Affinity-matured B cell responses neutralizing type-I interferons underlie severe viral infections

Area of Science:

• Immunology
• Virology
• Genetics

Background:

• Autoantibodies neutralizing type-I interferons (AAN-I-IFNs) are linked to severe viral infections.
• Understanding the origin and mechanisms of these autoantibodies is crucial for treating severe diseases.

Purpose of the Study:

• To investigate the characteristics of AAN-I-IFNs in patients with severe COVID-19 pneumonia.
• To explore the relationship between AAN-I-IFNs and T cell tolerance defects.
• To elucidate the structural basis of type-I IFN neutralization by patient-derived antibodies.

Main Methods:

• Analysis of circulating type-I IFN-specific B cells in AAN-I-IFNs+ patients.
• Comparison with patients having genetic T cell tolerance defects.
• X-ray crystallography and AlphaFold3 structural analysis of monoclonal antibodies.
• Epitope mapping of type-I IFNs targeted by autoantibodies.

Main Results:

• AAN-I-IFNs+ patients exhibit a diverse and stable B cell response targeting type-I IFNs, detectable before severe infection.
• This autoimmune response shares characteristics with genetic T cell tolerance defects.
• Structural analysis revealed antibodies targeting three major B cell epitopes across type-I IFNs.
• Antibodies demonstrated high affinity and neutralization potential for type-I IFNs via somatic hypermutation.

Conclusions:

• A pre-existing, germinal-center-derived memory B cell response against type-I IFNs is established before severe viral infection.
• This mechanism links T cell tolerance defects to pathogenic AAN-I-IFNs, underlying severe viral diseases.
• The findings provide insights into the pathogenesis of severe viral diseases driven by AAN-I-IFNs.