In some cases, significant impairment of T-cell immunity is associated with residual development and/or function of T lymphocytes. These conditions are also known as CID to distinguish them from SCID, in which both T-cell development and function are abrogated. The clinical features of CID overlap with SCID, but also include autoimmunity and/or inflammatory manifestations reflecting unbalanced immune homeostasis. CID is caused by two main mechanisms: (1) hypomorphic mutations in SCID-causing genes that allow for some T-cell development; and (2) genetic defects that affect late stages in T-cell development or peripheral T-cell function.
Originally described in 1965, Omenn syndrome is characterized by severe infections, associated with early onset diffuse rash or generalized erythroderma, alopecia, eosinophilia, lymphadenopathy, hepatosplenomegaly, hypoproteinemia with edema, and oligoclonal expansion of activated autologous T lymphocytes that infiltrate and damage target tissues.98,99
Various gene defects can cause this syndrome. Hypomorphic mutations in the RAG1 and RAG2 genes are most common,100 but virtually any gene defect that severely impairs, but does not abolish, T-cell development may cause the disease.101
Defects of immunologic tolerance have been implied in the pathophysiology of Omenn syndrome. Thymic expression of AIRE (autoimmune regulator), a transcription factor involved in presentation of self-antigens and negative selection of autoreactive thymocytes, is reduced.102 Impaired generation of natural regulatory T cells, and homeostatic proliferation of T lymphocytes in a lymphopenic environment, may also play a critical role in the pathophysiology of the disease.103
Laboratory investigations demonstrate that leukocytosis with eosinophilia and hypogammaglobulinemia are common findings, and that serum IgE is often elevated. The number of circulating T lymphocytes may vary, but they have a characteristic activated/memory (CD45R0+) phenotype. T cells have a restricted repertoire, and the distribution of CD4 and CD8 subsets is generally skewed. There is also a skewing to a T-helper (Th) type 2 (Th2) profile, with increased production of IL-4 and IL-5. The in vitro lymphocyte response to antigens is abrogated; responses to mitogens are variable, but in general are reduced.74,104 The number of circulating B and NK lymphocytes may vary, depending on the nature of the underlying genetic defect. Absence of invariant NK T cells has been reported in RAG-deficient Omenn syndrome.105
Differential diagnosis includes maternal T-cell engraftment in patients with SCID, complete atypical DiGeorge syndrome, CHARGE syndrome (coloboma of the eye, heart defects, atresia of the nasal choanae, retardation of growth and/or development, genital and/or urinary abnormalities, and ear abnormalities and deafness), immune dysregulation-polyendocrinopathy-enteropathy-X-linked (IPEX) syndrome and other conditions of neonatal erythroderma.106,107,108,109 Male infants with NEMO deficiency can also present with severe skin manifestations resembling Omenn syndrome.
In preparation for allogeneic HSCT, the only curative treatment available,56 patients require aggressive nutritional support, correction of hypoproteinemia, and treatment or prevention of infections with antibiotics, antifungals, and immunoglobulin replacement therapy. Immune suppression with steroids or cyclosporine is beneficial in controlling T-cell–mediated tissue damage.
DEFECTS OF T-CELL–RECEPTOR SIGNALING
TCR ligation promotes activation of the p56Lck kinase, which mediates phosphorylation of components of the CD3 complex. This allows recruitment and phosphorylation of the zeta-associated protein of 70 kDa (ZAP-70), activation of downstream signaling molecules, release of Ca2+ from intracellular endoplasmic reticulum stores, and initiation of Ca2+ influx. Mutations of lymphocyte-specific protein tyrosine kinase (LCK), ZAP-70, and of other TCR-associated signaling molecules (RHOH, MST1, IL-2–inducible T-cell kinase [ITK]) result in various forms of CID with dysfunctional T cells.110,111,112,113,114,115 Finally, PI3K, composed of a p110δ and a p85 subunit, is involved in generation of phosphatidylinositol 4,5-triphosphate (PIP3) and activation of mammalian target of rapamycin (mTOR) and AKT. Activating mutations of the PI3KD gene (encoding for the PI3K subunit p110δ) results in increased activation-induced cell death of T lymphocytes, and consequently immunodeficiency.29,30
Clinical and Laboratory Features
Patients with these disorders present with early onset and severe infections. Warts, molluscum contagiosum, infections caused by herpes viruses, and a high risk of Epstein-Barr virus (EBV)-driven lymphoproliferative disease have been reported in patients with LCK, RHOH, and MST1 deficiency, and with activating PI3KD mutations.29,30,110,113,114 Moreover, autoimmunity and lung granulomatous disease may also occur. From a laboratory standpoint, selective loss of CD8+ lymphocytes is observed in patients with ZAP-70 deficiency, and although the number of CD4+ lymphocytes is preserved, in vitro response to mitogens is markedly reduced, consistent with a signaling defect.111,112 Patients with LCK, RHOH, MST1, and ITK deficiency and with gain-of-function PI3KD mutations have a reduced number of naïve CD4+ T cells. Oligoclonality of the T-cell repertoire and an increased proportion of exhausted CD8+ T memory (TEMRA) cells have been reported in these patients.29,30,107,113,114,115
Differential diagnosis of ZAP-70 deficiency includes MHC class I deficiency and CD8α deficiency, two conditions characterized by a severe reduction of CD8+ lymphocytes. Patients with CD8α deficiency have an unusual population of CD3+ TCR αβ+ CD4– CD8– cells that have normal proliferative responses and usually survive to adulthood, although a late death from infections has been reported.116,117 The other defects of TCR signaling have an overlapping phenotype. Ultimately, biochemical and molecular tests are needed to define the diagnosis.
