Immunodeficiencies LO4

Focus on dissecting the mechanisms of X-linked SCID.
Explain the influence of gene defects on lymphocyte development and severe clinical outcomes.
Immunodeficiencies arise from defects in immune genes affecting lymphocyte maturation.

Various defects can lead to a lack of T and B cells, severely impacting both cellular and humoral immunity.
Consequence of total loss of T and B cells results in extremely severe clinical outcomes.
Example: Defect in Bruton's Tyrosine Kinase leads to failure to produce B cells.
Other genetic defects:
- RAG1 and RAG2 Genes: Abolish both B and T cells.
- Defects categorized as:
- Severe Combined Immunodeficiencies (SCID)
- B cell immunodeficiencies
- Disorders of T cell maturation

X-linked SCID is the most common form of SCID.
Characterized by:
- Markedly decreased T cells (T lymphocytes)
- Normal levels of B cells.
Severe combined immunodeficiency results in a defect in B cell development.
Depending on gene mutations, patients may also lack NK cells.

Patients survive the first few months of life due to protection from maternal antibodies (IgA from breast milk & IgG crossed the placenta).
Once weaned off maternal antibodies, severe opportunistic infections occur:
- Thrush: Oral or diaper area infection.
- Coughs and Pneumonia: Due to viral infections like Respiratory Syncytial Virus (RSV) or Cytomegalovirus (CMV).
- Intractable Diarrhea: Caused by viruses or pathogens like E. Coli.
Without appropriate treatment (prophylactic antibiotics, intravenous immunoglobulins, hygiene measures), patients may die within months.
Live attenuated vaccines pose a significant risk, as SCID patients cannot control infections from live pathogens.

Normal thymus structure includes a cortex and medulla where thymocytes develop.
In SCID, thymic architecture is disrupted, resulting in reduced thymus size and developmental impairment of thymocytes.

Defect occurs in the common gamma chain of the cytokine receptor located on the X chromosome.
Unique feature: Males only need one defective allele for the phenotype.
Mutation leads to absence of T cells and NK cells, while B cell numbers remain normal.
Several cytokines rely on this common gamma chain:
- Interleukin 15 (IL-15): Important for NK cell development.
- Interleukin 7 (IL-7): Critical for T cell development in the thymus.
Absence of the common gamma chain leads to abolished signal transduction and dysfunction of the corresponding cytokines.

IL-7 is essential for the proliferation and expansion of thymocytes, particularly during critical developmental stages:
- Hematopoietic stem cells -> Common lymphoid precursor -> Pro T cell -> Pre T cell (double-negative thymocytes).
Without IL-7, the number of pro T cells remains low, leading to inadequate generation of double positive thymocytes—which are necessary for T cell maturation.

B cell responses are compromised due to the lack of T cell help.
Interleukin 21 (IL-21): Important for germinal center responses, further hindering adaptive immunity in SCID patients.

Lived from 1971 to 1984, famous SCID patient who spent life in a sterile isolator due to X-linked SCID.
His older brother had previously died from the same condition.
David underwent a bone marrow transplant which was complicated by contamination with Epstein-Barr virus (EBV) from his sister’s transplant.
Resulted in leukemia, which led to David's eventual death.

Now treatable through:
- Bone Marrow Transplantation:
- Data shows high survival rates depending on HLA matching:
  - HLA Matched Sibling Donor: ~90% survival rate.
  - HLA Matched Unrelated Donor: ~67% survival rate.
  - Mismatched Donor: ~30% survival rate.
Patients with SCID cannot reject grafts due to absence of T cells, but must manage graft versus host disease (GVHD) resulting from T lymphocytes in the transplant attacking the host tissues.
Gene Therapy: Developing techniques to repair genetic defects in the patient’s autologous stem cells.
- Process involves retroviral transduction of stem cells to include a functional common gamma chain gene:
- Repaired cells have a selective growth advantage over mutated counterparts.
Clinical trials show promising results with 90% cure rate; however, some patients developed T cell leukemia post-treatment, where four survived and one did not.

X-linked SCID has evolved from a condition requiring sterile living due to severe immunodeficiency to a potentially curable disease through advancements in bone marrow transplantation and gene therapy.
The need for ongoing research and improvement in treatment outlining the successful restoration of immune function while minimizing risks of complications like cancer.