Primary Immunodeficiencies Overview

Primary Immunodeficiencies

• Severe Combined Immunodeficiency (SCID)

  • SCID: Aspergillus and Candida, GI, respiratory infections - Broad range of infections affecting multiple organ systems.
  • SCIDXI: Common γ chain, cytokine receptor - A common molecular factor in the receptor system is deficient.
  • SCID defect T-B-NK-: ADA (purine salvage) - Adenosine deaminase deficiency prevents proper purine metabolism, leading to impaired immune function across multiple cell types.
  • SCID defect T-B-NK+: RAG (no VDJ recombination but NK cells are still fine) - RAG deficiency prevents the rearrangement of variable, diversity, and joining regions of genes in lymphocytes, impacting B and T cells but not NK cells.

• Bare Lymphocyte Syndrome (BLS)

  • Pathophysiology: Defects in MHC I and II lead to impaired T-dependent humoral responses and T cell development.
  • BLS-1: MHC I defect (TAP transporter), low CD4+, bacterial upper respiratory infections - Defective transport of MHC I molecules leads to decreased CD4+ T-cells and elevated susceptibility to bacterial infections.
  • BLS-2: MHC II defect, low CD8+, - Defective MHC II molecules lead to decrease in CD8+ T-cells.

• Hyper IgM Syndrome (HIGM)

  • HIGM1: CD40L, X-linked - Dysfunction in the CD40 ligand, an X-linked condition.
  • HIGM2: AID mutation (somatic hypermutation and class switching), hyperplastic GCs, AR - Somatic hypermutations and class switching are affected by AID mutations, leading to accumulations of proliferating germinal centers, an autosomal recessive disorder.
  • HIGM3: CD40, AR - Dysfunction in the CD40 receptor, an autosomal recessive condition.

• Wiskott-Aldrich Syndrome (WAS)

  • WASP protein defect impacting cytoskeletal rearrangement in B and T cells, X-linked, eczema, thrombocytopenia, petechiae - A deficiency in WASP, an X-linked disorder, affects cytoskeletal structure affecting B and T cell functions leading to eczema, low platelets, and easy bruising.

• DiGeorge Syndrome

  • 22q11, thymic aplasia, T cell deficiency (because of no thymus!) - A chromosomal deletion leads to thymic atrophy, impacting T cell formation and function.

• Job's/Hyper IgE Syndrome

  • AD cytokine signaling defect from multiple sources, high IgE, cold abscesses, skeletal abnormalities, pneumatoceles (in lung) - Autoimmune disorders affect cytokine signaling mechanisms, leading to elevated IgE levels and various symptoms.

• Bruton's X-linked Agammaglobulinemia (XLA)

  • BTK signaling, X-linked, B cell deficiency, pre- to pro-B cell defect - Disruption in B cell signaling pathways lead to decreased B cell development.

• IgA Deficiency

  • Low IgA, other Igs normal. Mechanism unknown, anaphylactic to IVIg - Decreased levels of IgA, but other immunoglobulin types are normal, an unknown mechanism, and individuals are sensitive to intravenous immunoglobulin.

• Chediak-Higashi Syndrome

  • Partial albinism, LYST gene, no vesicle transport or fusion, low NK, defective CD8+, and phagocytes, hemophagocytic lymphohistiocytosis - A LYST gene deficiency affects vesicle transport affecting NK cells , CD8+ and phagocytes. Can lead to excessive inflammation.

• Familial Hemophagocytic Lymphohistiocytosis (FHL)

  • Perforin defect, NK and CD8+ defect - A deficiency in perforin leads to a defect in killing functions of NK and CD8+ lymphocytes.

• IPEX (Immune dysregulation, polyendocrinopathy, enteropathy, X-linked)

  • Fox3P gene, no Tregs, no peripheral tolerance - Decreased regulatory T-cells impact peripheral tolerance in immune response.

• ALPS (Autoimmune Lymphoproliferative Syndrome)

  • Fas/FasL defect, no apoptosis in either tolerance, lymphadenopathy and hepatosplenomegaly (buildup of cells that need to be dead) - Apoptosis is affected by Fas/ FasL defects, leading to a buildup of immune cells and lymphadenopathy.

• APECED (Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy)

  • AIRE deficiency, no central tolerance in cortical thymic epithelial cells - Deficient expression of AIRE impacts central tolerance in thymic epithelial cells.

• Chronic Granulomatous Disease (CGD)

  • cp91PHOX, no respiratory burst from phagocytes, negative nitroblue tetrazolium, symptoms – infection from catalase+ organisms (because the respiratory burst is ROS), granulomas, and Aspergillus pneumonia - Impaired respiratory burst in phagocytes, leading to increased susceptibility to certain bacteria.

• Leukocyte Adhesion Deficiencies (LAD)

  • Defect in leukocyte extravasation (leukocytosis, no pus when infected)
  • LAD1: CD18, low affinity integrin, no umbilical detachment - A deficiency in the CD18 protein leads to a low affinity integrin function causing delay in umbilical separation.
  • LAD2: selectin - Deficient selectins in leukocyte extravasation.
  • LAD3: high affinity integrin - Deficient high affinity integrins in leukocyte extravasation.