Pathogenesis of Autoimmunity/Systemic Lupus Erythematosus (SLE)

Area of Science:

• Immunology
• Rheumatology
• Autoimmune Diseases

Background:

• Systemic Lupus Erythematosus (SLE) is defined by diverse autoantibodies and organ damage.
• Identifying the specific factor causing SLE requires it to induce, persist in, and resolve with SLE.
• Previous candidates like interferon-alpha and BAFF (B cell activating factor) did not fully meet these criteria.

Purpose of the Study:

• To review and identify the definitive causative factor of Systemic Lupus Erythematosus (SLE).
• To evaluate candidate factors against established criteria for disease causation.
• To explore the role of T follicular helper (Tfh) cells and infection in SLE pathogenesis.

Main Methods:

• Review of existing literature on potential SLE-causing factors.
• Analysis of genetic models (BXSB mice, sanroque mice) and their association with SLE.
• Investigation of T follicular helper (Tfh) cell populations, including DOCK8-positive Tfh cells, in SLE pathogenesis.
• Application of self-organized criticality theory to understand infection-driven autoimmunity.

Main Results:

• Genetic factors like duplicated TLR7 and the Sle1 gene are implicated in SLE development.
• Mutations affecting ICOS regulation lead to increased Tfh cells, IL-21, and SLE.
• DOCK8-positive Tfh cells, generated post-infection (e.g., SARS-CoV-2), fulfill all criteria for causing SLE.
• Therapies targeting DOCK8-positive Tfh cells or DOCK8 itself showed promise in reducing SLE manifestations.

Conclusions:

• DOCK8-positive Tfh cells, arising from repeated infections, are identified as the causative factor for SLE.
• These autoreactive Tfh cells drive autoantibody production and SLE pathogenesis.
• Targeting DOCK8-positive Tfh cells represents a potential therapeutic strategy for SLE.