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MCP-1 and the MCP-1 Stimulation Test
Monocyte chemotactic protein-1 (MCP-1) acts as a chemoattractant, promoting infiltration of immune cells, and as a basophil agonist, which leads to histamine release. MCP-1 is elevated in postviral CFS, MCS, HT, lupus, CU, some types of asthma, and during infections (EBV, HHV-6).39-46
In a study of patients with allergic rhinitis, submucosa had increased MCAF/MCP-1 and associated histamine release from basophils, suggesting that MCP-1 "is stored in human nasal mucosa, possibly participates in protracted histamine release from basophils and in the pathogenesis of perennial allergic rhinitis."47
While in one study of atopic asthmatics, who had increased total IgE and eosinophils, a significant association with MCP-1 was not found in all patients; in a different study of asthmatics, MCP-1 was elevated in the serum during asymptomatic periods and further elevated during acute attacks.44 In addition, when testing patients with chemically (dissocyanate)-induced asthma, one team found that MCP-1 stimulation assays (MSA) with dissocyanate-human serum albumin (DIISO-HSA) were more sensitive than DIISO-HSA antibody tests in identifying patients.48
Potentially, MSA might be positive in those who developed MCS from sick building syndrome or another lengthy exposure.
Other Potential Non-IgE-Mediated Immune Mechanisms
T cells or inflammatory cytokines may play a role in some patients. T cells have been associated with non-IgE-mediated delayed-type hypersensitivity reactions and with ADR. In one CFS study, in response to intradermal administration of common antigens such as Candida albicans and in vitro T cell activation tests, patients had a delayed-type hypersensitive (DTH) response, and "the intensity of the DTH response correlated with the number of T-cells activated in vitro."49
Increased inflammatory cytokines have been found in the blood in several CFS cohorts and an MCS cohort. However, preliminary tests did not find increased cytokines in nasal fluid in one CFS cohort with rhinitis.39,50,51
While the exact mechanisms in MCS and CFS have yet to be elucidated, research on these diseases is getting closer to answers and the above pathways have the potential to play a role.
As researchers begin to gain more understanding of non-IgE-mediated hypersensitivity pathways, doctors may eventually be able to more readily recognize patients with nonallergic hypersensitivity reactions. Once doctors become familiar with some of the associations in these diseases, including the increased frequency of HT-related autoantibodies in patients with hypersensitivities, maybe someday patients, especially female patients with concurrent Hashimoto's thyroiditis, will be able go to their doctors and say, "I have a hard time taking medicine because I tend to react to everything," and doctors will no longer tell them, as they have told me, "That's impossible!"
1. Nogue Xarau S, Alarcon Romay M, Martinez Martinez JM, Delclos Clanchet J, Rovira Prate E, Fernandez-Sola J. Multiple chemical sensitivity: epidemiological, clinical and prognostic differences between occupational and non-occupational cases. Med Clin (Barc). 2010;135(2):52–58.
2. Meggs WJ. Hypothesis for induction and propagation of chemical sensitivity based on biopsy studies. Environ Health Perspect. 1997;105(Suppl 2):473–478.
3. Ross GH. Clinical characteristics of chemical sensitivity: an illustrative case history of asthma and MCS. Environ Health Perspect. 1997;105(Suppl 2):437–441.
4. Berg ND, Linneberg A, Thyssen JP, Dirksen A, Elberling J. Non-allergic cutaneous reactions in airborne chemical sensitivity –– a population based study. Int J Hyg Environ Health. 2011;214(3):239–245. doi:10.1016/j.ijheh.2011.01.003.
5. Ferre Ybarz L, Cardona Dahl V, Cadahia Garcia A, Ruiz E, Vazquez A, Fernandez de Sevilla T, Alegre Martin J. Prevalence of atopy in chronic fatigue syndrome. Allergol Immunopathol (Madr). 2005;33(1):42–47.
6. Rebora A, Drago F. Chronic fatigue syndrome: a novel disorder with cutaneous manifestations. Dermatology. 1994;188(1):3–5.
7. Hasegawa M, Ohtomo M, Mita H, Akiyama K. Clinical aspects of patients with MCS – from the standpoint of allergy. Arerugi. 2005;54(5):478–484.
8. Kowal K, Schacterele RS, Schur PH, Komaroff AL, DuBuske LM. Prevalence of allergen-specific IgE among patients with chronic fatigue syndrome. Allergy Asthma Proc. 2002;23(1):35–39.
9. Enestrom S, Bengtsson A, Frodin T. Dermal IgG deposits and increase of mast cells in patients with fibromyalgia –– relevant findings of epiphenomena? Scand J Rheumatol. 1997;26(4):308–313.
10. Heuser G. Mast cell disorder to be ruled out in MCS. Arch Environ Health. 2000;55(4):284–285.
11. Nijs J, De Becker P, De Meirleir K, et al. Associations between bronchial hyperresponsiveness and immune cell parameters in patients with chronic fatigue syndrome. Chest. 2003;123(4):998–1007.
12. Baraniuk JN, Zheng Y. Relationship among rhinitis, fibromyalgia, and chronic fatigue. Allergy Asthma Proc. 2010;31(3):169–78. doi:10.2500/aap.2010.31.3311.
