Immunological mechanisms underlying the clinical heterogeneity of Kikuchi disease: the potential role of atypical memory B cells.

Building on our previous research, which classified Kikuchi disease into three subtypes based on predominant symptoms and fever status - febrile type, febrile lymphadenopathy (FebLAP), and afebrile lymphadenopathy (aLAP) - we further investigated the underlying mechanisms contributing to their distinct clinical differences. Using NanoString nCounter technology, we analyzed the gene expression profiles of 35 Kikuchi disease lymph node specimens and compared them across the subtypes. Compared with the febrile type, aLAP exhibited higher AICDA expression, a trend observed in both germinal center positive and negative cases. The aLAP specimens also showed higher expression of B-cell markers; however, CD20 immunohistochemical staining did not reveal an increased number of B cells in aLAP. We therefore hypothesize that aLAP contains a higher proportion of atypical memory B cells, characterized by elevated AICDA and B-cell marker expression compared with other B-cell subsets. Immunohistochemical staining demonstrated that IRTA1+ atypical memory B cells were present in 64% (23/36) of aLAP cases, significantly higher than in FebLAP (0/8, 0%) and the febrile type (2/11, 18%) (p < 0.001). This finding confirms that aLAP is more likely to contain atypical memory B cells compared with the other subtypes. Pathway analysis revealed that the febrile type upregulates pathways associated with TLR2 and TLR4 signaling and neutrophil degranulation, while aLAP upregulates the TNFR2 non-canonical NF-κB pathway. RNAscope in situ hybridization demonstrated higher TLR4 expression in the febrile type compared with the aLAP type. These findings suggest that the triggering microbes for each subtype may differ, leading to distinct immune responses and clinical presentations. Overall, these results provide new insights into the immunopathogenesis of Kikuchi disease and highlight the potential role of atypical memory B cells in shaping its distinct clinical presentations. © 2026 The Pathological Society of Great Britain and Ireland.