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

ABSTRACT:

Abstract

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.

SUBMITTER: Verma V

PROVIDER: S-EPMC8942876 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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

Verma Vivek V Drury Gillian L GL Parisien Marc M Özdağ Acarli Ayşe N AN Al-Aubodah Tho-Alfakar TA Nijnik Anastasia A Wen Xia X Tugarinov Nicol N Verner Maria M Klares Richie R Linton Alexander A Krock Emerson E Morado Urbina Carlos E CE Winsvold Bendik B Fritsche Lars G LG Fors Egil A EA Piccirillo Ciriaco C Khoutorsky Arkady A Svensson Camilla I CI Fitzcharles Mary A MA Ingelmo Pablo M PM Ingelmo Pablo M PM Bernard Nicole F NF Dupuy Franck P FP Üçeyler Nurcan N Sommer Claudia C King Irah L IL Meloto Carolina B CB Diatchenko Luda L

Pain 20210924 7

<h4>Abstract</h4>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]

PMID: 34913882

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Project description:Abstract Background Influenza A virus (IAV) infection leads to significant morbidity and mortality. Biological sex influences the immune responses to IAV infection, resulting in higher mortality in women of reproductive age. Previous studies revealed increased activation of T and B cells in female mice after IAV infection, but extensive analysis of sex differences in both innate and adaptive immune cells over time is lacking. Invariant natural killer T (iNKT) cells are fast‐reacting forces and modulators of immune responses that are important to IAV immunity, but it is not known if the presence and function of iNKT cells differ between females and males. The aim of this study was to determine immunological mechanisms that contribute to the increased disease severity in female mice during IAV infection. Methods Female and male mice were infected with mouse‐adapted IAV and monitored for weight loss and survival. Immune cell populations and cytokine expression in bronchoalveolar lavage fluid, lung, and mediastinal lymph node were determined at three time points after infection using flow cytometry and ELISA. Results The results reveal increased severity and mortality in adult female mice compared to age‐matched males. Female mice show larger increases in innate and adaptive immune cell populations and cytokine production in lung compared to mock on Day 6 postinfection. On Day 9 postinfection, female mice express higher numbers of iNKT cells in lung and liver compared to males. Conclusions This comprehensive analysis of immune cells and cytokines over time following IAV infection reveals increased leukocyte expansion and stronger proinflammatory cytokine responses in female mice during disease initiation. Furthermore, this is the first study to report a sex bias in iNKT cell populations after IAV infection. The data suggests that the process of recovery from IAV‐induced airway inflammation is associated with increased expansion of several different iNKT cell subpopulations in female mice. In this study, comprehensive profiling of innate and adaptive immune cells following influenza A virus infection over time in adult female and male mice was performed. The data reveals higher numbers of lung leukocytes and increased cytokine production in female mice at the onset of symptom progression. Additionally, female mice show a sex‐dependent expansion of invariant natural killer T cell populations in lung at the start of disease recovery. Highlights Infection with influenza A virus (IAV) leads to increased weight loss and mortality in female mice. IAV infection induces increased leukocyte expansion and stronger proinflammatory cytokine responses in the lung of female mice compared to mock on Day 6 postinfection. IAV infection leads to a sex‐specific increase of invariant natural killer T (iNKT) cell populations in lung and liver of female mice on Day 9 postinfection. The association between weight gain and the sex‐specific increase in iNKT cells on Day 9 postinfection implicate a role for iNKT cells in the resolution of inflammation in female mice.

Dataset Information

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

Abstract

Publications

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

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