Sex-specific circulating unconventional neutrophils determine immunological outcome of auto-inflammatory Behçet's uveitis Neutrophils are the most abundant immune cells that first respond to insults in circulation. Although associative evidence suggests that differences in neutrophils may be linked to the sex-specific vulnerability of inflammatory diseases, mechanistic links remain elusive. Here, we identified extensive sex-specific heterogeneity in neutrophil composition under normal and auto-inflammatory conditions at single-cell resolution. Using a combination of single-cell RNA sequencing analysis, neutrophil-specific genetic knockouts and transfer experiments, we discovered dysregulation of two unconventional (interferon-α responsive and T cell regulatory) neutrophil subsets leading to male-biased incidence, severity and poor prognosis of auto-inflammatory Behçet's uveitis. Genome-wide association study (GWAS) and exosome study revealed that male-specific negative effects of both genetic factors and circulating exosomes on unconventional neutrophil subsets contributed to male-specific vulnerability to disease. Collectively, our findings identify sex-specifically distinct neutrophil subsets and highlight unconventional neutrophil subsets as sex-specific therapeutic targets to limit inflammatory diseases. Disease affects females and males differently, and sex-specific health differences are of particular interest. Differences in immune responses between females and males are well-recognized but ambiguous. Females have more effective immune responses fighting against immunization and infection, but are more likely to develop an autoimmune disease. Males are more prone to neurodegenerative diseases and cardiovascular diseases such as Parkinson's disease and myocardial infarction. Some of these cases may come down to genetic differences that are the results of differential X-chromosome inactivation, sex hormone level, gender, behavior, or life experiences. Identifying mechanisms underlying sex-related differences is essential for developing approaches to effectively modulate immune responses. The cellular immune response is an essential component of immune defense. Neutrophils, as first effector cells of the innate immune system, are involved in a diverse array of immunological and inflammatory processes. Under homeostatic conditions, neutrophils patrol the blood and tissues for the detection of stimuli, where they contribute to various physiological functions, including angiogenesis, coagulation and tissue repair. Different from autoimmune diseases, auto-inflammatory diseases are a group of inflammatory diseases characterized by recurrent and systemic inflammation caused by dysregulation of the innate immune system instead of perturbations in adaptive immune system. Behçet's disease is a heterogeneous auto-inflammatory vasculitis mainly involving neutrophils, with elevated prevalence in men and individuals of non-Swedish ancestry along the silk route. Uveitis is an intraocular inflammation which is one of the most severe and frequent manifestations of Behçet's disease. Although neutrophils have recently been reported as a critical factor in the pathogenesis of several systemic auto-inflammatory diseases, including but not limited to Behçet's uveitis (BU), the study of their sex-specific differences hasSex-specific circulating unconventional neutrophils determine immunological outcome of auto-inflammatory Behçet's uveitis Neutrophils are the most abundant immune cells that first respond to insults in circulation. Although associative evidence suggests that differences in neutrophils may be linked to the sex-specific vulnerability of inflammatory diseases, mechanistic links remain elusive. Here, we identified extensive sex-specific heterogeneity in neutrophil composition under normal and auto-inflammatory conditions at single-cell resolution. Using a combination of single-cell RNA sequencing analysis, neutrophil-specific genetic knockouts and transfer experiments, we discovered dysregulation of two unconventional (interferon-α responsive and T cell regulatory) neutrophil subsets leading to male-biased incidence, severity and poor prognosis of auto-inflammatory Behçet's uveitis. Genome-wide association study (GWAS) and exosome study revealed that male-specific negative effects of both genetic factors and circulating exosomes on unconventional neutrophil subsets contributed to male-specific vulnerability to disease. Collectively, our findings identify sex-specifically distinct neutrophil subsets and highlight unconventional neutrophil subsets as sex-specific therapeutic targets to limit inflammatory diseases. Disease affects females and males differently, and sex-specific health differences are of particular interest. Differences in immune responses between females and males are well-recognized but ambiguous. Females have more effective immune responses fighting against immunization and infection, but are more likely to develop an autoimmune disease. Males are more prone to neurodegenerative diseases and cardiovascular diseases such as Parkinson's disease and myocardial infarction. Some of these cases may come down to genetic differences that are the results of differential X-chromosome inactivation, sex hormone level, gender, behavior, or life experiences. Identifying mechanisms underlying sex-related differences is essential for developing approaches to effectively modulate immune responses. The cellular immune response is an essential component of immune defense. Neutrophils, as first effector cells of the innate immune system, are involved in a diverse array of immunological and inflammatory processes. Under homeostatic conditions, neutrophils patrol the blood and tissues for the detection of stimuli, where they contribute to various physiological functions, including angiogenesis, coagulation and tissue repair. Different from autoimmune diseases, auto-inflammatory diseases are a group of inflammatory diseases characterized by recurrent and systemic inflammation caused by dysregulation of the innate immune system instead of perturbations in adaptive immune system. Behçet's disease is a heterogeneous auto-inflammatory vasculitis mainly involving neutrophils, with elevated prevalence in men and individuals of non-Swedish ancestry along the silk route. Uveitis is an intraocular inflammation which is one of the most severe and frequent manifestations of Behçet's disease. Although neutrophils have recently been reported as a critical factor in the pathogenesis of several systemic auto-inflammatory diseases, including but not limited to Behçet's uveitis (BU), the study of their sex-specific differences has