Fc-Mediated Immune Responses in Autoimmune Diseases

Autoimmune diseases arise when self-reactive antibodies engage the immune system through their crystallisable fragment (Fc) regions, driving chronic inflammation and tissue injury. Binding of the IgG Fc domain to Fc gamma receptors (FcγRs) on leukocytes triggers phagocytosis, antibody-dependent cellular cytotoxicity and pro-inflammatory cytokine production. Concurrently, Fc engagement of the complement cascade via C1q amplifies local damage through membrane attack complex formation. The fine-tuning of these activities is governed by Fc glycosylation patterns, subclass distribution and affinity for activating versus inhibitory receptors. Dysregulated Fc-mediated signalling underlies pathologies such as rheumatoid arthritis, systemic lupus erythematosus and vasculitis, while therapeutic approaches exploit intravenous immunoglobulin, Fc engineering and glycoengineering to restore immune balance and prevent end-organ injury.

Research from Nature Portfolio

Structural analysis of human IgG3 bound to complement components has revealed that its uniquely extended hinge promotes the formation of elevated hexameric Fc platforms, optimising C1 complex engagement and C4b deposition adjacent to Fab domains. Cryo-electron microscopy demonstrated that these hexameric arrays project above the antigen surface to enhance both complement activation and receptor binding, offering a blueprint for the design of next-generation antibody therapies in autoantibody-driven conditions.

Fc-Mediated Immune Responses in Autoimmune Diseases publication trend

The graph below shows the total number of articles in fc-mediated immune responses in autoimmune diseases across all publications each year (not limited to Nature Index journals).

Technical terms

Fc region: The constant portion of an antibody that interacts with Fc receptors and complement, mediating effector functions.

FcγR: A family of cell-surface receptors for IgG that can be activating (e.g. FcγRIII) or inhibitory (FcγRIIb), determining downstream immune responses.

Complement system: A cascade of plasma proteins, initiated by C1q binding to antibody Fc, that amplifies inflammation and forms membrane attack complexes.

Glycosylation: The enzymatic attachment of sugar moieties to the Fc region, critically regulating antibody structure, receptor binding and effector potency.

Antibody-dependent cellular cytotoxicity (ADCC): A mechanism by which Fc-bound target cells are lysed by effector cells bearing activating FcγRs, notably natural killer cells.

References

1. Immunoglobulin G-dependent inhibition of inflammatory bone remodeling requires pattern recognition receptor Dectin-1. Immunity (2023).
2. Complement is activated by elevated IgG3 hexameric platforms and deposits C4b onto distinct antibody domains. Nature Communications (2023).
3. Loci Associated with N-Glycosylation of Human Immunoglobulin G Show Pleiotropy with Autoimmune Diseases and Haematological Cancers. PLOS Genetics (2013).