Unique immunologic patterns in fibromyalgia

Frederick G. Behm1, Igor M. Gavin2, Olesksiy Karpenko2, Valerie Lindgren1, Sujata Gaitonde1, P. Gashkoff1, Bruce S. Gillis1
1Department of Pathology, University of Illinois at Chicago (UIC), Chicago, IL, USA
2Research Resource Center, University of Illinois at Chicago, Chicago, IL, USA

Tóm tắt

AbstractBackground

Fibromyalgia (FM) is a clinical syndrome characterized by chronic pain and allodynia. The diagnosis of FM has been one of exclusion as a test to confirm the diagnosis is lacking. Recent data highlight the role of the immune system in FM. Aberrant expressions of immune mediators, such as cytokines, have been linked to the pathogenesis and traits of FM. We therefore determined whether cytokine production by immune cells is altered in FM patients by comparing the cellular responses to mitogenic activators of stimulated blood mononuclear cells of a large number of patients with FM to those of healthy matched individuals.

Methods

Plasma and peripheral blood mononuclear cells (PBMC) were collected from 110 patients with the clinical diagnosis of FM and 91 healthy donors. Parallel samples of PBMC were cultured overnight in medium alone or in the presence of mitogenic activators; PHA or PMA in combination with ionomycin. The cytokine concentrations of IFN-γ, IL-5, IL-6, IL-8, IL-10, MIP-1β , MCP-1, and MIP1-α in plasma as well as in cultured supernatants were determined using a multiplex immunoassay using bead array technology.

Results

Cytokine levels of stimulated PBMC cultures of healthy control subjects were significantly increased as compared to matched non-stimulated PBMC cultures. In contrast, the concentrations of most cytokines were lower in stimulated samples from patients with FM compared to controls. The decreases of cytokine concentrations in patients samples ranged from 1.5-fold for MIP-1β to 10.2-fold for IL-6 in PHA challenges. In PMA challenges, we observed 1.8 to 4-fold decreases in the concentrations of cytokines in patient samples.

Conclusion

The cytokine responses to mitogenic activators of PBMC isolated from patients with FM were significantly lower than those of healthy individuals, implying that cell-mediated immunity is impaired in FM patients. This novel cytokine assay reveals unique and valuable immunologic traits, which, when combined with clinical patterns, can offer a diagnostic methodology in FM.

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Tài liệu tham khảo

Wolfe F, Smythe HA, Yunus MB: The American College of Rheumatology 1990 criteria for the classification of fibromyalgia. Report of the multicenter criteria committee. Arthritis Rheum. 1990, 33: 160-172. 10.1002/art.1780330203.

Häuser W, Eich W, Herrmann M: Fibromyalgia syndrome: classification, diagnosis, and treatment. Dtsch Arztebl Int. 2009, 106: 383-391.

Goldenberg DL: Diagnosis and differential diagnosis of fibromyalgia. Am J Med. 2009, 122 (12 Suppl): S14-S21.

McCarberg BH: Clinical overview of fibromyalgia. Am J Ther. 2011, Epub ahead of print

Arnold LM, Clauw DJ, McCarberg BH: Improving the recognition and diagnosis of fibromyalgia. Mayo Clin Proc. 2011, 86: 457-464. 10.4065/mcp.2010.0738.

Clauw DJ, Arnold LM, McCarberg BH: The science of fibromyalgia. Mayo Clin Proc. 2011, 86: 907-911. 10.4065/mcp.2011.0206.

Arnold LM: The pathophysiology, diagnosis, and treatment of fibromyalgia. Psychiatr Clin North Am. 2010, 33: 375-408. 10.1016/j.psc.2010.01.001.

DeLeao JA, Yezierki RP: The role of neuroinflammation and neuroimmune activation in persistent pain. Pain. 2001, 90: 1-6. 10.1016/S0304-3959(00)00490-5.

Buskila D: Fibromyalgia, chronic fatigue syndrome, and myofascial pain syndrome. Curr Opin Rheumatol. 2001, 13: 117-127. 10.1097/00002281-200103000-00005.

Middleton GD, McFarlin JE, Lipsky PE: The prevalence and clinical impact of fibromyalgia in systemic lupus erythematosus. Arthritis Rheum. 1994, 37: 1181-1188. 10.1002/art.1780370812.

Morand EF, Miller MH, Whittingham S, Littlejohn GO: Fibromyalgia syndrome and disease activity in systemic lupus erythematosus. Lupus. 1994, 3: 187-191. 10.1177/096120339400300310.

Vitali C, Tavoni A, Vitali C, Tavoni A: Fibromyalgia et al. Fibromyalgia features in patients with primary Sjogren's syndrome. Evidence of a relationship with psychological depression. Scand J Rheumatol. 1989, 18: 21-27.

Tishler M, Barak Y, Paran D, Yaron M: Sleep disturbances, fibromyalgia and primary Sjogren's syndrome. Clin Exp Rheumatol. 1997, 15: 71-74.

Wolfe F, Michaud K: Severe rheumatoid arthritis (RA), worse outcomes, comorbid illness, and sociodemographic disadvantage characterize ra patients with fibromyalgia. J Rheumatol. 2004, 31: 695-700.

Di Franco M, Iannuccelli C, Valesini G: Neuroendocrine immunology of fibromyalgia. Ann N Y Acad Sci. 2010, 1193: 84-90. 10.1111/j.1749-6632.2009.05344.x.