The only curative treatment of this group of disorders is allogeneic HSCT. Treatment with rapamycin (an mTOR inhibitor) or phosphoinositide 3-kinase inhibitor may reduce lymphoproliferation and hepatosplenomegaly in patients with activating PI3KD mutations.29,30
T-CELL IMMUNODEFICIENCIES WITH IMPAIRED NUCLEAR FACTOR-κB ACTIVATION
Following TCR signaling, the complex composed of MALT1, BCL-10, and caspase recruitment domain-containing protein (CARD)-11 proteins is activated, resulting in recruitment of TRIF-related adaptor molecule (TRAF) 6 and activation of IKK, permitting nuclear translocation of the p50 and p65 subunits of NF-κB and consequently induction of activation of NF-κB–dependent genes. Mutations of MALT1,118 CARD11,119,120 and IKBKB121 (encoding for the IKKβ component of the IKK complex) genes are associated with increased susceptibility to bacterial, viral and fungal infections. Although the number of circulating T lymphocytes is normal, generation of memory T cells is impaired and proliferative responses to CD3 stimulation are decreased. Patients with CARD11 mutations have a block in B-cell development at the transitional stage,119,120 and virtual absence of class-switched memory B cells is observed in patients with IKBKB mutations.121
As reported above, mutations of the IKBKG/NEMO gene are responsible for X-linked immunodeficiency with ectodermal dysplasia, whose clinical manifestations may also include opportunistic infections, resembling CID. Finally, gain-of-functions mutations of the IKBA gene, that prevent phosphorylation and degradation of the IKB-α subunit of the IKB complex, cause T-cell immunodeficiency with ectodermal dystrophy. The immunologic phenotype includes deficiency of memory T cells, impaired in vitro proliferation of naïve T cells to TCR/CD3 stimulation, and hypogammaglobulinemia with inability to mount specific antibody responses.122 In addition to TCR signaling, activation of toll-like receptor (TLR) and tumor necrosis factor (TNF) pathways can also be compromised, causing increased susceptibility to a broad range of pathogens (pyogenic bacteria, mycobacteria, Candida, other opportunistic pathogens).123
Coronin-1A is an actin regulator that is predominantly expressed in hematopoietic cells, plays a key role in regulating T-cell survival and migration. Mutations affecting both alleles of the CORO1A gene have been reported in patients with CID and an increased risk of severe varicella and EBV lymphoproliferative disease.124,125 The immunologic phenotype includes naïve T-cell lymphopenia with normal numbers of B and NK cells, oligoclonal T-cell repertoire and reduced number of circulating invariant NKT (iNKT) cells and mucosa-associated invariant T (MAIT) lymphocytes. Immunoglobulin serum levels are low, and antibody responses to antigens are absent. The disease can be treated by allogeneic HSCT.124
The CD27 costimulatory molecule regulates survival and activation of T, B, and NK cells. CD27 deficiency is a CID with risk of EBV lymphoproliferative disease. In vitro T-cell proliferation to mitogens and antigens is reduced.126 Immunoglobulin serum levels may be initially high, but patients eventually become hypogammaglobulinemic.
