OVERVIEW

• Primary immunodeficiencies (aka, PIDs) are inherited, as opposed to the acquired secondary disorders.
• PIDs can arise as defects in the innate and/or adaptive immune systems.
• Defects in the innate system include: dysfunctional leukocytes, complement proteins, and toll-like receptors.
• Defects in the adaptive immune system include dysfunctional or absent T cells, natural killer cells, B cells, or antibodies (aka, immunoglobulins).
• Primary immunodeficiencies increase an individual’s susceptibility to infection, allergy, and autoimmune disorders; they are often diagnosed in infancy or early childhood.

INNATE IMMUNITY DEFECTS

• Adhesion deficiencies impair leukocyte trafficking:
  – Leukocyte adhesion deficiency 1 is due to defects in the CD 11/CD18 integrins, which adhere neutrophils to the vessel endothelium during recruitment.
  – Leukocyte adhesion deficiency 2 is due to defects in the selectin receptor, which neutrophils use to roll along the vessel wall to the site of diapedesis.
  – See acute inflammation for a reminder of leukocyte trafficking.
• Chediak-Higashi syndrome: defective phagosome-lysosome fusion prevents neutrophilic antimicrobial products from reaching their pathogen targets.
• Chronic granulomatous disease is caused by defects in NADPH oxidase; reactive oxygen species production and neutrophil respiratory burst are inhibited.
• Myeloperoxidase deficiency also impairs antimicrobial effects, though this deficiency tends to have less severe consequences.
• Dysfunctional complement proteins interrupt the complement cascade, and, in many cases, leave individuals more susceptible to invasive meningococcal infections.
  – C2 and/or C4 deficiencies interrupt the classical pathway, and are associated with the symptoms of lupus due to persistent immune complexes.
  – Defects in C3 interrupt both classical and alternative pathways.
  – Properdine &/or factor D deficiencies inhibit the alternative pathway.
  – Defects in late-acting complement proteins inhibit the formation of membrane attack complexes (MACs).
  – C1 inhibitor deficiency leads to angioedema caused by Bradykinin production; swellings in the gastrointestinal and respiratory tracts can have dire consequences.
• Dysfunctional toll-like receptors impair cytokine production; defective TLR also contribute some adaptive immune disorders.

ADAPTIVE IMMUNITY DISORDERS

Lymphocyte Cell Lineage

• Common lymphoid progenitor gives rise to Pro-T and Pro-B cells.
• Pro-T cells give rise to immature T cells; these cells ultimately give rise to CD4+ Helper and CD8+ Cytotoxic cells.
• Pro-B cells give rise to Pre-B cells.
• Upon stimulation by Bruton’s Tyrosine Kinase, Pre-B cells become immature B cells with IgM antibodies on their cell surfaces.
• Further maturation and class switching produces the full range of antibodies, including IgM, IgG, IgA, and IgE antibodies (we omit IgD, here, for simplicity).

Maturation Defects:

• Adenosine deaminase deficiency – severe combined immunodeficiency (ADA SCID) impairs T lymphocyte maturation.
  – This is an autosomal recessive form of SCID.
  – Individuals have low T cells and natural killer cells, and, because T cells are required for most B cell activation, reduced B cells and antibodies.
  – Clinically, ADA SCID manifests as thrush, rash, diarrhea and susceptibility to infections; neurologic abnormalities, pulmonary proteinosis, and liver dysfunction are also possible.

• X-linked SCID impairs progression from the Pro-T cell to immature T cell stage.
  – Serum values include low T cells, natural killer cells, and antibodies.
  – Individuals have increased susceptibility to thrush, rash, diarrhea, slow growth, and infection, particularly pneumonia.

• DiGeorge Syndrome impairs progression from the immature T cell to mature T cell stage.
  – Low T cell counts, and normal to low antibody levels.
  – Also known as thymic hypoplasia, DiGeorge syndrome presents with hypoparathyroidism, hypoplastic thymus, conotruncal heart defects, and facial abnormalities.

• X-linked ammaglobulinemia, aka, Bruton’s agammaglobulinemia, interrupts the development of Pre-B cells to the immature B cell stage.
  – Low B cells and antibodies, and an absence of plasma cells.
  – Individuals present with recurrent bacterial infections, especially in the respiratory tract, and viral infections in the gastrointestinal tract. Antibody therapy is required.

Activation defects:

• Common variable immunodeficiency (CVID) is a group of disorders that blocks activation of B cells.
  – This is the most common symptomatic primary adaptive immunity disorder.
  – Reduced antibody production.
  – Susceptible to pyogenic (pus-forming) and sinopulmonary infections, herpesvirus, enterovirus, and autoimmune disorders.
  – Unlike most of the other primary immunodeficiency disorders, CVID is commonly diagnosed in adults.

• Hyper-IgM disorder occurs when class switching fails to occur, for example, when the gene for the CD40 ligand is mutated.
  – As its name suggests, IgM levels are high, but all other antibody levels are reduced.
  – Thus, individuals are susceptible to pyogenic and sinopulmonary infections, autoimmune disorders, particularly hemolytic anemia, and diseases of the liver.

• Selective IgA deficiency is the most common asymptomatic disorder.
  – Occurs when class-switching to IgA is inhibited.
  – Though usually benign, individuals may have increased susceptibility to sinopulmonary and gastrointestinal infections, autoimmune disorders, and allergy.

• X-linked lymphoproliferative syndrome results in abnormal, usually low, antibody production and reduced levels of natural killer cells.
  – In many cases, this disorder is triggered by Epstein-Barr virus, and is associated with increased risk of lymphoma and fulminant infectious mononucleosis.

Systemic disorders that have immunological components:

• Wiskott-Aldrich syndrome is characterized by low levels of IgM, but elevated levels of IgE and IgA; individuals tend to present with thrombocytopenia, eczema, recurrent infections, autoimmune disorders, and B-cell lymphoma.
• Ataxia telangiectasia is characterized by low levels of A, G, and E antibodies; as the name suggests, individuals present with ataxia and telangiectasia, and have increased susceptibility to respiratory tract bacterial infections and cancers. They are sensitive to radiation exposure (including X-rays).

Primary immunodeficiencies of the adaptive system are often treatable with hematopoietic stem cell transplants or antibody therapy.