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

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

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

AR

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,

CD45

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. [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.


Did this answer your question?
Additional feedback? (Optional)
Thank you for your feedback!