Atypical memory B cell clonal expansion and inflammatory programs associate with platelet-activating antibody...

Area of Science:

• Immunology
• Molecular Biology
• Virology

Background:

• Patients with COVID-19 can develop platelet-activating antibodies, increasing thrombotic risk.
• The specific immune features driving this antibody response are not well-defined.

Purpose of the Study:

• To define the immune signatures differentiating COVID-19 patients with (PEA+) and without (PEA-) platelet-activating antibodies.
• To elucidate the B-cell and T-cell characteristics associated with platelet-activating antibody production.

Main Methods:

• Single-cell RNA sequencing of B- and T-cells.
• Single B-cell V(D)J sequencing.
• Plasma cytokine and chemokine analysis.

Main Results:

• PEA+ patients exhibited enriched inflammatory and antigen-presentation pathways in B-cells.
• Expanded atypical memory B-cells in PEA+ patients showed upregulated IFN-γ response, limited class switching, and RKH/Y5 heavy-chain motifs.
• T-cell profiling revealed IL-12 pathway enrichment, increased IFN-γ transcription, and elevated Th1 cytokines in PEA+ patients.

Conclusions:

• A coordinated inflammatory environment with Th1-skewed T-cell activation characterizes platelet-activating antibody development in COVID-19.
• Selective expansion of atypical memory B-cell clones with specific motifs is associated with this response.
• These findings define key immunologic features linked to heightened thrombotic risk in a subset of COVID-19 patients.