Sex-specific unconventional neutrophils determine immunological outcome in Behçet's uveitis
Purpose
Behçet's disease (BD) is a multi-systemic inflammatory vasculitis, with a high incidence and more serious course of intraocular inflammation (Behçet's uveitis, BU) in males. However, the etiology of male-biased Behçet's uveitis is largely unknown.
Methods
The retrospective study on 1,881 BU patients was performed to assess the sex-differences in the clinical manifestations and their correlation with neutrophils. Single cell sequencing was used to identify the sex-specific heterogeneity in neutrophil composition under normal and BU conditions at single-cell resolution. Neutrophil-specific genetic knockouts and transfer experiments were performed to determine the function of aberrant neutrophil subsets in vivo.
Results
The retrospective study on BU revealed male-biased exacerbated neutrophil responses and worse long-term prognosis. Male BU was enriched for conventional inflammatory neutrophil subsets compared with female BD, whereas unconventional neutrophil subsets characterized by IFN-α signaling and regulation of T cell activation were decreased. Mechanistically, we found that IFN-α2a treatment expanded circulating unconventional neutrophils and in turn induced the expansion of regulatory T cells. These results substantiate the therapeutic effect of IFN-α2a on the Behçet's uveitis pathogenesis. Accordingly, we further confirmed unconventional neutrophil subsets were able to directly regulate Th17 and Treg cell balance in EAU.
Conclusion
Our single-cell atlas defined sex-specific and disease-specific neutrophil heterogeneity in Behçet's uveitis pathogenesis and provided a resource characterizing the role of neutrophils in regulating peripheral immune homeostasis and Behçet's uveitis pathogenesis.
Conflict of interest
No
Authors 1
Last name
WANG
Initials of first name(s)
QF
Department
The First Affiliated Hospital of Chongqing Medical University
City
Chongqing
Country
China
Authors 2
Last name
Gao
Initials of first name(s)
Y
Department
Shanxi Medical University
City
Taiyuan
Country
China
Authors 3
Last name
Yang
Initials of first name(s)
PZ
Department
The First Affiliated Hospital of Chongqing Medical University
City
Chongqing
Country
China
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