The nuclear factor κ-B (NF-κB) signaling pathway is ubiquitous to all tissues and stages of development, playing critical roles in cell proliferation, oncogenesis, cell survival, and inflammatory responses. Several genetic defects affecting activation of NF-κB have been described that result in combined immune deficiency variably associated with extra immune manifestations. Hypomorphic mutations in the IKBKG gene, which encodes for the NF-κB essential modulator (NEMO; also known as IKK-γ), the regulatory subunit of the IκB kinase complex, are inherited as an X-linked trait and represent the prototype of dis orders of NF-κB signaling. Complete lack of NEMO expression is embryonically lethal in males; females who are heterozygous for null NEMO mutations suffer from incontinentia pigmenti. Typically, males with NEMO deficiency present with ectodermal dysplasia and immunodeficiency (EDA-ID). The phenotypic manifestations of EDA-ID are largely restricted to epithelial tissues and the immune system, with sparse hair, shiny skin, lack of sweat glands and other append ages, and rare conical-shaped teeth. There is often frontal bossing and a characteristic facies. Typical infections are caused by bacteria, including sepsis and meningitis, especially Streptococcus pneumoniae, Staphylococcus, and Haemophilus influenzae; DNA viral infections such as CMV and herpes simplex virus (HSV); and atypical mycobacterial infection. Pneumocystis and other opportunistic infections may also occur. Inflammatory colitis is a frequent manifestation of immune dysregulation. Lymphedema and osteopetrosis have been reported in some patients. Occasionally, manifestations of ectodermal dysplasia may be modest or even absent, thus adding to phenotypic heterogeneity. Immunological abnormalities include variable defects in T-cell proliferation to mitogen and antigens, hypogammaglobulinemia with normal or high IgM, defective antibody production (especially against polysaccharides), and impairment of NK-cell cytotoxicity. Finally, monocytes from patients with NEMO deficiency fail to elaborate inflammatory cytokines such as tumor necrosis factor (TNF)α in response to stimulation by a variety of Toll-like receptor ligands. A similar clinical and immunological phenotype is observed in patients with autosomal dominant EDA-ID caused by gain-of-function (GOF) mutations of the IKBA gene. In these patients, the mutated IκB-α protein cannot be phosphorylated at residues that are critical for its degradation. This prevents release of the cytoplasmic components of NF-κB, which cannot translocate to the nucleus and mediate transcription of target genes.
Aside from supportive therapy with intravenous immunoglobulin replacement, antibiotic prophylaxis and treatment of infections, SCT for these disorders has been used with variable success. Because of the role of NF-κB signaling in nonhematopoietic tissues, certain manifestations of the disease, such as colitis, may not be uniformly ameliorated by SCT.
Mutations of the IKBKB gene are responsible for an autosomal recessive disease, characterized by a SCID-like phenotype without ectodermal dystrophy.67 Patients lack regulatory T cells and TCRγδ+ T cells. The MAP3K14 gene encodes for NIK, a component of the noncanonical NF-κB signaling pathway. Patients with NIK deficiency suffer from recurrent infections. Immunological abnormalities include reduced T-cell proliferation, hypogammaglobulinemia with reduced number of total and switched memory B cells, and NK deficiency. Haploinsufficiency of RELA, encoding for the p65 subunit of NF-κB, is associated with impaired NF-κB activation and mucocutaneous ulcers.70 Finally, autosomal recessive RelB deficiency is associated with normal numbers of T cells but reduced proliferation to mitogens and antigens, and restricted T cell repertoire. B cells are present in increased number; immunoglobulin levels are normal, but specific antibody production is impaired.
The CARD11–BCL10–MALT1 complex regulates NF-κB signaling. Deficiency of any of these proteins causes combined immune deficiency with increased susceptibility to infections. T-cell proliferation is impaired. Defective antibody responses are observed in patients with BCL10 and CARD11 deficiency; the latter condition is also characterized by an increase in the proportion of transitional B cells.
