BackgroundImmunoglobulin G4-related disease (IgG4-RD) is a newly defined disease entity, with great heterogeneity among IgG4-RD subgroups with different organ involvement patterns. Identification of the proteomic characteristics of IgG4-RD subgroups will be critical for the understanding of the pathogenic mechanisms of IgG4-RD. MethodIn this study, we performed proteomic analysis using Tandem Mass Tags (TMT) technology with "high field" mass analyzer with improved resolution and sequencing speed to investigate the proteomic profile of saliva and plasma samples from ten untreated IgG4-RD patients and five healthy controls (HCs). Differentially expressed proteins (DEPs) were identified by "t test" function in R package. Functional enrichment analysis was used to investigate pathways enriched in IgG4-RD samples. ResultsMost salivary DEPs identified in IgG4-RD patients compared with HCs were mainly enriched in neutrophil mediated GO bioprocess. Within the comparisons between four IgG4-RD subgroups, more DEPs were identified in the comparison of Mikulicz group and Head and neck group. Among four subgroups of IgG4-RD, Head and neck group showed the most distinctive proteomic expression pattern when compared with HCs. Moreover, "Neutrophil mediated process" related GO bioprocess was commonly identified between comparisons of Mikulicz group and Head and neck group, Head and neck group and Retroperitoneal aorta group, Head and neck group and HCs, IgG4-RD patients with saliva gland involvement and those without saliva gland involvement. Key DEPs that involved in this GO bioprocess were identified. Besides, we performed proteomic analysis for plasma samples between ten IgG4-RD and five HCs and there were several DEPs identified overlapped in saliva and plasma. ConclusionWe identified multiple processes/factors and several signaling pathways in saliva that may be involved in the IgG4-RD pathogenesis.