Wallace DJ, Margolin K, Waller P: Fibromyalgia and interleukin-2 therapy for malignancy. Ann Intern Med. 1988, 108: 909-

Menzies V, Lyon DE: Integrated review of the association of cytokines with fibromyalgia and fibromyalgia core symptoms. Biol Res Nurs. 2010, 11: 387-394. 10.1177/1099800409348328.

Űceyler N, Hauser W, Sommer C: Systemic review with meta-analysis: cytokines in fibromyalgia syndrome. BMC Musculoskeltal Disorders. 2011, 12: 245-10.1186/1471-2474-12-245.http://www.biomedcentral.com/1471-2474/12/245,

R Development Core Team. R: A language and evironment for statistical computing. 2010, Vienna, Austria: R Development Core Team

Gatttachalk PG, Dunn JR: The five-parameter logistic. A characteriszation and comparison with the four-parameter logistic. Anal Biochem. 2005, 343: 54-65. 10.1016/j.ab.2005.04.035.

Yachnin S, Svenson RH: The immunological and physicochemical properties of mitogenic proteins derived from Phaseolus vulgaris. Immunology. 1972, 22: 871-883.

Leavitt RD, Felsted RL, Bachur NR: Biological and biochemical properties of Phaseolus vulgaris isolectins. J Biol Chem. 1977, 252: 2961-2966.

Tsuchida T, Sakane T: Intracellular activation signal requirements for the induction of IL-2 responsiveness in resting T cell subsets in humans. J Immunol. 1988, 140: 3446-3449.

Kurtzhals JA, Kemp M, Poulsen K: Interleukin-4 and interferon-gamma production by Leishmania stimulated peripheral blood mononuclear cells from nonexposed individuals. Scand J Immunol. 1995, 41: 343-349. 10.1111/j.1365-3083.1995.tb03577.x.

Jason J, Larned J: Single-cell cytokine profiles in normal humans: comparison of flow cytometric reagents and stimulation protocols. J Immunol Methods. 1997, 207: 13-22. 10.1016/S0022-1759(97)00079-3.

Eriksson P, Andersson C, Ekerfelt C: Sjogren's syndrome with myalgia is associated with subnormal secretion of cytokines by peripheral blood mononuclear cells. J Rheumatol. 2004, 31: 729-735.

Tsao CW, Lin YS, Chen CC: Cytokines and serotonin transporter in patients with major depression. Prog Neuropsychopharmacol Biol Psychiatry. 2006, 30: 899-905. 10.1016/j.pnpbp.2006.01.029.

Uceyler N, Valenza R, Stock M: Reduced levels of antiinflammatory cytokines in patients with chronic widespread pain. Arthritis Rheum. 2006, 54: 2656-2664. 10.1002/art.22026.

Backonja MM, Coe CL, Muller DA, Schell K: Altered cytokine levels in the blood and cerebrospinal fluid of chronic pain patients. J Neuroimmunol. 2008, 195: 157-163. 10.1016/j.jneuroim.2008.01.005.

Kim YK, Lee SW, Kim HS: Differences in cytokines between non-suicidal patients and suicidal patients in major depression. Prog Neuropsychopharmacol Biol Psychiatry. 2008, 32: 356-361. 10.1016/j.pnpbp.2007.08.041.

Krueger C, Hawkins K, Wong S: Persistent pro-inflammatory cytokines following the initiation of pegylated IFN therapy in hepatitis C infection is associated with treatment-induced depression. J Viral Hepat. 2011, 18: e284-e291. 10.1111/j.1365-2893.2010.01408.x.

Dubas-Slemp H, Kaminska T: Changes in serum concentrations and in cytokine production by blood cell cultures of a patient with major depression–case report. Ann Univ Mariae Curie Sklodowska Med. 2002, 57: 496-504.

Krause DL, Riedel M, Müller N: Effects of antidepressants and cyclooxygenase-2 inhibitor on cytokines and kynurenines in stimulated in vitro blood culture from depressed patients. Inflammopharmacology. 2012, 20: 169-176. 10.1007/s10787-011-0112-6.

Barth H, Berg PA, Klein R: Is there a relationship between eosinophilia myalgia syndrome (EMS) and fibromyalgia symdrome (FMS)? An analysis of clinical and immunologic data. Adv Exp Med Biol. 1999, 467: 487-496. 10.1007/978-1-4615-4709-9_61.

Wolfe F, Hawley DJ, Cathy MA, Russell IJ: Fibrositis: symptom frequency and criteria for diagnosis. An evaluation of 291 rheumatic disease patients and 58 normal individuals. J Rheumatol. 1985, 12: 1159-1163.

Amel Kashipaz MR, Swinden D, Todd I, Powell RJ: Normal production of inflammatory cytokines in chronic fatigue and fibromyalgia syndromes determined by intracellular cytokine staining in short-term cultured blood mononuclear cells. Clin Exp Immunol. 2003, 132: 360-365. 10.1046/j.1365-2249.2003.02149.x.

Wallace DJ, Linker-Israeli M, Hallegua D: Cytokines play an aetiopathogenetic role in fibromyalgia: a hypothesis and pilot study. Rheumatology (Oxford). 2001, 40: 743-749. 10.1093/rheumatology/40.7.743.