13. Galland L. Biochemical abnormalities in patients with multiple chemical sensitivities. Occup Med. 1987;2(4):713–720.
14. Hilgers A, Frank J. Chronic fatigue syndrome: immune dysfunction, role of pathogens and toxic agents and neurological and cardial changes. Wien Med Wochenschr. 1994;144(16):399–406.
15. Cunha BA. Crimson crescents – a possible association with the chronic fatigue syndrome. Ann Intern Med. 1992;116(4):347.
16. Chen T, Hudnall SD. Anatomical mapping of human herpes virus reservoirs of infection. Med Pathol. 2006;19(5):726–737.
17. Harberts E, Yao K, Wohler JE, et al. Human herpesvirus-6 entry into the central nervous system through the olfactory pathway. Proc Natl Acad Sci USA. 2011;108(33):13734–13739. doi:10.1073/pnas.1105143108.
18. Herbert RP, Harris J, Chong KP Chapman J, West AK, Chuah MI. Cytokines and olfactory bulb microglia in response to bacterial challenge in the compromised primary olfactory pathway. J Neuroinflammation. 2012;9:109. doi:10.1186/1742-2094-9-109
19. Thiebaud N, Da Silva SV, Jakob I, Sicard G, Chevalier J, et al. Odorant metabolism catalyzed by olfactory mucosal enzymes influences peripheral olfactory responses in rats. PLoS One. 2013;8(3):e59547. doi:10.1371/journal.pone.0059547
20. Schnakenberg E, Fabing KR, Stanulla M, et al. A cross-sectional study of self-reported chemical-related sensitivity is associated with gene variants of drug-metabolizing enzymes. Environ Health. 2007;6:6.
21. Caccamo D, Cesareo E, Mariani S, et al. Xenobiotic sensor- and metabolism-related gene variants in environmental sensitivity-related illnesses: a survey on the Italian population. Oxid Med Cell Longev. 2013;2013:831969. doi:10.1155/2013/831969.
22. Meggs W. Neurogenic inflammation and sensitivity to environmental chemicals. Environ Health Perspect. 1993;101(3):234–238.
23. Millquist E. Cough provocation with capsaicin is an objective way to test sensory hyperactivity in patients with asthma-like symptoms. Allergy. 2000;55(6):546–550.
24. Borson DB, Brokaw JJ, Sekizawa K, McDonald DM, Nadel JA. Neutral endopeptidase and neurogenic inflammation in rats with respiratory infections. J Appl Physiol. 1989;66(6):2653–2658.
25. Kimata H. Effect of exposure to volatile organic compounds on plasma levels of neuropeptides, nerve growth factor, and histamine in patients with self-reported multiple chemical sensitivity. Int J Hyg Environ Health. 2004;207(2):159–163.
26. Fletcher MA, Rosenthal M, Antoni M, et al. Plasma neuropeptide Y: a biomarker for symptom severity in chronic fatigue syndrome. Behav Brain Funct. 2010;6:76.
27. Shiasaki H, Kanaizumi E, Himi T. Immunohistochemical localization of the bradykinin B1 and B2 receptors in human nasal mucosa. Mediators Inflamm. 2009;2009:102406. doi:10.1155/2009/102406.
28. Samareh Fekri M, Shokoohi M, Gozashti MH, et al. Association between anti-thyroid peroxidase antibody and asthma in women. Iran J Allergy Asthma Immunol. 2012;11(3):241–245. doi:011.03/ijaai.241245
29. Comi AL, Tedeschi A, Lorini M, Miadonna A. Novel clinical and serological aspects in non-allergic asthma. Respir Med. 2007;101(12):2526–2533.
30. Viswsnathan RK, Biagtan MJ, Mathur SK. The role of autoimmune testing in chronic idiopathic urticaria. Ann Allergy Asthma Immunol. 2012;108(5):337–341.
31. Jang AS, Park JS, Lee JH, Park SW, Kim DJ, Park CS. Autologous serum skin test for autoantibodies is associated with airway hyperresponsiveness in patients with asthma. Respiration. 2007;74(3)293–296.
32. Comert S, Celebioglu E, Karakava G, Kalvoncu AE. The general characteristics of acute urticaria attacks and the factors predictive of progression to chronic urticaria. Allergol Immunopathol (Madr). 2012;2013;41(4):239–245. pii:S0301-0546(12)00179-6. doi:10.1016/j.aller.2012.05.007.
33. Vohra S, Sharma NL, Mahaian VK, Shanker V. Clinicoepidemiologic features of chronic urticaria in patients having positive verses negative autologous serum skin test: a study of 100 Indian patients. Indian J Dermatol Venereol Leprol. 2011;77(2):156–159. doi:10.4103/0378-6323.77454.
34. Asero R, Tedeschi A, Lorini M, Caldironi G, Barocci F. Sera from patients with multiple drug allergy syndrome contain circulating histamine-releasing factors. Int Arch Allergy Immunol. 2013;131(3):195–200.
