What is the mechanism of systemic lupus erythematosus (SLE)?

Mechanism of Systemic Lupus Erythematosus (SLE)

Systemic lupus erythematosus is fundamentally driven by a complex interplay between genetic susceptibility and environmental factors that leads to dysregulation of both innate and adaptive immune systems, with type-1 interferon pathway dysfunction serving as a common denominator. 1, 2

Key Pathogenic Mechanisms

Genetic Factors

• Multiple susceptibility genes have been identified, including:
  • Immune regulatory genes (IRF5, PTPN22, CTLA4, STAT4, BANK1) 3
  • PD-1 pathway genes 4
  • Interferon pathway genes 4
• No single gene is entirely responsible, but collectively they create predisposition 3

Immune System Dysregulation

Innate Immune System Abnormalities

• Neutrophil dysfunction and NETs (Neutrophil Extracellular Traps):

  • Release nuclear material that serves as autoantigens 5
  • Contribute to tissue damage and inflammation

• Plasmacytoid dendritic cells and Type I interferons:

  • Overproduction of type I interferons 5
  • Central to disease pathogenesis 1, 2

• Monocyte/macrophage abnormalities:

  • Aberrant phenotype and function 6
  • Defective clearance of apoptotic debris
  • Abnormal cytokine production

• Complement dysregulation:

  • Low complement levels contribute to impaired clearance of immune complexes 1
  • Functional asplenia further compromises immune function 1

Adaptive Immune System Abnormalities

• B cell abnormalities:

  • Loss of B cell tolerance to self-antigens 5, 7
  • Production of autoantibodies against nuclear components
  • Formation of circulating immune complexes (CIC)

• T cell dysfunction:

  • Abnormal T cell signaling and activation 5
  • Impaired regulatory T cell function
  • Enhanced T cell help for autoantibody production

Autoantigen Exposure and Immune Complex Formation

• Abnormal apoptosis and inefficient clearance:

  • Intracellular components (nucleosomes, DNA) persist in extracellular environment 7
  • These serve as autoantigens for immune recognition

• Immune complex deposition:

  • Autoantibodies bind to self-antigens forming immune complexes 1
  • These deposit in blood vessels and tissues throughout the body
  • Trigger complement activation and tissue inflammation

Environmental Triggers

• UV radiation:

  • Induces DNA damage and apoptosis 2
  • Releases nuclear antigens that trigger autoimmune responses

• Infections:

  • Viral infections (e.g., CMV) can trigger disease onset or flares 2
  • Molecular mimicry between microbial and self-antigens 1
  • TLR activation by microbial molecules 1

• Medications:

  • Certain drugs can trigger lupus-like syndromes 2
  • Examples include TNF-α inhibitors, procainamide, hydralazine, minocycline

Disease Perpetuation Cycle

1. Environmental triggers in genetically susceptible individuals
2. Enhanced cell death and impaired clearance of cellular debris
3. Exposure of nuclear autoantigens
4. Activation of innate immune cells (dendritic cells, neutrophils)
5. Production of inflammatory cytokines, especially type I interferons
6. Activation of autoreactive B and T cells
7. Production of autoantibodies
8. Formation of immune complexes
9. Deposition in tissues and blood vessels
10. Complement activation and tissue inflammation
11. Organ damage
12. Further release of autoantigens, perpetuating the cycle

Clinical Implications

• SLE affects multiple organ systems due to widespread immune complex deposition 1
• Disease heterogeneity reflects the complex interplay of genetic and environmental factors 3
• Patients have increased susceptibility to infections due to immune dysregulation and immunosuppressive treatments 1
• Preventive strategies include photo-protection, smoking cessation, and vaccinations 2

This complex pathogenesis explains why SLE treatment requires a multifaceted approach targeting different aspects of the immune dysregulation, with antimalarials as cornerstone therapy and judicious use of immunosuppressants for organ-threatening disease 1, 2.