Defects of Innate Immunity in Children

Introduction to Innate Immunity Defects in Children

Innate immunity is the body's first line of defense against pathogens. Defects in this system can lead to severe and recurrent infections in children. Key components of innate immunity include:

  • Physical barriers (skin, mucous membranes)
  • Cellular components (neutrophils, macrophages, NK cells)
  • Humoral factors (complement system, antimicrobial peptides)
  • Pattern recognition receptors (e.g., Toll-like receptors)

Defects in any of these components can compromise a child's ability to fight infections effectively, leading to a variety of clinical presentations and increased susceptibility to specific pathogens.

Toll-like Receptor (TLR) Defects

TLRs are crucial for recognizing pathogen-associated molecular patterns (PAMPs) and initiating immune responses. Defects in TLR signaling can lead to severe infections.

Common TLR Defects:

  • IRAK-4 Deficiency: Affects TLR and IL-1R signaling, leading to recurrent pyogenic infections.
  • MyD88 Deficiency: Similar to IRAK-4 deficiency, causes susceptibility to pyogenic bacteria.
  • TLR3 Deficiency: Increases susceptibility to herpes simplex encephalitis.

Clinical presentation often includes recurrent invasive bacterial infections, particularly with Streptococcus pneumoniae, Staphylococcus aureus, and Pseudomonas aeruginosa. Patients may have normal inflammatory markers despite severe infections.

Complement System Deficiencies

The complement system plays a crucial role in pathogen opsonization, inflammation, and membrane attack complex formation. Deficiencies can lead to increased susceptibility to infections and autoimmune disorders.

Key Complement Deficiencies:

  • C3 Deficiency: Severe recurrent pyogenic infections, autoimmune diseases.
  • C1q, C1r, C1s, C4 Deficiencies: Associated with systemic lupus erythematosus (SLE)-like syndrome.
  • Terminal Complement Deficiencies (C5-C9): Increased susceptibility to Neisseria infections.
  • Properdin Deficiency: X-linked disorder, increased risk of meningococcal infections.

Diagnosis involves measuring complement levels and functional assays. Treatment focuses on infection prevention, prompt antibiotic therapy, and in some cases, complement replacement therapy.

Phagocyte Disorders

Phagocytes, including neutrophils and macrophages, are essential for innate immune defense. Disorders affecting phagocyte number or function can lead to severe bacterial and fungal infections.

Major Phagocyte Disorders:

  • Chronic Granulomatous Disease (CGD): Defect in NADPH oxidase, leading to impaired respiratory burst and intracellular killing.
  • Leukocyte Adhesion Deficiency (LAD): Impaired leukocyte migration to infection sites.
  • Chediak-Higashi Syndrome: Defective lysosomal trafficking protein, affecting granule formation and function.
  • Severe Congenital Neutropenia: Various genetic causes leading to severely reduced neutrophil counts.

Clinical features include recurrent bacterial and fungal infections, often affecting the skin, lungs, and lymph nodes. Diagnosis involves functional assays (e.g., nitroblue tetrazolium test for CGD) and genetic testing. Management includes prophylactic antibiotics, antifungals, and in some cases, hematopoietic stem cell transplantation.

Natural Killer (NK) Cell Deficiencies

NK cells are critical for early defense against viral infections and tumor surveillance. Deficiencies in NK cell number or function can lead to severe viral infections and increased cancer risk.

Types of NK Cell Deficiencies:

  • Classical NK Cell Deficiency: Absence or profound reduction of NK cells.
  • Functional NK Cell Deficiency: Normal NK cell numbers but impaired function.

Clinical presentation often includes severe herpesvirus infections (especially with varicella-zoster virus and cytomegalovirus), respiratory viral infections, and HPV-associated cancers. Diagnosis involves flow cytometry to assess NK cell numbers and functional assays to evaluate cytotoxicity. Treatment may include antiviral prophylaxis and, in severe cases, hematopoietic stem cell transplantation.

Diagnosis and Management of Innate Immunity Defects

Diagnosing and managing innate immunity defects in children requires a comprehensive approach:

Diagnostic Approach:

  • Detailed medical history and family history
  • Physical examination for signs of recurrent infections or associated syndromes
  • Laboratory tests: Complete blood count, immunoglobulin levels, complement levels
  • Functional assays: Neutrophil function tests, NK cell cytotoxicity assays
  • Genetic testing for suspected specific defects

Management Strategies:

  • Prophylactic antibiotics and/or antifungals
  • Immunoglobulin replacement therapy in some cases
  • Cytokine therapies (e.g., G-CSF for neutropenia)
  • Hematopoietic stem cell transplantation for severe defects
  • Gene therapy (emerging option for some disorders)
  • Patient and family education on infection prevention
  • Regular follow-up and monitoring for complications

Early diagnosis and appropriate management are crucial for improving outcomes and quality of life for children with innate immunity defects. A multidisciplinary approach involving immunologists, infectious disease specialists, and other relevant subspecialties is often necessary for optimal care.



