Before discussing the different types of SCID phenotypes, one should describe the normal steps involved in T-cell development, maturation, differentiation, and activation. Each step in the normal process that generates normal, functional T cells is genetically controlled by many structural and regulatory genes, and, therefore, the potential for genetic defects resulting in an abnormal number or function of T cells – and subsequently, SCID phenotype – is great.
Pluripotential hematopoietic stem cells develop into lymphoid stem cells, which differentiate into T, B, or NK cells depending on the organs or tissues to which these stem cells migrate. T-cell progenitors occur in the embryonic thymus as early as 8 weeks of gestation and, by the age of 10 weeks, 25% of thymocytes bear the mature, specific T-cell receptor (TCR). TCRs consist of two chains (α and β) that are coexpressed on the cell surface with CD3 – a multichain signaling complex of five polypeptides: γ, δ,
, ζ, and η. Together, the TCR and the CD3 molecule form the TCR complex. This complex also includes tyrosine phosphatase CD45, which is found on all hematopoietic cells and is essential for the normal maturation of T cells. Early development of TCR in the thymus requires the expression of specific markers such as CD1, CD2, and interleukin 2 receptor (IL-2R) molecules, which serve critical receptor–ligand functions during the early stages of ontogeny. The next step involves the lymphoid-specific recombinase activating genes
, which are responsible for the V(D)J rearrangement process, and are critical for the normal development of TCRs. As immature cortical thymocytes begin to express TCRs, they move through the processes of positive and negative selection. Mature T cells that survive positive selection either express CD4 and are restricted to interacting only with self class II molecules or express CD8 and are restricted to interacting with self class I human histocompatibility leukocyte antigens (HLAs). The purpose of negative selection is to remove autoreactive T cells and, subsequently, by the end of the process, 97% of all cortical thymocytes die. During negative selection, mature single positive T cells emigrate from the thymus to secondary lymphoid organs such as the spleen, lymph nodes, tonsils, and appendix at 12 weeks of embryonic life. Immune cell interaction is crucial for the adequate response and activation of T cells, since TCRs can only recognize processed antigenic peptides, presented to it by antigen-presenting cells (APCs) such as B cells, macrophages, and dendritic cells, in the context of class I or II HLA molecules. Normal activation of CD4 T cells by B cells requires a transient expression of CD40 ligand molecules on the surface of CD4 T cells, which bind to CD40 molecules on B cells. The TCR then interacts with the peptide-bearing HLA molecule and, through the multichain, CD3 signaling complex, sends a signal to produce cytokines, ultimately resulting in T-cell activation and proliferation. The most important cytokine involved in the activation and proliferation of T cells is IL-2, which binds to its high affinity, multi-chain (α, β, γ) receptor; namely, IL-2R.
Activation of the TCR complex results in the following activation events: (1) Production of lipid mediators such as inositol triphosphate and diacylglycerol and activation of protein kinase C. (2) Phosphorylation and activation of tyrosine kinases such as Lck and ZAP-70. (3) Elevation of intracellular calcium levels. All these activation events convey messages to the cell nucleus resulting in the normal functioning of T cells.6
Although it is more appropriate to refer to SCID syndromes according to the specific molecular defect (once it has been identified), phenotypic classification is still viewed as a simpler, more useful, and more intuitive approach. Thus, we decided to take this approach in order to classify the different types of SCID (). However, some forms of SCID do not fit into this classification and, therefore, we will use the alternative approach involving cellular function for characterization of these forms ().
Classification of SCID syndromes based on immunophenotype
Classification of SCID variants based on normal T-cell development