Immunodeficiency is the genetic or acquired failure of the patient's innate or adaptive immunity, resulting in an increased frequency and severity of infections that may lead to catastrophic morbidity, early death, or both.
There has been a considerable gain in knowledge of the pathologic conditions of the immune system since the recognition of primary immunodeficiency as an entity in 1950, highlighted by the discovery of X-linked agammaglobulinemia, congenital neutropenia, and severe combined immunodeficiency (SCID). The description of over 200 diseases with more than 100 genetic etiologies has been described, which has provided opportunities for diagnosis and genetic counseling. Moreover, an understanding of the pathogenesis of primary immunodeficiencies has paved the way for immunologic interventions and new treatments, such as immunoglobulin G (IgG) replacement, bone marrow transplantation, and gene therapy.
Combined B-cell and T-cell immunodeficiencies, or SCID, is a group of medical disorders that are the result of genetic defects in both cellular and humoral immunity. The defects in humoral and cellular immunity have an early clinical presentation and, if untreated, result in a fatal outcome in the first few years of life. This article focuses only on SCID disorders and outlines recent advances in therapeutics options for patients.
The profound degree of immune compromise in SCID leads to infections with bacterial, viral, and fungal pathogens that cause significant morbidity and eventually mortality in patients.
B and T cells, type 2 dendritic cells, and natural killer (NK) cells share a common ancestor: the common lymphoid progenitor (CLP). CLP differentiates into 2 intermediate progenitors, termed early B cells and T/NK/DC trilineage cells. Both intermediate progenitors continue their development in the bone marrow through primary lymphopoiesis, which is an antigen-independent process. Secondary B-cell lymphopoiesis is an antigen-dependent process that occurs in the germinal centers of peripheral lymphoid organs with specific antibody production. Secondary T-cell lymphopoiesis is also antigen-dependent and occurs in the thymus.
The earlier the defect, the more devastating the effect on lymphopoiesis. Defects occurring at the CLP stage or those affecting processes common to B- and T-cell development result in SCID involving B, T, and NK cells. According to the type of defect that leads to a SCID phenotype, Combined B- and T-cell disorders can be divided into specific groups with unique pathophysiologies that invariably result in an absence of nonfunctional B cells and absence of T cells (see Table 1).
Table 1. Classification of SCID (Open Table in a new window)
|Pathophysiology||Cells Affected||Inheritance||Genes Involved|
|Premature cell death||T, B, NK||AR||ADA|
|Defective cytokine–dependent survival signaling||T, NK||
γ c type-XL
|JAK3, IL7RA (T cells only), γ c|
|Defective V(D)J rearrangement||T, B||AR||RAG1, RAG2, Artemis|
|Defective pre-TCR and TCR signaling||T||AR||
CD3 δ, CD3 ζ, CD3 ε,
|AR = autosomal recessive; JAK3 =Janus tyrosine kinase 3; RAG1, RAG2 = recombinase activating gene 1 and 2, respectively; TCR = T-cell receptor; XL = X-linked; V(D)J = variable diversity joining.|
Adapted from Cavazzana-Calvo M, Fischer A. Gene therapy for severe combined immunodeficiency: are we there yet? J Clin Invest. Jun 2007;117(6):1456-65. 
In other circumstances, the defect can affect later events in lymphopoiesis; a major loss or dysfunction in T cells can cause secondary B-cell deficiency, resulting in a clinical disorder that manifests as a combined B- and T-cell deficiency.
There are 4 characterized pathways that can result in SCID are the following:
Premature cell death caused by the accumulation of purine metabolites (seen in adenosine deaminase (ADA) deficiency)
Defective V(D)J rearrangements of the TCR and B-cell receptor genes (BCR) (accounts for 30% of SCID cases)
Defective cytokine-dependent survival signaling in T-cell precursors and sometimes NK-cell precursors (accounts for more than 50% of SCID cases)
Defective pre-TCR and TCR signaling. Pure T-cell deficiencies are caused by defects in either a CD3 subunit (such as CD3 δ, CD3 ζ, CD3 ε ) or in CD45 tyrosine phosphatase, key proteins involved in pre-TCR and/or TCR signaling at the positive selection stage.
