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Mucosal-associated invariant T cell is a potential marker to distinguish fibromyalgia syndrome from arthritis.

Sugimoto C, Konno T, Wakao R, Fujita H, Fujita H, Wakao H - PLoS ONE (2015)

Bottom Line: There was a decrease in the MAIT cell population in FMS, RA, and SpA compared with HD.Among the cell surface antigens in MAIT cells, three chemokine receptors, CCR4, CCR7, and CXCR1, a natural killer (NK) receptor, NKp80, a signaling lymphocyte associated molecule (SLAM) family, CD150, a degrunulation marker, CD107a, and a coreceptor, CD8β emerged as potential biomarkers for FMS to distinguish from HD.Furthermore, the drug treatment interruption resulted in alternation of the expression of CCR4, CCR5, CXCR4, CD27, CD28, inducible costimulatory molecule (ICOS), CD127 (IL-7 receptor α), CD94, NKp80, an activation marker, CD69, an integrin family member, CD49d, and a dipeptidase, CD26, in FMS.

View Article: PubMed Central - PubMed

Affiliation: Department of Hygiene & Cellular Preventive Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, 060-8638, Japan.

ABSTRACT

Background: Fibromyalgia (FM) is defined as a widely distributed pain. While many rheumatologists and pain physicians have considered it to be a pain disorder, psychiatry, psychology, and general medicine have deemed it to be a syndrome (FMS) or psychosomatic disorder. The lack of concrete structural and/or pathological evidence has made patients suffer prejudice that FMS is a medically unexplained symptom, implying inauthenticity. Furthermore, FMS often exhibits comorbidity with rheumatoid arthritis (RA) or spondyloarthritis (SpA), both of which show similar indications. In this study, disease specific biomarkers were sought in blood samples from patients to facilitate objective diagnoses of FMS, and distinguish it from RA and SpA.

Methods: Peripheral blood mononuclear cells (PBMCs) from patients and healthy donors (HD) were subjected to multicolor flow cytometric analysis. The percentage of mucosal-associated invariant T (MAIT) cells in PBMCs and the mean fluorescent intensity (MFI) of cell surface antigen expression in MAIT cells were analyzed.

Results: There was a decrease in the MAIT cell population in FMS, RA, and SpA compared with HD. Among the cell surface antigens in MAIT cells, three chemokine receptors, CCR4, CCR7, and CXCR1, a natural killer (NK) receptor, NKp80, a signaling lymphocyte associated molecule (SLAM) family, CD150, a degrunulation marker, CD107a, and a coreceptor, CD8β emerged as potential biomarkers for FMS to distinguish from HD. Additionally, a memory marker, CD44 and an inflammatory chemokine receptor, CXCR1 appeared possible markers for RA, while a homeostatic chemokine receptor, CXCR4 deserved for SpA to differentiate from FMS. Furthermore, the drug treatment interruption resulted in alternation of the expression of CCR4, CCR5, CXCR4, CD27, CD28, inducible costimulatory molecule (ICOS), CD127 (IL-7 receptor α), CD94, NKp80, an activation marker, CD69, an integrin family member, CD49d, and a dipeptidase, CD26, in FMS.

Conclusions: Combined with the currently available diagnostic procedures and criteria, analysis of MAIT cells offers a more objective standard for the diagnosis of FMS, RA, and SpA, which exhibit multifaceted and confusingly similar clinical manifestations.

No MeSH data available.