Defects of Innate Immunity in Children
  1. What is innate immunity?
    Innate immunity is the first line of defense against pathogens, consisting of physical barriers, cellular components, and soluble factors that respond rapidly to infection.
  2. Which cells are primarily involved in innate immunity?
    Neutrophils, macrophages, dendritic cells, natural killer cells, and epithelial cells are primarily involved in innate immunity.
  3. What are pattern recognition receptors (PRRs)?
    Pattern recognition receptors are proteins expressed by cells of the innate immune system that recognize pathogen-associated molecular patterns (PAMPs).
  4. What is the function of Toll-like receptors (TLRs)?
    Toll-like receptors recognize specific PAMPs and activate signaling pathways that lead to the production of inflammatory cytokines and type I interferons.
  5. What is the underlying defect in IRAK-4 deficiency?
    IRAK-4 deficiency is caused by mutations in the IRAK4 gene, which impairs signaling through multiple Toll-like receptors and IL-1 receptors.
  6. Which pathogens are patients with IRAK-4 deficiency particularly susceptible to?
    Patients with IRAK-4 deficiency are particularly susceptible to invasive pneumococcal infections and staphylococcal infections.
  7. What is the role of complement in innate immunity?
    The complement system enhances phagocytosis, promotes inflammation, and directly lyses some pathogens through the formation of membrane attack complexes.
  8. What is the most common complement deficiency?
    C2 deficiency is the most common complement deficiency.
  9. Which complement deficiency is associated with an increased risk of Neisseria infections?
    Deficiencies in the terminal complement components (C5-C9) are associated with an increased risk of Neisseria infections.
  10. What is the underlying defect in C1 inhibitor deficiency?
    C1 inhibitor deficiency leads to uncontrolled activation of the classical complement pathway, resulting in hereditary angioedema.
  11. What is the role of mannose-binding lectin (MBL) in innate immunity?
    Mannose-binding lectin is a pattern recognition molecule that activates the lectin pathway of complement and enhances phagocytosis.
  12. What is the clinical significance of MBL deficiency?
    MBL deficiency is associated with an increased susceptibility to respiratory tract infections, particularly in young children.
  13. What is the underlying defect in chronic mucocutaneous candidiasis?
    Chronic mucocutaneous candidiasis can be caused by defects in the IL-17 signaling pathway, including mutations in STAT1, STAT3, or IL-17 receptor genes.
  14. What is the role of NK cells in innate immunity?
    Natural killer cells recognize and kill virus-infected cells and tumor cells without prior sensitization.
  15. What is the underlying defect in familial hemophagocytic lymphohistiocytosis (FHL)?
    Familial hemophagocytic lymphohistiocytosis is caused by defects in proteins involved in the cytotoxic function of NK cells and CD8+ T cells.
  16. What is the characteristic finding in patients with NEMO deficiency?
    Patients with NEMO deficiency have ectodermal dysplasia and susceptibility to pyogenic infections due to impaired NF-κB signaling.
  17. What is the underlying defect in X-linked agammaglobulinemia (XLA)?
    X-linked agammaglobulinemia is caused by mutations in the BTK gene, leading to a lack of mature B cells and severe antibody deficiency.
  18. What is the role of type I interferons in innate immunity?
    Type I interferons play a crucial role in antiviral immunity by inducing an antiviral state in cells and enhancing the function of immune cells.
  19. What is the underlying defect in chronic granulomatous disease (CGD)?
    Chronic granulomatous disease is caused by defects in the NADPH oxidase complex, impairing the ability of phagocytes to generate reactive oxygen species.
  20. What is the role of autophagy in innate immunity?
    Autophagy plays a role in the clearance of intracellular pathogens, antigen presentation, and regulation of inflammatory responses.
  21. What is the underlying defect in Mendelian susceptibility to mycobacterial diseases (MSMD)?
    MSMD is caused by defects in the IL-12/IFN-γ axis, leading to increased susceptibility to mycobacterial infections.
  22. What is the role of antimicrobial peptides in innate immunity?
    Antimicrobial peptides are small proteins that directly kill microorganisms and modulate immune responses.
  23. What is the underlying defect in WHIM syndrome?
    WHIM syndrome is caused by gain-of-function mutations in the CXCR4 chemokine receptor, leading to impaired neutrophil egress from the bone marrow.
  24. What is the role of inflammasomes in innate immunity?
    Inflammasomes are cytoplasmic protein complexes that activate inflammatory caspases, leading to the production of IL-1β and IL-18.
  25. What is the underlying defect in cryopyrin-associated periodic syndromes (CAPS)?
    CAPS are caused by gain-of-function mutations in the NLRP3 gene, leading to excessive activation of the NLRP3 inflammasome and overproduction of IL-1β.
  26. What is the role of NOD-like receptors (NLRs) in innate immunity?
    NOD-like receptors are intracellular pattern recognition receptors that recognize bacterial peptidoglycan and activate inflammatory responses.
  27. What is the underlying defect in X-linked lymphoproliferative disease (XLP)?
    XLP is caused by mutations in the SH2D1A or XIAP genes, leading to impaired NK cell and T cell function, particularly in response to Epstein-Barr virus infection.
  28. What is the role of neutrophil extracellular traps (NETs) in innate immunity?
    Neutrophil extracellular traps are networks of extracellular fibers composed of DNA, histones, and antimicrobial proteins that trap and kill pathogens.
  29. What is the underlying defect in DOCK8 deficiency?
    DOCK8 deficiency is caused by mutations in the DOCK8 gene, leading to impaired T cell and NK cell function, as well as defects in B cell memory.
  30. What is the role of the acute phase response in innate immunity?
    The acute phase response is a systemic reaction to infection or injury, characterized by the production of acute phase proteins that enhance host defense and modulate inflammation.


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