12.1 Primary immunodeficiencies

Primary immunodeficiencies are genetic disorders that impair the immune system's ability to fight infections. These conditions can affect various components of immunity, including T cells, B cells, phagocytes, and complement proteins, leading to recurrent or severe infections.

Understanding the classification and genetic basis of primary immunodeficiencies is crucial for diagnosis and treatment. This knowledge helps healthcare providers identify specific defects, predict inheritance patterns, and develop targeted management strategies to improve patients' quality of life and long-term outcomes.

Classification and Genetic Basis of Primary Immunodeficiencies

Types of primary immunodeficiencies

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• T cell deficiencies disrupt cellular immunity leading to severe infections
  • Severe combined immunodeficiency (SCID) causes profound T cell dysfunction resulting in life-threatening opportunistic infections
  • DiGeorge syndrome impairs thymus development affecting T cell maturation and function (cardiac defects, facial abnormalities)
• B cell deficiencies impair humoral immunity increasing susceptibility to encapsulated bacteria
  • X-linked agammaglobulinemia (XLA) blocks B cell development resulting in absent antibodies and recurrent infections
  • Common variable immunodeficiency (CVID) reduces antibody production causing recurrent sinopulmonary infections and autoimmune disorders
• Combined T and B cell deficiencies affect both cellular and humoral immunity
  • Wiskott-Aldrich syndrome impairs T and B cell function leading to eczema, thrombocytopenia, and recurrent infections
  • Ataxia-telangiectasia causes progressive neurodegeneration and immunodeficiency increasing cancer risk
• Phagocyte defects compromise innate immunity against bacteria and fungi
  • Chronic granulomatous disease (CGD) impairs phagocyte oxidative burst resulting in recurrent catalase-positive bacterial infections
  • Leukocyte adhesion deficiency (LAD) disrupts neutrophil migration causing delayed wound healing and severe bacterial infections
• Complement deficiencies increase susceptibility to specific pathogens
  • C1 inhibitor deficiency leads to hereditary angioedema causing recurrent swelling episodes
  • C3 deficiency increases susceptibility to encapsulated bacteria and impairs immune complex clearance

Genetics of immunodeficiencies

• X-linked inheritance affects males more severely
  • X-linked agammaglobulinemia (XLA) results from mutations in Bruton's tyrosine kinase (BTK) gene blocking B cell development
  • Wiskott-Aldrich syndrome stems from mutations in WAS gene affecting cytoskeletal regulation in immune cells
• Autosomal recessive inheritance requires two mutated alleles
  • Severe combined immunodeficiency (SCID) often caused by mutations in adenosine deaminase (ADA) gene disrupting lymphocyte development
  • Chronic granulomatous disease (CGD) results from mutations in CYBB gene (X-linked form) or NCF1, NCF2, or CYBA genes (autosomal recessive forms) impairing phagocyte function
• Autosomal dominant inheritance affects each generation
  • Hyper-IgE syndrome (Job's syndrome) caused by mutations in STAT3 gene leading to elevated IgE levels and recurrent infections
• Variable inheritance patterns complicate genetic counseling
  • Common variable immunodeficiency (CVID) associated with mutations in various genes (TNFRSF13B, ICOS, CD19) affecting B cell function and antibody production

Clinical Manifestations and Management of Primary Immunodeficiencies

Diagnosis of immunodeficiencies

• Common clinical presentations guide initial suspicion
  • Recurrent infections particularly with opportunistic pathogens
  • Failure to thrive in infants and children
  • Autoimmune disorders indicating dysregulated immunity
  • Malignancies especially lymphomas
• Diagnostic approaches employ multiple testing modalities
  • Complete blood count (CBC) with differential assesses cell populations
  • Immunoglobulin levels (IgG, IgA, IgM, IgE) evaluate antibody production
  • Lymphocyte subset analysis quantifies T, B, and NK cell populations
  • Neutrophil function tests assess phagocyte capabilities
  • Complement assays measure individual complement components
  • Genetic testing identifies specific mutations
    • Next-generation sequencing allows rapid multi-gene analysis
    • Whole exome sequencing detects novel mutations
• Specific manifestations and diagnostic tests for selected PIDs guide targeted evaluation
  • Severe combined immunodeficiency (SCID) presents with lymphopenia and absent T cell proliferation
  • X-linked agammaglobulinemia (XLA) shows absent B cells and low or absent immunoglobulins
  • Chronic granulomatous disease (CGD) diagnosed using dihydrorhodamine (DHR) flow cytometry test assessing oxidative burst

Management of immunodeficiencies

• Prophylactic measures reduce infection risk
  • Antimicrobial prophylaxis prevents common pathogens
  • Immunizations protect against vaccine-preventable diseases (avoiding live vaccines in some cases)
  • Hygiene practices minimize exposure to pathogens
• Immunoglobulin replacement therapy restores antibody levels
  • Intravenous immunoglobulin (IVIG) administered monthly
  • Subcutaneous immunoglobulin (SCIG) allows home administration
• Hematopoietic stem cell transplantation (HSCT) offers curative potential
  • Curative option for severe PIDs replacing defective immune system
  • Matching donor selection crucial for success
  • Conditioning regimens prepare recipient for engraftment
• Gene therapy emerges as promising treatment
  • Ex vivo gene correction of autologous stem cells
  • Clinical trials ongoing for specific PIDs (ADA-SCID, X-linked SCID)
• Enzyme replacement therapy addresses specific deficiencies
  • Adenosine deaminase (ADA) replacement for ADA-SCID improves immune function
• Management of complications requires vigilance
  • Prompt treatment of infections prevents severe sequelae
  • Monitoring for autoimmune disorders and malignancies enables early intervention
• Supportive care improves quality of life
  • Nutritional support ensures adequate growth and development
  • Growth hormone therapy addresses growth delays when indicated
• Patient education and genetic counseling empower families
  • Family planning discussions guide reproductive decisions
  • Lifestyle modifications minimize infection risk and optimize health