Defects in purine pathway enzymes that result in buildup of metabolites toxic to lymphocytes
ADA is an enzyme of the purine salvage pathway that is responsible for adenosine deamination to inosine and deoxyadenosine deamination to deoxyinosine. The deficiency of this enzyme leads to the accumulation of deoxyadenosine triphosphate (dATP) and 2'-deoxyadenosine. An increase in the intracellular levels of dATP is toxic to lymphocytes because it inhibits the enzyme ribonucleotide reductase, leading to suppression of DNA synthesis, whereas 2'-deoxyadenosine inhibits the enzyme S- adenosyl-L-homocysteine (SAH) hydrolase, which results in accumulation of SAH, a potent inhibitor of all cellular methylation reactions. Both B and T cells are affected, leading to SCID.
Defects in recombination of the antigen receptor genes (RAG) of B-cells and T-cells
Immunoglobulin gene rearrangement begins with heavy-chain gene rearrangement, which is followed by light-chain gene rearrangement. Once the rearrangement process is finished, recombination signal sequences that served to approximate the different genes from each other are removed with the help of the RAG1 and RAG2 proteins. RAG1/RAG2 deficiency is responsible for the B- and T-cell maturation defects in some persons with SCID.
Omenn syndrome is a rare, inherited disorder with a pooly understood pathogenesis. This condition produces a paradoxical combination of immunodeficiency and immune dysregulation, which is the result of mutations in the genes coding for the recombinases (ie, RAG1 and RAG2) t hat cause a defect in the VDJ rearrangement that is needed for mature B-and T-cells to develop.
In study by Khiong et al, the authors identified a C57BL/10 mouse with a spontaneous mutation in and reduced activity of RAG1.  Mice bred from this animal exhibited major symptoms of Omenn syndrome, including having high numbers of memory-phenotype T cells, experiencing hepatosplenomegaly and eosinophilia, having oligoclonal T cells, and demonstrating elevated levels of IgE. When the CD4+ T cells in the mice were depleted, a reduction in their IgE levels resulted. Thus, Khiong et al concluded the these "memory mutant" mice may be a model for human Omenn syndrome, and many symptoms of the murine disease were direct results of the RAG hypomorphism, whereas some were caused by malfunctions of their CD4+ T-cells. 
Artemis deficiency (with mutations in the Artemis protein that result in defective VDJ recombination) decreases both B and T cells and can be considered part of a subset of SCIDs. DNA ligase IV deficiency likewise results in defective circulating T- and B-cells and serum immunoglobulins.
Bloom syndrome, or congenital telangiectatic erythema, results from a mutation in the helicase enzyme called BLM RecQ. This mutation leads to defects in DNA repair and is characterized by an increased risk of malignancy and radiation sensitivity.
Defects in cytokine receptors and/or cytokine signaling (B cells are generally present but nonfunctional)
An extensive number of disorders with SCID manifestations belong to this category in which Defects in cytokine receptors and/or cytokine signaling are present. Many cytokine receptors (eg, interleukin [IL], IL-2, IL-4, IL-7, IL-9, IL-15) share a common gamma chain, which is necessary for the normal signaling from the receptors after binding with their ligands. 
After binding of IL-2 to its receptor (ie, IL-2R), JAK3 is recruited to the cytoplasmic tail of the receptor and then phosphorylated. In turn, JAK3 phosphorylates a docking site for src homology-containing (SHC) signal transducer and activator of transcription (STAT) proteins. Subsequent phosphorylation and dimerization of STAT with its translocation into the nucleus results in gene transcription and/or activation.
The gene that encodes the gamma chain is located on band Xq13. Approximately 100 mutations have been described in this gene, resulting in an abnormal (two thirds of cases) or absent (one third of cases) gamma C-chain. The absence of the gamma-C chain or the presence of aberrant forms affect signaling events that are mediated via various cytokine receptors, thus explaining the multiple cell types that are affected in X-linked SCID, which include T, NK, and B cells.