Cytidine 5-triphosphate synthase 1 (CTPS1) is involved in de novo synthesis of cytidine 5-triphosphate (CTP), a nucleotide required for DNA and RNA metabolism. Impaired de novo synthesis of CTP causes a proliferation defect in both T and B lymphocytes. CTPS1 mutations have been identified in several infants from Northwestern England. The disease is characterized by severe bacterial and viral infections since early in life, and an increased risk of EBV-driven non-Hodgkin lymphoma. There are no extra-immune manifestations. Variable degrees of lymphopenia (especially of CD4+ cells), increased proportion of effector memory T cells and reduced in vitro proliferation to mitogens and antigens have been reported. Immunoglobulin levels may be normal, but specific antibody titers are reduced, and there is a low number of memory B cells.127
MAJOR HISTOCOMPATIBILITY COMPLEX CLASS I DEFICIENCY
MHC class I deficiency is characterized by reduced expression of MHC class I molecules at the cell surface. The disease is inherited as an autosomal recessive trait, and may be caused by defects in the TAP1,128 TAP2,129 or Tapasin130 genes. These defects interfere with intracellular transport of peptide antigens and their loading onto MHC class I molecules, and cell-surface expression of the complex.
Clinical and Laboratory Features
MHC class I deficiency manifests with recurrent respiratory infections in childhood, and chronic inflammatory lung disease and skin lesions, mimicking Wegener granulomatosis in patients with transporter-associated with antigen-processing (TAP)-1 and TAP-2 deficiencies.131,132 Chronic lung disease is a prominent cause of death. Glomerulonephritis and herpes zoster infections have been reported in Tapasin deficiency.130
The number of circulating CD8+ T cells is reduced, because positive selection of CD8+ lymphocytes in the thymus depends on the recognition of MHC class I molecules. In vitro T-cell function is normal, which facilitates differential diagnosis with ZAP-70 deficiency in patients who have significantly reduced CD8+ cells. The NK cytolytic activity is usually significantly reduced (see Table 80–2). Serum immunoglobulin levels are variable.
Prophylactic measures, similar to those used in cystic fibrosis, may be beneficial. Treatment of the granulomatous lesions is based on use of topical antiseptics; immunosuppressive drugs may worsen symptoms and should be avoided.
MAJOR HISTOCOMPATIBILITY COMPLEX CLASS II DEFICIENCY
MHC class II deficiency is defined by the lack of MHC class II expression and autosomal recessive inheritance. There is a higher prevalence in populations of North African origin. MHC class II deficiency is caused by mutations of transcription factors that bind to the proximal promoters of the MHC class II gene. Four different gene defects are known and include mutations of the CIITA, RFXANK, RFX5, and RFXAP genes.133
Clinical and Laboratory Features
Typically, patients present early in life with increased susceptibility to bacterial, viral, and opportunistic infections. Severe lung infections, chronic diarrhea, and sclerosing cholangitis, often secondary to Cryptosporidium or CMV infection, are frequently observed. Less-severe presentations and survival into adulthood have been reported.133
The number of circulating CD4+ T cells is markedly reduced, reflecting an impairment of positive selection in the thymus. Delayed-type hypersensitivity responses are absent, but in vitro proliferative responses to mitogens are preserved. Hypogammaglobulinemia is common and poor antibody response to immunization antigens is consistently observed (see Table 80–2).133 The diagnosis is based on demonstrating lack of MHC class II expression on monocytes, B lymphocytes and in vitro activated T cells. Differential diagnoses include HIV infection and idiopathic CD4 lymphopenia; however, in these conditions expression of MHC class II molecules is preserved.
MHC class II deficiency has a poor prognosis. If untreated, most patients die in infancy or childhood. Respiratory infections are the predominant cause of death. Liver failure is observed in patients who develop sclerosing cholangitis. Antibiotic prophylaxis and immunoglobulin replacement therapy, with adequate nutritional support, are required. HSCT is the only curative approach, but survival rate is lower than in other forms of CID and graft-versus-host disease is common, especially in patients with preexisting viral infections.133
DEFECTS OF STORE-OPERATED Ca2+ ENTRY
Calcium mobilization is a key event in the activation process of lymphocytes and nonimmune cells. Two molecules, calcium release-activated calcium channel protein 1 (ORAI1) and stromal interaction molecule 1 (STIM1), mediate the function of Ca2+ entry channels. ORAI1 is a ubiquitously expressed protein that constitutes the pore-forming subunits of the Ca2+ release-activated channels located in the cell membrane. STIM1 senses the Ca2+ concentration in the endoplasmic reticulum and activates Ca2+ release-activated channels. Mutations of both the ORAI1 and STIM1 genes in humans result in an autosomal recessive immunodeficiency with increased susceptibility to severe infections, especially from herpesviruses infections, associated with nonprogressive myopathy and ectodermal dysplasia. Manifestations of immune dysregulation (autoimmune cytopenias, hepatosplenomegaly) are common, especially in STIM1 deficiency.134,135 Although T-cell development is unaffected, in vitro proliferation of circulating T cells to mitogens and to a combination of phorbol ester and ionomycin is drastically reduced, and the Ca2+ influx following T-cell activation is absent. Lack of natural killer T (NKT) cells and functional defects of NK lymphocytes have been reported. In spite of hypergammaglobulinemia, specific antibody responses are typically absent. Allogeneic HSCT has been used in some patients to correct the defect.135
