What is the role of cytokine receptors in the pathophysiology of severe combined immunodeficiency (SCID)?

Updated: May 27, 2020
  • Author: Francisco J Hernandez-Ilizaliturri, MD; Chief Editor: Emmanuel C Besa, MD  more...
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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.

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