What is the pathogenesis of severe combined immunodeficiency (SCID)?

Updated: Apr 28, 2021
  • Author: Robert A Schwartz, MD, MPH; Chief Editor: Harumi Jyonouchi, MD  more...
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Answer

The pathogenesis of SCID may be further divided into the following 5 mechanisms on the basis of the stage or stages at which lymphopoiesis is arrested.

Defective lymphokine signaling

An early block may occur within the T-cell differentiation pathway. The most common form of SCID, occurring in 40-60% of patients, is XL-SCID, which arises from defects in the common γ chain of interleukin receptors. This molecular defect results in absent T-cell and NK-cell maturation, although evidence suggests that the γ chain is also involved in B-cell development.

The cytokine receptors that share the common γ chain include IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21. These function to increase cytokine binding affinity and signal transduction. [29, 30] Cytokine binding to the γ chain of these cytokines activate the signaling pathway that includes the intracellular tyrosine kinase JAK3. JAK3 is upregulated as the T cell is activated; downstream signaling by JAK3 triggers 3 additional signaling pathways, including the signal transducers and activators of transcription (STATs).

In the absence of the common γ chain or of the alpha chain of the IL-7 receptor, JAK3 cannot be activated in pro-T cells in the bone marrow; thus, T-cell maturation and differentiation cannot occur. Similarly, mutations in JAK3 prevent proliferation and differentiation in pro-T cells. The common γ chain is shared as a receptor of IL-15, which is a key growth factor for NK cells. Thus, defects in the common γ chain and JAK3 result in T B+ NK SCID, whereas IL-7 receptor alpha-chain mutations result in T B NK+ SCID.

In addition, defects in signaling molecules that associate with the T-cell receptor can lead to SCID; examples include mutations in the LCK and ZAP70 genes. Another cytokine receptor–associated gene is JAK1, which, when defective, can lead to SCID.

Apoptosis secondary to accumulation of toxic metabolites

Abnormal purine metabolism may be involved in the pathogenesis of SCID. ADA and PNP are required for purine salvage pathways. Defects in ADA and PNP can lead to apoptosis, resulting in T B NK SCID.

ADA deficiency accounts for 20% of all SCID cases. It leads to the accumulation of intermediates (eg, adenosine diphosphate, guanosine triphosphate, and dATP), which results in lymphocyte toxicity, particularly with immature thymic lymphocytes. PNP deficiency is mechanistically similar to ADA deficiency in that the accumulation of an intermediate (in this case, deoxyguanosine triphosphate [dGTP]) exerts a lymphotoxic effect. In both conditions, T-cell function is most severely affected.

Defective cell signaling at and before level of TCR

CD45, a tyrosine phosphatase found in the cell membranes of hematopoietic cells, is essential in regulating the transmission of cell surface signals in B cells and T cells. Deficiency of CD45 can lead to in T B+ NK SCID.

CD3 is a complex of transmembrane proteins (δ, γ, ε, and ζ) that forms a heterodimer with the TCR; upon ligand binding by the TCR, the immunoreceptor tyrosine-based activation motifs (ITAMs) of CD3 become activated, and these then activate the kinase ZAP-70 to propagate downstream signaling events.

Deficiency of CD3δ is associated with defective pre-TCR signaling, whereas the lack of CD3ε results in the absence of mature TCRs in the periphery; both are associated with T B+ NK+ SCID. Deficiency of ZAP-70 causes a preferential decrease of CD8 cells, causing an atypical SCID. Likewise, CD3 deficiency presents with close-to-normal absolute lymphocyte count, although these T cells are dysfunctional.

Defective expression of MHC molecules disrupts antigen (Ag) presentation at the pre-TCR level, leading to bare lymphocyte syndrome, which then results in an inability of the T cells to function. Patients with this condition can have defects in the regulatory region of the MHC class II gene or a defect in a transcription regulator, CTIIA, which is responsible for controlling the expression of MHC class II genes.

Defective TCR and Ig gene rearrangement

Abnormal TCR and Ig gene rearrangement may occur. Both B-cell maturation and T-cell maturation involve a process of recombination in which various combinations of VDJ genes are assembled to create unique and specific antigen receptors. Several recombinases play critical roles in this process.

RAG1 and RAG2, which mediate initial DNA double-strand breaking at specific sequences, enable subsequent joining of the various gene segments. Mutations in RAG1 and RAG2 result in a T B NK+ SCID phenotype and Omenn syndrome, in which residual VDJ recombination activity occurs. [26]

The ARTEMIS gene, located on chromosome 10, encodes a product that plays a role in VDJ recombination and is associated with SCID that develops from an early block in B- and T-cell development. Artemis splice defects may cause atypical relatively mild combined immunodeficiency. [24]

The gene DNA-PK is a DNA-dependent serine-threonine protein kinase that is required for correct recombination. Mutations in this gene are autosomal recessive and can also lead to combined deficiency. DNA from the cells of these patients is associated with an increased radiosensitivity.

Thymic dysgenesis

Severe thymic dysgenesis results in lack of T cells, causing a T B+ NK+ SCID. This is typically seen in severe forms of DiGeorge syndrome and CHARGE association.


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