Related in: MedlinePlus

MAIT cells in HD, FMS, RA, and SpA.A, Representative FACS profile of MAIT cells and NKG2D expression in total, CD8+, and DN MAIT cells in PBMC from a FMS patient. The number in the figure shows the percentage of the populations. MAIT cells are defined as Vα7.2+CD161high within CD3+ cells. B, The frequency of total MAIT cells in HD (n = 16), FMS (n = 26), RA (n = 21), and SpA (n = 36, missing one sample). The percentage of MAIT cells (Vα7.2+CD161high) within total T cells (CD3+) is shown. C, The frequency of CD8+ MAIT cells in HD, FMS, RA, and SpA. The percentage of CD8+ MAIT cells (Vα7.2+CD161highCD8+) within total T cells (CD3+) is shown. D, The frequency of DN MAIT cells in HD, FMS, RA, and SpA. The percentage of DN MAIT cells (Vα7.2+CD161highDN) within total T cells (CD3+) is shown. E, The frequency of CD4+ MAIT cells in HD, FMS, RA, and SpA. The percentage of CD4+MAIT cells (Vα7.2+CD161highCD4+) within total T cells (CD3+) is shown. F, The percentage of CD8+ MAIT cells (CD8+Vα7.2+CD161high) among total MAIT cells (Vα7.2+CD161high) in HD, FMS, RA, and SpA. G, The percentage of DN MAIT cells (CD8-CD4-Vα7.2+CD161high) among total MAIT cells (Vα7.2+CD161high) in HD, FMS, RA, and SpA. H, The percentage of CD4+ MAIT cells (CD4+Vα7.2+CD161high) among total MAIT cells (Vα7.2+CD161high) in HD, FMS, RA, and SpA. B-H. All data are presented as median. Horizontal line: Median; boxes: 25th percentile and 75th percentile; whiskers: Minimum and Maximum. Asterisk shows the group-pair exhibiting significance. *: P< 0.05, **: P < 0.01 (P value adjusted with the Dunn's multicomponent test after the Kruskal-Wallis test).
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pone.0121124.g001: MAIT cells in HD, FMS, RA, and SpA.A, Representative FACS profile of MAIT cells and NKG2D expression in total, CD8+, and DN MAIT cells in PBMC from a FMS patient. The number in the figure shows the percentage of the populations. MAIT cells are defined as Vα7.2+CD161high within CD3+ cells. B, The frequency of total MAIT cells in HD (n = 16), FMS (n = 26), RA (n = 21), and SpA (n = 36, missing one sample). The percentage of MAIT cells (Vα7.2+CD161high) within total T cells (CD3+) is shown. C, The frequency of CD8+ MAIT cells in HD, FMS, RA, and SpA. The percentage of CD8+ MAIT cells (Vα7.2+CD161highCD8+) within total T cells (CD3+) is shown. D, The frequency of DN MAIT cells in HD, FMS, RA, and SpA. The percentage of DN MAIT cells (Vα7.2+CD161highDN) within total T cells (CD3+) is shown. E, The frequency of CD4+ MAIT cells in HD, FMS, RA, and SpA. The percentage of CD4+MAIT cells (Vα7.2+CD161highCD4+) within total T cells (CD3+) is shown. F, The percentage of CD8+ MAIT cells (CD8+Vα7.2+CD161high) among total MAIT cells (Vα7.2+CD161high) in HD, FMS, RA, and SpA. G, The percentage of DN MAIT cells (CD8-CD4-Vα7.2+CD161high) among total MAIT cells (Vα7.2+CD161high) in HD, FMS, RA, and SpA. H, The percentage of CD4+ MAIT cells (CD4+Vα7.2+CD161high) among total MAIT cells (Vα7.2+CD161high) in HD, FMS, RA, and SpA. B-H. All data are presented as median. Horizontal line: Median; boxes: 25th percentile and 75th percentile; whiskers: Minimum and Maximum. Asterisk shows the group-pair exhibiting significance. *: P< 0.05, **: P < 0.01 (P value adjusted with the Dunn's multicomponent test after the Kruskal-Wallis test).