FCHO1 Deficiency and Transferrin Receptor Deficiency
FCH and Mu Domain Containing Endocytic Adaptor 1 (FCHO1) is an adaptor protein involved in clathrin mediated endocytosis.
Autosomal recessive FCHO1 deficiency is characterized by numerical and functional defects of T cells and impaired clathrin-mediated endocytosis, including defective transferrin and iron intake. Patients suffer from severe infections early in life. An autosomal recessive missense mutation (Tyr20His) in the transferrin receptor (TFRC) gene causing impaired internalization of the transferrin receptor causes recurrent infections, neutropenia and thrombocytopenia associated with reduced T cell proliferation and low number of switched memory B cells. Both FCHO1 and TFRC deficiency can be corrected by SCT.
Moesin Deficiency
Moesin is a member of family of proteins (also including ezrin and radixin) involved in reorganization of the actin cytoskeleton. X-linked moesin deficiency is a combined immunodeficiency disorder chara terized by recurrent bacterial and viral infections (especially, varicella), molluscum contagiosum and eczema. Immunological abnormalities include profound lymphopenia, fluctuating neutropenia and antibody deficiency.
Dedicator of Cytokinesis 2 Deficiency
The dedicator of cytokinesis (DOCK) proteins are atypical guanine exchange factors containing a phosphatidylinositol (3,4,5)-triphosphate (PIP3) binding domain and a Rho-family guanosine triphosphate phosphohydrolases (GTPase) binding domain with guanine exchange factor activity. DOCK2 is predominantly expressed in various hematopoietic cell lineages and is activated in response to engagement of the TCR, BCR, and chemokine receptors. DOCK2 activation allows formation of GTP Ras-related C3 botulinum toxin substrate 1 (GTP-Rac1), thereby promoting reorganization of the cellular cytoskeleton, and intracellular signaling. DOCK2 deficiency is an autosomal recessive combined immunodeficiency characterized by increased susceptibility to severe infections starting early in life. Severe varicella has been reported in multiple patients. T-cell lymphopenia, with marked reduction of naïve T cells and impaired T-cell proliferation, defective antibody responses, reduced NK cell function, poor migration of T and B lymphocytes in response to chemokines, NKT-cell deficiency, and markedly reduced secretion of interferon-alpha (IFN-α) by plasmacytoid dendritic cells represent the major immunological abnormalities. Low TREC levels at birth have been reported in two patients. The prognosis is very poor, but definitive cure may be achieved with SCT. Use of systemic IFN-α may help in the treatment of severe viral infections.
Dedicator of Cytokinesis 8 Deficiency
DOCK8 deficiency is an autosomal recessive combined immunodeficiency characterized by severe and recurrent infections, particularly systemic and cutaneous viral infections (molluscum contagiosum, HSV-1 and HSV-2, human papillomavirus), allergic manifestations (early-onset eczema, food allergies) with elevated serum IgE, impaired humoral immunity (with frequent sino-pulmonary infections), and increased risk for squamous cell carcinoma and lymphoma. Large intragenic deletions account for the majority of the mutations. Affected patients have low numbers of naive CD8 T cells, and accumulation of CD8 memory cells with an “exhausted phenotype”. A profound impairment in the generation of CD8+ memory T cells in response to influenza or other viral infections has been reported. Humoral immunity is also compromised, with loss of germinal center B cells and defective immunoglobulin affinity maturation. The disease has a severe prognosis, with considerable mortality. SCT represents the only definitive treatment. Use of systemic IFN-α may ameliorate manifestations of severe cutaneous viral infection.
Activated RAC2 Defect
RAC2 is a small GTPase. Heterozygous GOF mutations of RAC2 cause a profound immunodeficiency with low number of T and B cells, poor antibody production and neutropenia, associated with increased susceptibility to infections and lymphoproliferation.