X-linked SCID is characterized by the absence of T and NK cells but a normal number of dysfunctional B cells (T– B+ NK– SCID). The development of T cells is dependent on functional IL-7/IL-7R, and that of NK cells is dependent on functional IL-15/IL-15R, whereas the abnormalities of IL-2 and IL-4 pathways affect the function of B cells.
The gene encoding JAK3 is located on band 19p13. JAK3 deficiency results in a rare SCID syndrome that is also associated with absent T and NK cells but a normal number of dysfunctional B cells (T–B+NK–SCID).
The Wiskott-Aldrich syndrome protein (WASP) is encoded by a gene located on band Xp11.22–11.23. This protein has a dual role: (1) it affects immune cell motility and trafficking through its binding with CDC42H2 and rac, members of the Rho family of GTPases, which then results in changes in actin polymerization; and (2) it relays external signals into the nucleus. The mutated gene encodes a WASP that lacks the hydrophobic transmembrane domain and results in defective immune cell trafficking and motility. The abnormality affects all immune cells, including dendritic cells, macrophages, and B and T cells, leading to abnormal initiation and regulation of the immune response and, ultimately, to ineffective secondary lymphopoiesis.
In common variable immunodeficiency (CVID), mature B cells are normal in number and morphology, but they fail to differentiate into plasma cells because of defective interaction between the B and T cells, mostly caused by a T-cell defect. This defect is thought to be related to a decreased number and/or function of CD4+ T lymphocytes or, occasionally, to an increased number of CD8+ T lymphocytes; however, abnormal responses of B cells to many usual stimuli have also been identified in vitro.
The underlying abnormality in selective IgM deficiency is a defect of helper T cells and excessive suppressor T-cell activity. The condition is characterized by a low IgM level. IgG) levels are normal, but the IgG response is usually decreased.
Primary B-cell disorders result in a complete or partial absence of one or more immunoglobulin isotypes. Regardless of the primary cause, the symptoms depend on the type and severity of the immunoglobulin deficiency and the association of cell-mediated immunodeficiency. In general, severe immunoglobulin deficiency results in recurrent infections with specific microorganisms at certain anatomic sites.
Immunoglobulins play a dual role in the immune response by recognizing foreign antigens and triggering a biologic response that culminates in the elimination of the antigen. Their role in the fight against bacterial infections has been recognized for many years. Emerging evidence from animal and clinical studies suggests a more important role for humoral immunity in the response to viral infections than was initially thought.
IgM plays a pivotal role in the primary immune response. IgG represents the major component of serum antibodies (ie, approximately 85%). By binding to the Fc receptors, they mediate many functions, including antibody-dependent cell-mediated cytotoxicity, phagocytosis, and clearance of immune complexes. IgG1 is the major component of the response to protein antigens (eg, antitetanus/diphtheria antibodies); IgG2 is produced in response to polysaccharide antigens (eg, antipneumococcal antibodies); and IgG3 seems to play an important role in the response to respiratory viruses.
Complement fixation and activation is carried out by IgG1, IgG3, IgM, and, to a lesser degree, IgG2. IgA and, to a lesser extent, IgM, produced locally and secreted in the secretions of mucous membranes, are the major determinants of mucosal immunity.
IgG antibodies are the only immunoglobulin class that crosses the placenta and provides the infant with effective humoral immunity during the first 7-9 months of life.
Deficiency of the expression of major histocompatibility complex (MHC) class I and II cellular proteins also commonly manifests in early infancy with classic symptoms of SCID. Symptoms in affected patients indicate the crucial involvement of MHC proteins in the immune recognition of self and non-self.
In other B- and T-cell disorders, additional anomalies may predominate, and clinical manifestations suggestive of immunodeficiency may occur late in life. Patients with short-limbed skeletal dysplasia with cartilage-hair hypoplasia (CHH) can also have either a T-cell or combined defect.
