Mechanisms of development and general features
SCID is caused by various genetic mutations that block lymphocyte maturation, activation, or survival. Regardless of whether B lymphocytes or NK cells are simultaneously affected, the pathology always involves T cells. A deficiency of T-helper or cytotoxic lymphocytes collapses the entire adaptive immune system.
In mice with a homozygous scid mutation, T, B, and NK cells are completely absent. In humans, however, manifestations depend on the specific gene. For example, in X-linked SCID, B cells can develop almost normally (since human IL-7 is replaceable for them), but T and NK lymphocytes will be absent.
Receptor gene rearrangement defects
For a lymphocyte to recognize antigens, it requires a unique receptor. Its genes are assembled piecemeal (V-gene rearrangement). If this process breaks down, cell development is arrested.
- RAG-1/RAG-2 deficiency. RAG enzymes initiate rearrangement. Without them, T cells get stuck at the DN2 stage and B cells at the pro-B stage. Formula: T⁻ B⁻ NK⁺.
- DNA-dependent protein kinase deficiency. This enzyme resolves hairpin loops—interlinked DNA strands formed during rearrangement. Its deficiency blocks T and B cells at the same stages. DNA repair upon radiation injury is also impaired.
- Omenn syndrome. Partial defect of RAG1/RAG2 genes. VDJ recombination is incomplete, lymphocyte development is partially impaired (T± B⁺ NK⁻). Th1 cell development is particularly affected.
Signaling and survival pathway disorders
Some mutations kill precursor cells or make them deaf to activation signals.
- IL-7 receptor and Jak3 kinase defects. Normally, IL-7 stimulates cell survival by activating the anti-apoptotic factor Bcl-2 via Jak3 kinase. The absence of the receptor $\gamma$(c)-chain (X-linked form), the IL-7 receptor $\alpha$-chain, or Jak3 kinase leads to apoptosis. Outcome: absence of T and NK cells (T⁻ B⁺ NK⁻).
- CD45 deficiency. The CD45 molecule with tyrosine phosphatase activity activates Lck kinase. Without CD45, signaling in lymphocytes is not initiated.
- CD3 complex deficiencies (CD3$\gamma$, CD3$\varepsilon$). TCR-CD3 expression and signal transduction into the T cell are impaired.
- ZAP-70 deficiency. The first stage of signal transduction is blocked. CD8⁺ T cell development is critically impaired (T (CD4⁺ CD8⁻) B⁺ NK⁺).
Metabolic defects (cellular toxicosis)
If nucleotide salvage enzymes do not function, toxic products accumulate within cells.
- Adenosine deaminase (ADA) deficiency. Adenosine and deoxyadenosine accumulate. Developing thymocytes are extremely sensitive to them and undergo apoptosis. Both T and B cells are affected (T⁻ B⁺ NK⁺).
- Purine nucleoside phosphorylase (PNP) deficiency. Toxic guanosine derivatives accumulate. They are lethal only to T lymphocytes. The clinical course is milder than that of ADA deficiency.
Antigen presentation and co-reception defects
Contact with MHC (major histocompatibility complex) molecules is required for T cell maturation and function.
- MHC-II deficiency. Regulatory gene mutations (e.g., CIITA). Without MHC-II, CD4⁺ T cells (helpers) do not mature.
- CD4 deficiency. Similar effect — T helpers cannot recognize MHC-II.
- TAP deficiency. TAP proteins transport peptides for MHC-I assembly. Without them, MHC-I is unstable, leading to the absence of CD8⁺ T lymphocytes.
Briefly: answers to topical questions
Which mutations cause bare lymphocyte syndrome type II (MHC-II deficiency)?
MHC-II molecule deficiency is caused by mutations in genes controlling MHC class II gene activity. These include:
- Transactivator gene (CIITA) — controls the class II gene transactivator.
- Regulatory factor genes (RFXNK, RFX5, RFXAP) — belong to the RFX family.
As a result of these mutations, MHC-II molecule expression on cells is absent, preventing the normal differentiation and selection of CD4+ T cells.
Which specific metabolites accumulate in purine nucleoside phosphorylase (PNP) deficiency?
Purine nucleoside phosphorylase deficiency leads to the accumulation of toxic guanine nucleotide metabolites. Specific accumulating metabolites include:
- Deoxyguanosine — a toxic metabolic product.
- Guanosine — a guanine nucleotide metabolic product.
These metabolites exert a toxic effect exclusively on developing T lymphocytes, causing their death.
Which forms of SCID are characterized by increased cellular sensitivity to ionizing radiation?
Increased cellular sensitivity to ionizing radiation characterizes the radiosensitive form of SCID caused by DNA-dependent protein kinase deficiency. In this pathology, the enzyme gene mutation prevents the resolution of DNA damage caused by radiation and other factors. Normally, this enzyme participates in resolving hairpins during V-gene rearrangement and repairing DNA double-strand breaks. Its defect leads to a block in T and B cell development.
Which gene encodes the common cytokine receptor $\gamma$ chain in X-linked SCID?
The common cytokine receptor $\gamma$ chain in X-linked severe combined immunodeficiency is encoded by the IL2RG gene. A mutation in this gene leads to a defect in encoding the $\gamma$ chain for receptors of six key interleukins (IL-2, -4, -7, -9, -15, -21). Because these cytokines are critically important for lymphocyte maturation, the defect causes a significant decrease in T lymphocyte and NK cell levels with nearly normal B lymphocyte development.
Which enzymes participate in resolving DNA hairpins during VDJ recombination?
DNA hairpins during VDJ recombination are resolved by the following enzymes:
- DNA-dependent protein kinase — participates in hairpin resolution by breaking bonds and subsequently establishing final connections between homologous strand segments.
- Endonuclease — introduces an asymmetric single-strand break into the closed hairpin structure, leading to DNA strand unwinding and P-nucleotide insertion formation.
Class and exam questions
Why is humoral immunity always impaired in SCID even if B cells are normal?
Humoral response to most antigens requires T-helper assistance. Because the T-cell lineage is always impaired in SCID, B cells do not receive necessary signals to function.
Which immunodeficiency was the first to be successfully treated with gene therapy?
Adenosine deaminase (ADA) deficiency. Patients received autologous bone marrow cells engineered with a healthy ADA gene.
What is the difference between ADA deficiency and PNP deficiency?
In ADA deficiency, toxic metabolites destroy both T and B cells, and the condition is extremely severe. In PNP deficiency, toxins affect only T lymphocytes, and the defect is partially compensated, making the clinical presentation milder.
What else to study on this topic
- Pathogenetic features of DiGeorge syndrome and the role of the Tbx1 gene
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- Functional consequences of CD25 molecule deficiency
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