Mentions: Given that FMS features widespread pain, fatigue, and distressed mood, it has been believed that inflammatory cytokines play a role in triggering neuroendocrine aberrations, eventually leading to these symptoms. Accordingly, some reports have demonstrated the aberrant expression of inflammatory cytokines in FMS [4,20,21]. Nevertheless, the source of cytokines remained unidentified, counting against their potential utility as a biomarker. Thus, we analyzed MAIT cells that produce a plethora of the inflammatory cytokines and chemokines [19]. A representative FACS profile of MAIT cells and concomitant cell surface antigen expression (NKG2D, a NK receptor) from a FMS patient is shown in Fig. 1A. We then compared the percentage of total MAIT cells (defined as Vα7.2+CD161high cells within CD3+ cells) in the diseases, and found that they represented [median (25th percentile; 75th percentile): 2.9% (0.9; 4.7), 1.5% (0.8; 2.8), 0.9% (0.4; 2.4), 1.6% (0.6; 2.9] in HD, FMS, RA, and SpA, respectively (Fig. 1B and S2A Table). However, there was no statistical significance in difference of the MAIT cell populations among diseases. Because MAIT cells consist of primarily CD8+ and double negative (DN), and few CD4+ cells [13], each subset was further analyzed. Difference in MAIT cell frequency was seen in CD4+ and DN MAIT cells after the Kruskal-Wallis test (S2B Table). P value adjustment uncovered that there was a difference in frequency of DN MAIT cells between HD and SpA and that of CD4+ MAIT cells between HD and FMS (Fig. 1D-E and S2A–B Table). When the proportion of CD8+, DN, and CD4+ MAIT cells were analyzed within Vα7.2+CD161high cells (considered to be total MAIT cells) in different settings, a significant increase in CD8+ MAIT cells concomitant with a decrease in DN MAIT cells was observed in SpA as compared with HD (Fig. 1F-G). This suggested that SpA is characterized by the increase in proportion of CD8+MAIT cells that is most likely counterbalanced by the decrease of DN MAIT cells. We then focused our study on total, CD8+, and DN MAIT cells for cell surface antigen analysis, as CD4+ MAIT cells were rare.


Mucosal-associated invariant T cell is a potential marker to distinguish fibromyalgia syndrome from arthritis.

Sugimoto C, Konno T, Wakao R, Fujita H, Fujita H, Wakao H - PLoS ONE (2015)