Combined immunodeficiency due to caspase-8 deficiency presents with recurrent sinopulmonary bacterial infections, poor growth, lymphadenopathy and splenomegaly, asthma, and herpesvirus infection. Caspases are a family of proteases that play roles in signal transduction by inflammatory cytokine receptors (eg, IL-1 and IL-18) as well as in pathways leading to apoptosis. The percentage of CD4+ T cells is low (about 25% of lymphocytes) and the CD4/C8 ratio is 0.5. T cells showed decreased proliferation and IL-2 production in vitro with mitogens, and NK cell function was also impaired.
There are 2 autosomal recessive syndromes that indicate some interaction of the immune system with neurologic function: ataxia-telangiectasia (AT) and Nijmegen breakage syndrome (NBS). These are part of various mutations of DNA proteins. AT is a rare, autosomal recessive, neurodegenerative disorder in which the diagnosis is based on the presence of both ataxia and telangiectasia; combined immunodeficiency can be quite variable in this condition. Other multisystemic manifestations of AT include motor impairments secondary to a neurodegenerative process, oculocutaneous telangiectasia, sinopulmonary infections, and hypersensitivity to ionizing radiation.
NBS is also an autosomal recessive chromosomal instability syndrome in which patients have increased susceptibility to infection or lymphatic tumor development due to defects in humoral and cellular immune functions. NBS is also characterized by microcephaly with growth retardation, normal or impaired intelligence, and birdlike facies. Nearly all patients with NBS are homozygous for the same founder mutation, ie, deletion of 5 bp (657del5) in the NBS1 gene, which encodes the protein nibrin.
Both AT and NBS are associated with decreased circulating levels of T cells and often decreased levels of the IgA, IgE, and IgG subclasses, whereas circulating levels of B cells are normal.
The accurate incidence of SCID in the United States is unknown, but it has been estimated to be in 1 per 50,000-100,000 births across all ethnic groups. A postulated reason for the lack of exact epidemiologic information is that infants with SCID may die of infections without having been diagnosed with the condition.
X-linked SCID is the most common form of this disorder (approximately 42%), followed by autosomal recessive SCID (22%), ADA deficiency (approximately 15%), and JAK3 deficiency (6%).
The incidence of reticular dysgenesis and CHH are less than 1% each. In approximately 14% of cases, the etiology remains unknown. 
Estimates for Europe are thought to approximate those in the United States. CHH may be more frequent in Finland. SCID is underreported, but several countries now maintain registries of patients with primary immunodeficiency diseases.
The estimated prevalence of SCID in Australia is 0.15 cases per 100,000; in Norway, 0.045 cases per 100,000; in Switzerland, 0.47 cases per 100,000; in Sweden, 2.43 of every 100,000 live births. 
SCID is a devastating disease with a high risk of early death in infancy or childhood: a large number of patients die during their first year of life, and most do not survive beyond their second year.
The condition is notable for recurrent failure to thrive and common infections (eg otitis media, diarrhea, mucocutaneous candidiasis). Moreover, if infants are not diagnosed by age 6 months, opportunistic infections follow, especially Pneumocystis carinii pneumonia and invasive fungal infections, and mortality may ensue from common viral illnesses (eg, infections with varicella (VZV), respiratory syncytial virus (RSV), rotavirus, parainfluenza virus, cytomegalovirus (CMV), Epstein-Barr virus (EBV), enterovirus, adenovirus). [4, 6]
Although there is no racial predilection for combined B-cell and T-cell disorders, some forms of combined immunodeficiency have been reported more in some ethnic groups, such as the following  :
JAK3 mutations in Italy
MHC class II deficiency of North African origin
ZAP70 mutations in the Mennonite population
Artemis gene product–deficiency in Navaho Indians of Athabasca descent
RAG1/ RAG2 –deficient SCID in Europe
CHH in the Finnish population and the old Amish order in the United States
The disorders associated with the X chromosome manifest only in males, whereas females are carriers. Approximately 50% of SCID cases are X-linked.
Most patients with these disorders become symptomatic with recurrent infections, failure to thrive, or both in the first months of life.
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