The axis of complement C1 and nucleolus in antinuclear autoimmunity

Area of Science:

• Immunology
• Molecular Biology
• Autoimmunity

Background:

• Antinuclear autoantibodies (ANA) are self-reactive antibodies targeting nuclear components, implicated in systemic lupus erythematosus (SLE).
• While SLE is typically polygenic, complement deficiencies (C1q, C1r, C1s) can lead to a monogenic form, suggesting a role for the complement system.
• Nuclear regions, including chromatin, speckled areas, and nucleoli, contain intrinsic autoantigens and alarmins that can trigger autoimmune responses.

Purpose of the Study:

• To explore the intrinsic autoimmunogenicity of nuclear regions.
• To elucidate the role of complement C1 complex in regulating nuclear autoantigenicity.

Main Methods:

• Analysis of nuclear components and their associated autoantigens and alarmins.
• Investigation of the interaction between complement C1 complex (C1q, C1r, C1s) and nuclear components.
• Assessment of the effect of C1 proteases on nuclear autoantigens and alarmins.

Main Results:

• Necrotic cells release nucleosomes with HMGB1, activating TLRs and promoting anti-chromatin autoimmunity.
• Speckled regions contain snRNAs in Sm/RNP and SSA/Ro, contributing to their autoimmunogenicity.
• Nucleoli harbor GAR/RGG-containing alarmins, and C1q binding activates C1 proteases (C1r, C1s) which degrade HMGB1 and nucleolar autoantigens like nucleolin.

Conclusions:

• Nuclear regions possess inherent autoimmunogenicity due to the presence of autoantigens and alarmins.
• The extracellular complement C1 complex acts as a crucial regulator, dampening nuclear autoimmunogenicity by degrading these nuclear proteins.