MAIT cells in HD, FMS, RA, and SpA.A, Representative FACS profile of MAIT cells and NKG2D expression in total, CD8+, and DN MAIT cells in PBMC from a FMS patient. The number in the figure shows the percentage of the populations. MAIT cells are defined as Vα7.2+CD161high within CD3+ cells. B, The frequency of total MAIT cells in HD (n = 16), FMS (n = 26), RA (n = 21), and SpA (n = 36, missing one sample). The percentage of MAIT cells (Vα7.2+CD161high) within total T cells (CD3+) is shown. C, The frequency of CD8+ MAIT cells in HD, FMS, RA, and SpA. The percentage of CD8+ MAIT cells (Vα7.2+CD161highCD8+) within total T cells (CD3+) is shown. D, The frequency of DN MAIT cells in HD, FMS, RA, and SpA. The percentage of DN MAIT cells (Vα7.2+CD161highDN) within total T cells (CD3+) is shown. E, The frequency of CD4+ MAIT cells in HD, FMS, RA, and SpA. The percentage of CD4+MAIT cells (Vα7.2+CD161highCD4+) within total T cells (CD3+) is shown. F, The percentage of CD8+ MAIT cells (CD8+Vα7.2+CD161high) among total MAIT cells (Vα7.2+CD161high) in HD, FMS, RA, and SpA. G, The percentage of DN MAIT cells (CD8-CD4-Vα7.2+CD161high) among total MAIT cells (Vα7.2+CD161high) in HD, FMS, RA, and SpA. H, The percentage of CD4+ MAIT cells (CD4+Vα7.2+CD161high) among total MAIT cells (Vα7.2+CD161high) in HD, FMS, RA, and SpA. B-H. All data are presented as median. Horizontal line: Median; boxes: 25th percentile and 75th percentile; whiskers: Minimum and Maximum. Asterisk shows the group-pair exhibiting significance. *: P< 0.05, **: P < 0.01 (P value adjusted with the Dunn's multicomponent test after the Kruskal-Wallis test).
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pone.0121124.g001: MAIT cells in HD, FMS, RA, and SpA.A, Representative FACS profile of MAIT cells and NKG2D expression in total, CD8+, and DN MAIT cells in PBMC from a FMS patient. The number in the figure shows the percentage of the populations. MAIT cells are defined as Vα7.2+CD161high within CD3+ cells. B, The frequency of total MAIT cells in HD (n = 16), FMS (n = 26), RA (n = 21), and SpA (n = 36, missing one sample). The percentage of MAIT cells (Vα7.2+CD161high) within total T cells (CD3+) is shown. C, The frequency of CD8+ MAIT cells in HD, FMS, RA, and SpA. The percentage of CD8+ MAIT cells (Vα7.2+CD161highCD8+) within total T cells (CD3+) is shown. D, The frequency of DN MAIT cells in HD, FMS, RA, and SpA. The percentage of DN MAIT cells (Vα7.2+CD161highDN) within total T cells (CD3+) is shown. E, The frequency of CD4+ MAIT cells in HD, FMS, RA, and SpA. The percentage of CD4+MAIT cells (Vα7.2+CD161highCD4+) within total T cells (CD3+) is shown. F, The percentage of CD8+ MAIT cells (CD8+Vα7.2+CD161high) among total MAIT cells (Vα7.2+CD161high) in HD, FMS, RA, and SpA. G, The percentage of DN MAIT cells (CD8-CD4-Vα7.2+CD161high) among total MAIT cells (Vα7.2+CD161high) in HD, FMS, RA, and SpA. H, The percentage of CD4+ MAIT cells (CD4+Vα7.2+CD161high) among total MAIT cells (Vα7.2+CD161high) in HD, FMS, RA, and SpA. B-H. All data are presented as median. Horizontal line: Median; boxes: 25th percentile and 75th percentile; whiskers: Minimum and Maximum. Asterisk shows the group-pair exhibiting significance. *: P< 0.05, **: P < 0.01 (P value adjusted with the Dunn's multicomponent test after the Kruskal-Wallis test).
Mentions: Given that FMS features widespread pain, fatigue, and distressed mood, it has been believed that inflammatory cytokines play a role in triggering neuroendocrine aberrations, eventually leading to these symptoms. Accordingly, some reports have demonstrated the aberrant expression of inflammatory cytokines in FMS [4,20,21]. Nevertheless, the source of cytokines remained unidentified, counting against their potential utility as a biomarker. Thus, we analyzed MAIT cells that produce a plethora of the inflammatory cytokines and chemokines [19]. A representative FACS profile of MAIT cells and concomitant cell surface antigen expression (NKG2D, a NK receptor) from a FMS patient is shown in Fig. 1A. We then compared the percentage of total MAIT cells (defined as Vα7.2+CD161high cells within CD3+ cells) in the diseases, and found that they represented [median (25th percentile; 75th percentile): 2.9% (0.9; 4.7), 1.5% (0.8; 2.8), 0.9% (0.4; 2.4), 1.6% (0.6; 2.9] in HD, FMS, RA, and SpA, respectively (Fig. 1B and S2A Table). However, there was no statistical significance in difference of the MAIT cell populations among diseases. Because MAIT cells consist of primarily CD8+ and double negative (DN), and few CD4+ cells [13], each subset was further analyzed. Difference in MAIT cell frequency was seen in CD4+ and DN MAIT cells after the Kruskal-Wallis test (S2B Table). P value adjustment uncovered that there was a difference in frequency of DN MAIT cells between HD and SpA and that of CD4+ MAIT cells between HD and FMS (Fig. 1D-E and S2A–B Table). When the proportion of CD8+, DN, and CD4+ MAIT cells were analyzed within Vα7.2+CD161high cells (considered to be total MAIT cells) in different settings, a significant increase in CD8+ MAIT cells concomitant with a decrease in DN MAIT cells was observed in SpA as compared with HD (Fig. 1F-G). This suggested that SpA is characterized by the increase in proportion of CD8+MAIT cells that is most likely counterbalanced by the decrease of DN MAIT cells. We then focused our study on total, CD8+, and DN MAIT cells for cell surface antigen analysis, as CD4+ MAIT cells were rare.

