Unbiased immune profiling reveals a natural killer cell-peripheral nerve axis in fibromyalgia

The pathophysiology of fibromyalgia syndrome (FMS) remains elusive, leading to a lack of objective diagnostic criteria and targeted treatment. We globally evaluated immune system changes in FMS by conducting multiparametric flow cytometry analyses of peripheral blood mononuclear cells and identified a natural killer (NK) cell decrease in patients with FMS. Circulating NK cells in FMS were exhausted yet activated, evidenced by lower surface expression of CD16, CD96, and CD226 and more CD107a and TIGIT. These NK cells were hyperresponsive, with increased CCL4 production and expression of CD107a when co-cultured with human leukocyte antigen null target cells. Genetic and transcriptomic pathway analyses identified significant enrichment of cell activation pathways in FMS driven by NK cells. Skin biopsies showed increased expression of NK activation ligand, unique long 16-binding protein, on subepidermal nerves of patients FMS and the presence of NK cells near peripheral nerves. Collectively, our results suggest that chronic activation and redistribution of circulating NK cells to the peripheral nerves contribute to the immunopathology associated with FMS.

Automated summary

The pathophysiology of fibromyalgia syndrome (FMS) is still unknown. This study found that patients with FMS had a decrease in natural killer (NK) cells, which were exhausted yet activated. Genetic and transcriptomic analysis showed enrichment of cell activation pathways in FMS driven by NK cells. Skin biopsies also revealed the presence of NK cells near subepidermal nerves in FMS patients.