DEFECTS OF MAGNESIUM TRANSPORTER 1
Mg2+ is an important second messenger in the immune system. Mutations of the X-linked magnesium transporter 1 (MAGT1) gene, that encodes for a protein that permits transport of Mg2+ across the cell membrane, cause immunodeficiency with increased susceptibility to bacterial and viral infections, and a high risk of EBV-driven lymphoproliferative disease.136 Patients have CD4 lymphopenia, defective lymphocyte proliferation in vitro and impaired NK cytolytic function.137
DEDICATOR OF CYTOKINESIS 8 DEFICIENCY
Dedicator of cytokinesis 8 (DOCK8) is an atypical guanosine triphosphatase (GTPase) that regulates cytoskeleton reorganization and intracellular signaling. Although it is broadly expressed, it plays a critical role in T, B, and NK lymphocytes. DOCK8 deficiency is inherited as an autosomal recessive trait, and is characterized by recurrent and severe bacterial, fungal, and viral infections, eczema and other manifestations of immune dysregulation, including autoimmune cytopenias. Cutaneous viral infections (warts, molluscum contagiosum, herpes simplex) are especially common, but systemic viral disease (varicella, CMV, EBV) has been also reported. Cutaneous infections frequently evolve into squamous cell carcinoma. Vascular thrombosis in the central nervous system has been described in several patients.138,139 Multiple immunologic abnormalities have been reported,138,139,140,141,142 including a variable degree of lymphopenia that affects especially naïve T cells, increased proportion of CD8+ TEMRA cells, decreased in vitro proliferation to CD3 stimulation, impaired generation of Th17 cells, and defects of NK cytolytic function. Immunoglobulin levels are variable, but IgM serum levels are often low. B-cell response to TLR9 stimulation is defective, and specific antibody responses are blunted. Large, intragenic deletion of the gene has been frequently reported in affected patients,139 and lack of DOCK8 protein expression can be demonstrated by flow cytometry.143 The disease has a poor prognosis, but can be cured by allogeneic HSCT.144 Good results have been reported in the treatment of severe herpetic infections with interferon (IFN)-α (see also “The Hyperimmunoglobulin E Syndromes” below).145
COMBINED IMMUNODEFICIENCY WITH MULTIPLE INTESTINAL ATRESIA
Multiple intestinal atresia is a congenital disease characterized by atresias that may affect the gastrointestinal tract, from stomach to anus.146,147,148,149 In many cases, CID is associated, with reduced number of T (and in some patients, B) lymphocytes, impaired in vitro proliferation to mitogens, and profound hypogammaglobulinemia. A high risk of sepsis because of Gram-negative bacteria has been reported, but viral, fungal, and opportunistic infections are also common. The disease is inherited as an autosomal recessive trait and is caused by mutations of the tetratricopeptide repeat domain 7A (TTC7A) gene,146,147 which plays an important role in intestinal and immune homeostasis by maintaining cell polarity and regulation of cell survival, proliferation, adhesion, and migration.148,149 In the thymus, TTC7A is expressed both by thymic epithelial cells and by thymocytes.147,148 Multiple surgeries are often required to establish canalization of the gastrointestinal tract. Total parenteral nutrition often leads to severe liver disease, and combined small bowel and liver transplantation may be needed.150 Most patients die early in life. Partial immune reconstitution has been reported in a few cases following HSCT.147
VENOOCCLUSIVE DISEASE WITH IMMUNODEFICIENCY
Venoocclusive disease with immunodeficiency (VODI) is a congenital disorder characterized by liver abnormalities and immunodeficiency, with onset in the first months of life.151 Liver abnormalities include venoocclusive disease, fibrosis, hepatomegaly, and hepatic failure. Patients are prone to recurrent infections, sustained by viruses, bacteria, and opportunistic pathogens (P. jirovecii, Candida, CMV). Thrombocytopenia is frequent. Infections may precede development of liver abnormalities. Immunologic defects include low number of memory T and B lymphocytes, defective B-cell differentiation in vitro into antibody-secreting cells, and hypogammaglobulinemia.151 The disease is more common in the Lebanese population. It is inherited as an autosomal recessive trait and is caused by mutations of the SP110 gene,152 which encodes for a nuclear body protein that acts as a transcription factor driving expression of genes with a retinoic acid response element. Treatment is based on immunoglobulin replacement therapy, prophylactic antibiotics, prompt treatment of infections, and ursodiol; however, the prognosis remains dismal. HSCT is the only curative approach, but the outcome is often problematic because of liver toxicity as a result of conditioning regimen.153