Lecture 16

Organized Notes: Immunodeficiencies

1. Overview: Acquired vs. Primary Immunodeficiencies

• Primary Immunodeficiencies

  • 300 genetic defects identified

  • ~1/500 incidence

  • Varying severity

  • Can affect any immune pathway or cell type

2. Characteristics of Primary Immunodeficiencies

• Opportunistic infections

• Pattern of infections depends on defect

3. Detection of Primary Immunodeficiencies

• Usually detected early in life

• Challenges in diagnosis:

  • Masked by maternal immunity

  • Requires tracking vaccine responses & infection history

  • Often takes years to identify specific defects

  • Push for neonatal screening in severe cases

4. Causes of Primary Immunodeficiencies

• Failures in immune development or processes

  • Affect different immune pathways or cell types

  • Many mutations are recessive or X-linked

  • Difficult to identify until recent advances

5. Immunoregulation Deficiencies

• Failures in immune system control mechanisms

  • Failure in Central Tolerance → Autoimmunity

  • Failure in Treg development → Uncontrolled immune responses

6. Innate Immunodeficiencies

• Defects in innate immune functions:

  • Chronic Granulomatous Disease (CGD): Failure in macrophage effector mechanisms

  • Leukocyte Adhesion Deficiencies (LADs): Failure in leukocyte recruitment cascade

7. Combined Immunodeficiencies

• T cell deficiencies impact antibody responses

• Severe Combined Immunodeficiencies (SCID):

  • Complete absence of functional T cells

  • Often failure in lymphoid development or hematopoiesis

  • Multiple genetic mutations, categorized into five broad types

  • Phenotypic differences (e.g., T-B-NK+, T-B+NK-)

8. SCIDs: Molecular Defects & Examples

• Defects in immune receptor recombination

  • Mutations in RAG1, RAG2, Artemis

• Defects in cytokine signaling pathways

  • Mutations in common γ chain, JAK3

  • T- NKint B+ (mouse: B-)

• Defects in TCR signaling

  • Mutations in the CD3 signaling complex

9. SCID & The Bubble Boy Case

• David Vetter (1971-1984)

  • X-linked SCID (xSCID): Common γ chain defect

  • Lived 12 years in isolation

  • Bone marrow transplant attempted → died from infection

10. B Cell Immunodeficiencies

• Specific Absence of B Cells

  • X-linked Agammaglobulinemia

• Defects in T Cell Help

  • Loss of function of CD40 or CD40L

  • Limited class switching

11. Treatment of Immunodeficiencies

• Replacing missing immune components:

  • IVIG for antibody deficiencies

  • Hematopoietic stem cell transplant (SCID) (performed early in life)

• Gene Therapy Approaches:

  • Common γ chain: Some success (20 cases), risk of leukemia

  • ADA (Adenosine Deaminase Deficiency): Good success (>24 cases)

12. Mouse Models for Immunodeficiencies

• Naturally occurring or genetically engineered

• Humanized mouse models

  • Recipients of human immune cells