Immunodeficiency Diseases



  • Immunodeficiency can be either primary or secondary (acquired). There are numerous causes; each may lead to increased risk of infections, autoimmune diseases, and cancers (1).
  • Primary immunodeficiency disease: an intrinsic defect in the immune system affecting receptor function, cytoplasmic enzymes, and gene regulatory proteins. These defects affect the maturation and function of B cells, T cells, phagocytes, the complement system, and NK cells. Depending on the defect, ≥1 organ systems are affected.
  • B cells: humoral immunodeficiencies: defects in antibody production typically presenting as recurrent sinopulmonary or gastrointestinal infections. Represent the most common form of primary immunodeficiency (~2/3):
    • IgA deficiency: most common primary immunodeficiency: Clinical symptoms range from asymptomatic/mild to severe. Sporadic more common than inherited. Spanish and Arabian populations are more at risk than European (~1:150 to 1:400+). Asians are at least risk (~1:2,600 to 1:18,000). Associated with autoimmune diseases such as rheumatoid arthritis (RA) (at any age) and systemic lupus erythematosus (SLE). Children <5 years presenting with IgA deficiency may outgrow it.
    • Common variable immunodeficiency (CVID): a heterogeneous form of severe antibody deficiency. Low immunoglobulins (IgG, IgA, and/or IgM) leave patients susceptible to pyogenic infections. Moderate to severe clinical presentations are more common than mild/asymptomatic. Adult onset (mid-20s) is more common than childhood. Sporadic (~90%) is more common than inherited. Incidence for CVID 1:25,000 to 1:66,000. Northern European descent higher risk than African, Asian, and Hispanic. Men and women are at equal risk. Similar risks and family history as with IgA deficiency. Treatment helps prevent bronchiectasis, malabsorption, and vitamin deficiencies.
    • X-linked agammaglobulinemia (XLA): Xq22; Bruton tyrosine kinase. Recurrent infections with encapsulated bacteria after birth are common. Growth and development are usually normal. All serum immunoglobulins are extremely low. T and NK cells’ function are preserved. Lymph nodes are diminished in size.
    • Hyper-IgM (HIGM) syndrome: Similar infections as XLA. Pneumocystis jiroveci pneumonia is possible as initial presentation. Defect of either B-cell isotype switching from IgM-secreting to IgG, A, or E (HIGM 1 to 4: autosomal recessive [AR], NEMO) or helper T cell inability to signal/activate B cells (X-linked: Xq26 and formerly a T cell PID). Serum IgM concentration is polyclonal and normal to elevated.
  • Plasma cell deficiency; may have normal immunoglobulins that transiently decrease with infections or sustained hypogammaglobulinemia (2)
  • T cells (cellular-mediated immunodeficiencies): defects in maturation or function of T lymphocytes predisposed to infections such as Candida, parasite, and P. jiroveci:
    • 22q11.2 deletion syndrome/DiGeorge syndrome: defect of embryogenesis. Involved structures include thymus, parathyroid, and aortic arch. De novo or autosomal dominant (AD). Prevalence is ~1:4,000. Normally diagnosed in infancy. Characteristics (CATCH 22): cardiac abnormalities, hypognathus, long philtrum, low-set ears, hypertelorism, downward slanted eyes, “carp-shaped” mouth, thymic abnormalities (absent thymic shadow), cleft palate, hypoparathyroidism
    • Immune dysregulation polyendocrinopathy enteropathy X-linked (IPEX): classically presents as a syndrome of diarrhea, polyendocrinopathy, and fatal infection in infancy. Involves neonatal-onset diabetes mellitus, hypothyroidism, enteritis (diarrhea/villous atrophy), hemolytic anemia and thrombocytopenia, and dermatitis. Death normally occurs by 1 to 2 years of age. Missense mutations in FOXP3 result in impaired development and function of CD4+, CD25, and regulatory T cells and may repress cytokine promoters.
  • Combined immunodeficiencies: defects in the cellular effector and humoral mechanisms directly involving a combination of B and T lymphocytes and NK cells. Typically present as failure to thrive, often associated with diarrhea and severe eczema:
    • Severe combined immunodeficiency (SCID): Depending on mutation, patients may have absent T cells with/without impairment to B cells and/or NK cells. Presents in infancy with failure to thrive, recurrent or persistent thrush, and gastrointestinal illnesses. Prevalence 1/50,000 to 100,000. If treatment is unsuccessful or delayed, death normally occurs before 1 to 2 years of age; X-linked, AR, and known mutations in adenosine deaminase deficiency gene, purine nucleoside phosphorylase deficiency gene, interleukin-γ chain, JAK3, CD45, ZAP70, RAG1, and RAG2
