What diseases primarily involve the innate immune system?

Diseases Primarily Involving the Innate Immune System

The innate immune system serves as the body's first line of defense against pathogens, and disorders affecting this system primarily include chronic granulomatous disease, complement deficiencies, phagocyte defects, Toll-like receptor signaling defects, and autoinflammatory disorders. 1

Components of the Innate Immune System

The innate immune system consists of several key components that work together to provide immediate protection against infections:

• Physical barriers: Integument and mucosa
• Antimicrobial elements: Complement and other factors in blood and body fluids
• Pattern recognition receptors: Toll-like receptors (TLRs)
• Cellular components: Phagocytes (neutrophils, macrophages) and natural killer (NK) cells 1, 2

Primary Disorders of the Innate Immune System

1. Phagocyte Disorders

• Chronic Granulomatous Disease (CGD)

  • Incidence: Approximately 1/200,000 live births
  • Characterized by defective phagocyte oxidative burst
  • Presents with recurrent infections with catalase-positive organisms
  • Patients develop granulomatous inflammation in multiple organs 1, 2

• Leukocyte Adhesion Deficiency (LAD)

  • Defective neutrophil migration to sites of infection
  • Presents with delayed umbilical cord separation, poor wound healing, and severe bacterial infections 2

2. Complement Deficiencies

• Relatively rare (<1% of all primary immunodeficiencies)
• Associated with:
  • Increased susceptibility to infections
  • Autoimmunity
  • Impaired immune complex clearance 1, 2

3. Pattern Recognition Receptor Defects

• TLR Signaling Defects
  • Mutations in NEMO, IKBA, MyD88, and IRAK4
  • Impaired recognition of pathogen-associated molecular patterns
  • Susceptibility to specific types of infections 2

4. Autoinflammatory Disorders

• Characterized by dysregulated inflammation without autoantibodies or autoreactive T cells
• Examples include:
  • Familial Mediterranean Fever
  • TNF receptor-associated periodic syndrome
  • Cryopyrin-associated periodic syndromes 1

5. NK Cell Defects

• Impaired early defense against viral infections and malignant cells
• Often present with severe or recurrent viral infections 2

Clinical Presentations of Innate Immune Disorders

Patients with innate immune system disorders typically present with:

• Infections with pathogens that are prevalent in the community but with unusual severity, frequency, and duration
• Poor response to standard antimicrobial therapy
• Infections with opportunistic or low-grade pathogens
• Specific patterns of infection based on the underlying defect:
  • Phagocyte disorders: Bacterial and fungal infections of skin, lungs, lymph nodes
  • Complement deficiencies: Encapsulated bacterial infections, meningococcal disease
  • TLR defects: Susceptibility to specific pathogens (e.g., herpes simplex encephalitis, mycobacterial infections) 1, 2

Innate Immune System in Disease Processes

Sepsis

• Involves dysregulated innate immune response with initial hyperactivation followed by immunosuppression
• Characterized by excessive production of pro-inflammatory cytokines (cytokine storm)
• Can lead to immune cell death and ongoing complications 3

Acute Respiratory Distress Syndrome (ARDS)

• Severe inflammatory responses increase vascular permeability
• Results in acute pulmonary edema and respiratory failure
• Often develops as a complication of sepsis 4

COVID-19

• Innate immune system acts as first line of defense against SARS-CoV-2
• Pattern recognition receptors sense the virus and activate inflammatory pathways
• Severe disease characterized by dysregulated inflammation, cytokine storm, and ARDS
• Involves monocyte and macrophage hyperactivation with increased pro-inflammatory cytokines (TNF-α, IL-6, IL-1, IFN-γ) 1, 5

Diagnostic Approach

When evaluating patients with suspected innate immune defects:

• Confirm the precise focus of infection and identify specific pathogens
• Look for characteristic patterns of infections
• Consider imaging, biopsy, and/or culture data to support diagnosis
• Rule out secondary causes of immunodeficiency (e.g., immunosuppressive therapies, malnutrition, HIV) 1

Clinical Pitfalls and Caveats

• Many innate immune disorders are rare but have significant morbidity and mortality
• Diagnosis is often delayed due to lack of awareness
• Not all recurrent infections indicate an immune deficiency - consider other conditions that increase infection susceptibility (cystic fibrosis, ciliary dyskinesia, anatomic abnormalities)
• Children with invasive pneumococcal disease should undergo immunologic investigation, as up to 26% of those older than 2 years have an identifiable primary immunodeficiency 1
• Autoimmune diseases and malignancies can be complications of primary immunodeficiencies and may sometimes be the presenting feature

Understanding the specific defect in the innate immune system is crucial for appropriate management and prevention of complications in affected patients.