Innate Immune System Defects Summary

Innate Immune System Overview

  • First line of defense against pathogens.
  • Includes:
    • Physical barriers (skin, mucosa).
    • Cells (neutrophils, NK cells).
    • Pattern recognition receptors (PRRs).
    • Complement proteins.
    • Cytokines.
  • Defects lead to susceptibility to infections.

When to Suspect Innate Immunodeficiency

  • Recurrent bacterial, mycobacterial, viral, or fungal infections.
  • Particularly with autoimmunity symptoms.

Toll-Like Receptor (TLR) Defects

  • TLRs recognize pathogen-associated molecular patterns (PAMPs).
  • Activate inflammatory cascades via NF-κB.
  • Defects include mutations in NEMO, IKBA, MyD88, IRAK4.
  • Classical pathway activated by all TLRs except TLR3.
  • TLRs 3 and 4 activate an alternative pathway.

NEMO Deficiency and IκBα Mutations

  • NEMO (IKBKG) mutations: X-linked, variable phenotypes.
  • IKBA mutations: autosomal dominant, similar phenotype to NEMO.
  • Clinical: recurrent infections, ectodermal dysplasia.
  • Lab: impaired antibody responses, lymphocyte proliferation.
  • Treatment: antibiotic prophylaxis, IgG replacement, HSCT.

MyD88 and IRAK-4 Deficiencies

  • Impaired TLR and IL-1R mediated immunity.
  • Recurrent bacterial infections in infancy, improve with age.
  • Lack fever/inflammation signs during infection.
  • Normal immunoglobulin levels, impaired pneumococcal responses.
  • Treatment: prophylactic antibiotics, immunizations.

Susceptibility to Herpes Simplex Encephalitis (HSE)

  • TLR3 pathway defects: TLR3, TRAF3, TRIF, TBK1, UNC93B1, IRF3 deficiencies.
  • HSE in childhood.
  • Normal immune screening tests.
  • Treatment: aggressive antiviral treatment, prophylaxis, IFN-α.

Other Viral Infections

  • STAT2, IRF7, IFNAR2 deficiencies: severe viral illnesses.

Type 1 Interferonopathies

  • Aicardi-Goutières syndrome (AGS): encephalopathy, microcephaly, autoimmunity; due to TREX1, RNASEH2B, RNASEH2C, RNASEH2A, SAMHD1, ADAR1 defects.
  • SPENCD: skeletal dysplasia, neurological dysfunction, autoimmunity; caused by ACP5 mutations.

Mendelian Susceptibility to Mycobacterial Disease (MSMD)

  • Defects in IL-12/IFN-γ axis.
  • Susceptibility to weakly virulent mycobacteria and Salmonella.
  • Mutations in IFNGR1/2, IL12B, IL12RB1, STAT1, etc.
  • Treatment: aggressive treatment of infections, recombinant IFN-γ, HSCT.

Chronic Mucocutaneous Candidiasis (CMC)

  • Persistent fungal infections of skin, nails, mucosae.
  • Defects in TLRs, C-type lectin receptors, CARD9, CLEC7A, IL-17, IL-17R, STAT1.
  • Treatment: antifungal prophylaxis, GM-CSF, HSCT.

Epidermodysplasia Verruciformis (EV)

  • Severe cutaneous papillomatosis caused by beta-HPV.
  • Mutations in EVER1/TMC6, EVER2/TMC8, CIB1.
  • Avoidance of UVB/radiation, skin cancer screening.

Isolated Congenital Asplenia (ICA)

  • Invasive infections with encapsulated bacteria.
  • Mutations in RPSA.
  • Vaccination and antibiotic prophylaxis.

Phagocyte Defects

  • Recurrent bacterial and fungal infections.
  • Neutrophil defects: severe congenital neutropenia (SCN), LAD, WHIM syndrome.
  • Treatment varies depending on the specific defect (G-CSF, HSCT, etc.).

Severe Congenital Neutropenia (SCN)

  • Neutrophil count < 0.5 \times 10^9
  • cells/L.
  • Mutations in ELANE, GFI1, HAX1, G6PC3 etc.

Leukocyte Adhesion Deficiency (LAD)

  • Impaired leukocyte trafficking.
  • LAD1: ITGB2 mutations.
  • LAD2: SLC35C1 mutations.
  • LAD3: FERMT3 mutations.

WHIM Syndrome

  • Warts, hypogammaglobulinemia, infections, myelokathexis.
  • CXCR4 and CXCR2 mutations.

Chronic Granulomatous Disease (CGD)

  • Defects in NADPH oxidase complex.
  • CYBB, CYBA, NCF1, NCF2, NCF4 mutations.

Natural Killer (NK) Cell Deficiencies (NKD)

  • Susceptibility to viral infections.
  • Classical NKD: GATA2, MCM4 mutations.
  • Functional NKD: FCGR3A mutations.

Complement Defects

  • Susceptibility to infections, autoimmunity, impaired immune complex clearance.
  • Deficiencies in C2, C3, C5-C9, Factor D, properdin, Factor H, Factor I, etc.
  • Treatment: vaccination, prophylactic antibiotics. Hemolytic assay to determine the functional activity of complement pathways. The CH50 assay used to test for deficiencies of the classical pathway components and the AH50 assay measures the functional activity of the alternative pathway. Falsely low CH50 levels can be seen with poor sample handling.