    • Others: Wiskott-Aldrich syndrome (X-linked), MHC II deficiency, and ataxia telangiectasia (AR)
  • Phagocytic immunodeficiencies: defects in the function and/or quantity of phagocyte cells. Recurrent pyogenic infections with staphylococcal species, Aspergillus, Klebsiella, and Pseudomonas. Granuloma formation and poor wound healing are common.
    • Chronic granulomatous disease: 90% inherited disorder (X-linked and AR) of phagocytic cells; results from an inability of phagocytes to undergo respiratory burst (key enzyme: NADPH oxidase). Recurrent life-threatening bacterial and fungal infections, often involving lymph nodes, liver, spleen, and skin. Normally occurs early in life. X-linked: mutation of cytochrome gp91 or b558 genes, called CYBB; AR: chromosome 7, NCF1 (p47phox) gene
    • Leukocyte adhesion deficiency: an AR disorder resulting in a dysfunction of cell surface adhesion. The defect is in CD18; important in stabilizing macrophage interaction with T cells and bacterial opsonization. Delayed separation of the umbilical cord may be seen in the neonatal period. Later in life, recurrent pyogenic infections without pus formation are common.
    • Glucose-6-phosphate dehydrogenase deficiency: X-linked (Xq28) defect preventing generation of NADPH via the hexose monophosphate shunt. Lack of NADPH oxidase produces a clinical picture similar to CGD; later age of onset (>10 years): commonly presents as hemolytic anemia
    • Myeloperoxidase deficiency: facilitates the oxidation of chloride and iodide by hydrogen peroxide. Deficiency results in the attenuation of bactericidal PMNs activity. Most individuals are asymptomatic, but some may have recurrent candidal infections; AR: 17q21.3–q23
    • Other examples: Chédiak-Higashi syndrome and lazy leukocyte syndrome
  • Complement deficiencies: inherited or acquired; complete or partial
    • Classical (C1, C4, C2): immune complex diseases (e.g., discoid or SLE, pneumococcal infections)
    • Alternative (properdin, factor B, factor D): severe fulminant pyogenic neisserial infections with a high mortality rate
    • Mannose-binding lectin: recurrent infections, accelerated course of SLE and RA
    • Other examples: C3, factor H, and factor I (pyogenic bacterial infections); terminal pathway C5–C9 (neisserial and bacterial infections)
  • Gene regulatory protein defects
    • (STAT1) Chronic mucocutaneous candidiasis: a heterogenous group of disorders involving recurrent Candida infections. May occur anywhere on the body and at any point in life. Disease can be familial (STAT1: AD). Although Candida is the defining infection, it may include others. Endocrine abnormalities are common.
    • (STAT3) Hyper-IgE syndrome: recurrent severe staphylococcal abscesses (skin, lungs, and viscera). Characteristic facial features include prominent forehead, deep-set eyes, broad nasal bridge, wide fleshy nasal tip, mild prognathism, facial asymmetry, and hemihypertrophy. Extremely high serum IgE, elevated serum IgD, and normal concentrations of IgG, IgA, and IgM; STAT3 gene mutation (AD with incomplete penetrance) (3)
    • (STAT5B) deficiency: early onset diarrhea, eczema, splenomegaly. Dwarfism, prominent forehead, and saddle nose. Normal growth hormone level, low insulin-like growth factor-1; immune deficiency: reduction in number of FOXP3+ Tregs, low NK cells
  • Secondary immunodeficiency disease: either acquired as a result of age, malnutrition, pregnancy, illness (autoimmune, cancers, leukemias, HIV), treatment(s) (chemotherapy, corticosteroids, immunosuppressants, radiation), or injury (burns, trauma). May be transient (newborn) or permanent (HIV); more common than PID and tends to occur later in life

General Prevention

  • Early identification is key to prevent infection and possible comorbidity. For newborns with known family history, consider genetic counseling and prenatal diagnostic testing.
  • Proper hygiene and nutrition for all ages regardless of type of immunodeficiency
  • For certain secondary immunodeficiencies such as HIV and hepatitis B and C, emphasize safe needle practices and safe sexual practices.

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