Bottom Line: There was a decrease in the MAIT cell population in FMS, RA, and SpA compared with HD.Among the cell surface antigens in MAIT cells, three chemokine receptors, CCR4, CCR7, and CXCR1, a natural killer (NK) receptor, NKp80, a signaling lymphocyte associated molecule (SLAM) family, CD150, a degrunulation marker, CD107a, and a coreceptor, CD8β emerged as potential biomarkers for FMS to distinguish from HD.Furthermore, the drug treatment interruption resulted in alternation of the expression of CCR4, CCR5, CXCR4, CD27, CD28, inducible costimulatory molecule (ICOS), CD127 (IL-7 receptor α), CD94, NKp80, an activation marker, CD69, an integrin family member, CD49d, and a dipeptidase, CD26, in FMS.

View Article: PubMed Central - PubMed

Affiliation: Department of Hygiene & Cellular Preventive Medicine, Graduate School of Medicine, Hokkaido University, Sapporo, 060-8638, Japan.

ABSTRACT

Background: Fibromyalgia (FM) is defined as a widely distributed pain. While many rheumatologists and pain physicians have considered it to be a pain disorder, psychiatry, psychology, and general medicine have deemed it to be a syndrome (FMS) or psychosomatic disorder. The lack of concrete structural and/or pathological evidence has made patients suffer prejudice that FMS is a medically unexplained symptom, implying inauthenticity. Furthermore, FMS often exhibits comorbidity with rheumatoid arthritis (RA) or spondyloarthritis (SpA), both of which show similar indications. In this study, disease specific biomarkers were sought in blood samples from patients to facilitate objective diagnoses of FMS, and distinguish it from RA and SpA.

Methods: Peripheral blood mononuclear cells (PBMCs) from patients and healthy donors (HD) were subjected to multicolor flow cytometric analysis. The percentage of mucosal-associated invariant T (MAIT) cells in PBMCs and the mean fluorescent intensity (MFI) of cell surface antigen expression in MAIT cells were analyzed.

Results: There was a decrease in the MAIT cell population in FMS, RA, and SpA compared with HD. Among the cell surface antigens in MAIT cells, three chemokine receptors, CCR4, CCR7, and CXCR1, a natural killer (NK) receptor, NKp80, a signaling lymphocyte associated molecule (SLAM) family, CD150, a degrunulation marker, CD107a, and a coreceptor, CD8β emerged as potential biomarkers for FMS to distinguish from HD. Additionally, a memory marker, CD44 and an inflammatory chemokine receptor, CXCR1 appeared possible markers for RA, while a homeostatic chemokine receptor, CXCR4 deserved for SpA to differentiate from FMS. Furthermore, the drug treatment interruption resulted in alternation of the expression of CCR4, CCR5, CXCR4, CD27, CD28, inducible costimulatory molecule (ICOS), CD127 (IL-7 receptor α), CD94, NKp80, an activation marker, CD69, an integrin family member, CD49d, and a dipeptidase, CD26, in FMS.

Conclusions: Combined with the currently available diagnostic procedures and criteria, analysis of MAIT cells offers a more objective standard for the diagnosis of FMS, RA, and SpA, which exhibit multifaceted and confusingly similar clinical manifestations.

No MeSH data available.


Related in: MedlinePlus