FcRn is a CD32a coreceptor that determines susceptibility to IgG immune complex-driven autoimmunity

Area of Science:

• Immunology
• Autoimmunity
• Molecular Biology

Background:

• IgG immune complexes (ICs) drive autoimmune diseases by engaging Fc fragment crystallizable gamma receptors (FcγRs).
• The FcγRIIa (CD32a) histidine (H)-131 variant (CD32aH) is prevalent and linked to autoimmune diseases, but its specific mechanism remains unclear.
• FcγRs mediate cellular responses to IgG ICs, influencing innate and adaptive immunity.

Purpose of the Study:

• To elucidate the mechanism by which the FcγRIIaH variant promotes autoimmunity.
• To investigate the interaction between FcγRIIa variants, IgG ICs, and the neonatal Fc receptor (FcRn).
• To determine the role of FcRn in IgG IC-mediated inflammation and its potential as a therapeutic target.

Main Methods:

• Comparative binding assays of human IgG1 ICs to FcγRIIa variants (CD32aH vs. CD32aR).
• Analysis of ternary complex formation between FcγRIIa variants, IgG ICs, and FcRn under acidic conditions.
• Assessment of innate and adaptive immune responses in primary human and mouse cells stimulated with IgG ICs.
• In vivo studies using a rheumatoid arthritis model with FcRn blockade.

Main Results:

• FcγRIIaH exhibits higher avidity for human IgG1 ICs and forms a ternary complex with FcRn under acidic conditions compared to FcγRIIaR.
• Both FcγRIIa variants require FcRn for inducing immune responses to IgG ICs, with CD32aH showing augmented responses.
• FcRn can induce responses to IgG ICs independently of FcγR, but optimal responses necessitate both receptors.
• FcRn blockade reduced inflammation in a rheumatoid arthritis model, suggesting a direct role in IgG IC-associated inflammation.

Conclusions:

• FcγRIIa and FcRn act in concert to regulate IgG IC-mediated immunity, with a preference for the disease-associated CD32aH variant.
• This interaction provides a novel molecular mechanism explaining the strong association of CD32aH with human autoimmune diseases.
• FcRn blockade represents a potential therapeutic strategy for mitigating IgG IC-driven inflammation in autoimmune conditions.