Severe Combined Immunodeficiency (SCID)

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)

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. ^[3]

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, as follows:

• Premature cell death caused by the accumulation of purine metabolites (seen in adenosine deaminase (ADA) deficiency)

• Defective V(D)J rearrangements of the T-cell and B-cell receptor genes (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 the deamination of adenosine to inosine and the deamination of deoxyadenosine 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. In this condition, mutations in the genes coding for the recombinases (ie, RAG1 and RAG2) cause a defect in the VDJ rearrangement that is needed for mature B-cells and T-cells to develop, resulting in a paradoxical combination of immunodeficiency and immune dysregulation.

In study by Khiong et al, the authors identified a C57BL/10 mouse with a spontaneous mutation in and reduced activity of RAG1. ^[4] Mice bred from this animal exhibited major manifestations of Omenn syndrome, including high numbers of memory-phenotype T cells, hepatosplenomegaly and eosinophilia, oligoclonal T cells, and 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 that these "memory mutant" mice may be a model for human Omenn syndrome, and that many manifestations of the murine disease were direct results of the RAG hypomorphism, whereas some were caused by malfunctions of their CD4+ T-cells. ^[4]

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. ^[5]

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.

In selective IgM deficiency, the underlying abnormality 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.

T-helper lymphocyte deficiency has been incriminated in the pathogenesis of transient hypogammaglobulinemia of infancy (THI) and immunodeficiency with thymoma.

Primary B-cell disorders result in a complete or partial absence of one or more immunoglobulin isotypes. Regardless of the primary cause, the clincal manifestations 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. It is the first immunoglobulin class produced in a primary response to an antigen. IgM binds the C1 component of complement and activates the classical pathway, leading to opsonization of antigens and cytolysis. Binding of IgM to the polyimmunoglobulin receptor brings IgM to mucosal surfaces.

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 by mucous membranes, are the major determinants of mucosal immunity.

IgG antibodies are the only immunoglobulin class that crosses the placenta. These placental antibodies provide 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 expressions of SCID. Manifestations 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 as 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 is 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 involve 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: 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.

Frequency

United States

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.

With implementation of SCID newborn screening in unbiased populations, Kwan et al reported that 1 in 58,000 infants (95% CI 1/46,000–80,000) are born with SCID or leaky SCID (ie, forms of SCID, such as Omenn syndrome, characterized by normal or elevated levels of nonfunctional T cells, in contrast to the low or absent T cell counts of typical SCID). That prevalence rate is nearly twice the previous estimates based on population data or experience of centers performing hematopoietic cell transplantation therapy for SCID. ^[6]

The approximate frequency of the most common forms of SCID is as follows:

• X-linked SCID -  42%
• Autosomal recessive SCID - 22%
• ADA deficiency - 15%
• JAK3 deficiency - 6%

The incidence of reticular dysgenesis and CHH are less than 1% each. In approximately 14% of cases, the etiology remains unknown. ^[7]

International

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 specific countries is as follows ^[8] :

• Australia - 0.15 cases per 100,000 population
• Norway - 0.045 cases per 100,000 population
• Switzerland - 0.47 cases per 100,000 population
• Sweden, 2.43 of every 100,000 live births

Mortality/Morbidity

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 jirovecii pneumonia and invasive fungal infections, and mortality may ensue from infections with common viruses, such as the following ^{[7, 9]} :

• Varicella-zoster virus (VZV)
• Respiratory syncytial virus (RSV)
• Rotavirus
• Parainfluenza virus
• Cytomegalovirus (CMV)
• Epstein-Barr virus (EBV) 
• Enterovirus 
• Adenovirus

Race-, sex-, and age-related demographics

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 ^[7] :

• JAK3 mutations in Italy
• MHC class II deficiency of North African origin
• ADA-SCID in the Somali population has an incidence of 1 in 5,000 ^[10]
• ZAP70 mutations in the Mennonite population
• Artemis gene product–deficiency in Navajo Indians of Athabasca descent has a reported incidence of 1 in 2,000 ^[10]
• 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 typically 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.

See the list below:

• Without treatment, most of the patients with combined B-cell and T-cell disorders die within the first 6 months of life.

• Patients who are well nourished, uninfected, and younger than 6 months before transplantation have the best outcomes.

• Patients with SCID barely survive without stem cell reconstitution. However, gene therapy is an alternative for those cases in which donors are unavailable.

• Patients with less severe mutations in the ADA gene have survived into adulthood.