impaired IL-2 Signaling
IL-2 signaling maintains peripheral immune homeostasis. Deficiency of the α chain of the IL-2 receptor (IL-2Rα, CD25) causes immune dysregulation and lymphoproliferation, often associated with early-onset viral and bacterial infections, oral thrush and chronic diarrhea, associated with lymphadenopathy and hepatosplenomegaly.
STAT5b is a transcription factor that is activated in response to growth hormone (GH) and cytokines, including IL-2. STAT5b deficiency is characterized by short stature with GH insensitivity, and a variable degree of immune deficiency and immune dysregulation.
IL-21 Receptor (IL-21R) Deficiency
Loss-of-function mutations of IL-21R have been reported in four patients with sclerosing cholangitis due to Cryptosporidium, recurrent pneumonia, chronic diarrhea and failure to thrive. The proportion of switched memory B cells was reduced. T cell proliferation to mitogens was preserved, but proliferation to antigens was impaired.
CD27 Deficiency
CD27 is a costimulatory molecule. CD27 mutations are responsible for an autosomal recessive combined immunodeficiency with EBV lymphoproliferative disease, reduced T cell proliferation to mitogens and antigens, and progressive hypogammaglobulinemia.
T cell Defects with Impaired NF-κB Activation
The MALT1, BCL-10, and CARD11 proteins form a complex that is activated in response to TCR stimulation, allowing nuclear translocation of NF-κB. Autosomal recessive MALT1 deficiency causes recurrent bacterial, viral and fungal infections. In spite of normal T and B lymphocyte count, proliferative responses to CD3 stimulation and antigens are decreased, and specific antibody responses are also impaired.
CARD11 deficiency causes increased susceptibility to opportunistic infections. A reduced number of memory T cells, and hypogammaglobulinemia with increased proportion of transitional B cells are present.
Mutations of the IKBKB gene, encoding for the IKKβ component of the IKK complex, have been reported in four unrelated infants with early-onset infections and hypogammaglobulinemia. Immunologic abnormalities included lack of memory T and B cells and of T REG lymphocytes, and defective in vitro T cell proliferation to CD3 stimulation.
Immunodeficiency due to Activating PI3K-δ Mutations
Phosphatidylinositol-3-OH kinases (PI3K) include a series of molecules that participate in cell signaling, enabling generation of PIP 3 from PIP 2 , and activation of mTOR and AKT. Heterozygous, gain-of-function mutations of the PI3KCD gene, encoding for the p110δ subunit of phosphatidylinositol-3-OH kinase (PI3K), cause increased susceptibility to recurrent respiratory tract infections, EBV lymphoproliferative disease (frequently associated with hepatosplenomegaly and lymphadenopathy) and CMV viremia. Reduction of naïve CD4 + cells, expansion of memory and T EMRA CD8 + cells, and decreased number of switched memory B cells have been reported. IgM serum levels are increased. Constitutive activation of AKT is associated with increased activation-induced cell death of patients’ lymphocytes. Treatment with rapamycin, an mTOR inhibitor, may reduce lymphoproliferation and organomegaly.
Cytidine 5′ Triphosphate Synthase 1 (CTPS1) Deficiency
Autosomal recessive mutations of the CTPS1 gene, involved in the synthesis of cytidine 5′ triphosphate (CTP), cause early-onset viral and bacterial infections and an increased risk of EBV-driven non-Hodgkin B cell lymphoma, associated with CD4 lymphopenia, increased proportion of effector memory T cells, absence of iNKT and MAIT lymphocytes, impaired proliferation to mitogens and antigens, and reduced number of memory B cells.
Differential Diagnosis of SCID and Other Combined Immunodeficiencies
SCID and other combined immunodeficiencies are characterized by typical clinical signs ( Box 9-1 ), with early-onset severe infections sustained by bacteria, viruses and fungi, including opportunistic pathogens (such as Pneumocystis jirovecii, CMV), and growth failure ( Figure 9-2 ). Skin manifestations (rash, generalized erythroderma, alopecia) are also common and may reflect the presence of autoreactive T cell clones (such as in OS) or true graft-versus-host disease (GvHD) caused by transplacental passage of alloreactive maternal T lymphocytes. Other manifestations of maternal T cell engraftment include liver dysfunction, cytopenia (as a result of bone marrow aggression) and eosinophilia.