35. Sun RS, Chen XH, Sui JF, et al. Detecting anti-FcepsilonRI autoantibodies in patients with asthma by flow cytometry. J Int Med Res. 2008;36(6):1214–1219.
36. Yim H, Kim JE, Shin JY, Ye YM, Park HS, Nahm DH. Antigen-binding characteristics of circulating IgG autoantibodies to cytokeritin 18 protein in patients with nonallergic asthma. J Korean Med Sci. 2006;21(4):652–655. doi:10.3346/jkms.2006.21.4.652.
37. Ye YM, Nahm DH, Kim CW, et al. Cytokeratin autoantibodies: useful serologic markers for toluene diisocyanate-induced asthma. Yonsei Med J. 2006;47(6):773–781. doi:10.3349/ymj.2006.47.6.773.
38. Ye YM, Nahm DH, Kim SH, et al. Circulating autoantibodies in patients with aspirin-intolerant asthma: an epiphenomenon related to airway inflammation. J Korean Med Sci. 2006;21(3):412–417. doi:10.3346/jkms.2006.21.3.412.
39. Kerr JR, Tyrrell DA. Cytokines in parvovirus B19 infection as an aid to understanding chronic fatigue syndrome. Curr Pain Headache Res. 2003;7(5):333–341.
40. DeLuca C, Scordo MG, Cesareo E, Pastore S, Mariani S. Biological definition of multiple chemical sensitivity from redox state and cytokine profiling and not from polymorphisms of xenobiotic-metabolizing enzymes. Toxicol Appl Pharmacol. 2010;248(3):285–292. doi:10.1016/j.taap.2010.04.017.
41. Kemp EH, Metcalfe RA, Smith KA, Woodroofe MN, Watson PF, Weetman AP. Detection and localization of chemokine gene expression in autoimmune thyroid disease. Clin Endocrinol (Oxf). 2003;59(2):207–213.
42. Kaneko H, Ogasawana H, Naito T, et al. Circulating levels of beta-chemokines in systemic lupus erythema toss. L Rheumatol. 1999;26(3):568–573.
43. Santos JC, de Brito CA, Futata EA, et al. Up-regulation of chemokine C-C ligand 2 (CCL2) and C-X-C chemokine 8 (CXCL8) expression by monocytes in chronic idiopathic urticaria. Clin Exp Immunol. 2012;167(1):129–136.
44. Chan CK, Kuo ML, Yeh KW, et al. Sequential evaluation of serum monocyte chemotactic protein 1 among a symptomatic state and acute exacerbation and remission of asthma in children. J Asthma. 2009;46(3):225–8. doi:10.1080/02770900802553805.
45. Gaudreault E, Fiola S, Olivier M, Gosselin J. Epstein-Barr virus induces MCP-1 secretion by human monocytes via TLR2. J Virol. 2007;81(15):8016–8024.
46. Arena A, Stassi G, Speranza A, Ianello D, Mastroeni P. Modulatory effect of HHV-6 on MCP-1 production by human monocytes. New Microbiol. 2002;25(3):335–340.
47. Fujikura T, Otsuka H. Monocytes chemotactic and activating factor/monocyte chemoattractant protein-1- mediated histamine release from human nasal mucosa. Arch Otolaryngeal Head Neck Surg. 1998;124(12):1331–1335.
48. Bernstein DI, Cartier A, Cote J, et al. Dissocyanate antigen-stimulated monocyte chemoattractant protein-1 synthesis has greater test efficacy than specific antibodies for identification of dissocyanate asthma. Am J Respir Crit Care Med. 2002;166(4):445–450.
49. Brunet JL, Fatoohi F, Liaudet AP, Cozon GJ. Role of pathological delayed-type hypersensitivity in chronic fatigue syndrome: importance of the evaluation of lymphocyte activation by flow cytometry and the measurement of urinary neopterin. Allerg Immunol (Paris). 2002;34(2):38–44.
50. Dantoft TM, Elberling J, Brix S, Szecsi PB, Vesterhauge S, Skovbjerg S. An elevated pro-inflammatory cytokine profile in multiple chemical sensitivity. Psychoneuroendocrinology. 2014;40:140–150. doi:10.1016/j.psyneuron.2013.11.012.
51. Repka-Ramirez S, Naranch K, Park YJ, Clauw D, Baraniuk JN. Cytokines in nasal lavage fluids from acute sinusitis, allergic rhinitis, and chronic fatigue syndrome subjects. Allergy Asthma Proc. 2002;23(3):185–190.
© 2014 Laurie Dennison Busby, BEd
Laurie Busby received a BEd from the University of Missouri. At age 30, she developed chronic fatigue syndrome and the hypersensitivities that sometimes accompany it. Shortly thereafter, her aunt, a nurse anesthetist, handed her a huge medical dictionary and some studies, insisting that Laurie learn how to read them because she had something with no answers. Since that time, Laurie has asked for several tests that have given her incredible clues about her illness, conducted a family medical health survey among patients, testified before the CFS Advisory Committee to the US Department of Health and Human Services, and started a chronic illness blog, cfsfmmcsandrelatedstudies.tumblr.com, in an attempt to share what she has learned.
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