Clinical correlation of peripheral CD4+‑cell sub‑sets, their imbalance and Parkinson's disease

Chen,Yuhua; Qi,Benquan; Xu,Wenfang; Ma,Bo; Li,Li; Chen,Qiming; Qian,Weidong; Liu,Xiaolin; Qu,Hongdang

doi:10.3892/mmr.2015.4136

Clinical correlation of peripheral CD4+‑cell sub‑sets, their imbalance and Parkinson's disease

Authors:
- Yuhua Chen
- Benquan Qi
- Wenfang Xu
- Bo Ma
- Li Li
- Qiming Chen
- Weidong Qian
- Xiaolin Liu
- Hongdang Qu
View Affiliations

Affiliations: Department of Neurology, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui 233004, P.R. China, Department of Emergency Internal Medicine, The First Affiliated Hospital of Bengbu Medical College, Bengbu, Anhui 233004, P.R. China
Published online on: July 29, 2015 https://doi.org/10.3892/mmr.2015.4136
Pages: 6105-6111

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Emerging evidence suggests that the peripheral immune system has an active role in the progression of Parkinson's disease (PD). The finding of T‑helper (Th; CD4+) cells infiltrating into the substantia nigra in PD patients demonstrated that Th cells are involved in PD. However, the association between peripheral T‑helper cell sub‑sets (Th1, Th2, Treg and Th17) and the sub‑set balance (Th1/Th2 and Th17/Treg) and PD has remained elusive. In the present study, sixty PD patients of the First Affiliated Hospital of Bengbu Medical College as well as 40 age‑ and environment‑matched healthy individuals were enrolled. The fraction of CD4+ T cells in the peripheral blood was assessed by automated hematology analysis and its sub‑sets (Thl, Th2, Thl7, Treg) were quantified by flow cytometry. The results showed that in the PD group, the proportion of Th1 and Th17 cells was increased, while that of Th2 and Treg cells was decreased. Compared with the control group, the Th1/Th2 and Th17/Treg ratios were significantly enhanced, and shifted towards Th1 and Th17, respectively. Furthermore, this Th1‑type response (Th1/Th2 balance shifting towards Th1) were associated with motor function scores determined by Unified Parkinson's Disease Rating Scale III (UPDRS‑III) scores. However, no correlation was found between the change in the Th17/Treg cell balance (Th17/Treg balance shifting towards Th1) and UPDRS‑III scores. These data supported that chronic immune stimulation, specifically CD4+‑cell sub‑set imbalance, is linked to PD pathobiology and disease severity. CD4+‑cell sub‑sets and their imbalance may therefore represent novel biomarkers or therapeutic targets for PD.

View Figures

View References

1	Dorsey ER, Constantinescu R, Thompson JP, et al: Projected number of people with Parkinson's disease in the most populous nations, 2005 through 2030. Neurology. 68:384–386. 2007. View Article : Google Scholar
2	Mori F, Nishie M, Kakita A, Yoshimoto M, Takahashi H and Wakabayashi K: Relationship among alpha-synuclein accumulation, dopamine synthesis, and neurodegeneration in Parkinson disease substantia nigra. J Neuropathol Exp Neurol. 65:808–815. 2006. View Article : Google Scholar : PubMed/NCBI
3	Croisier E, Moran LB, Dexter DT, Pearce RK and Graeber MB: Microglial inflammation in the parkinsonian substantia nigra: Relationship to alphaa-synuclein deposition. J Neuroinflammation. 2:142005. View Article : Google Scholar
4	Stevens CH, Rowe D, Morel-Kopp MC, Orr C, Russell T, Ranola M, Ward C and Halliday GM: Reduced T helper and B lymphocytes in Parkinson's disease. J Neuroimmunol. 252:95–99. 2012. View Article : Google Scholar : PubMed/NCBI
5	Umemura A, Oeda T, Tomita S, Hayashi R, Kohsaka M, Park K, Sugiyama H and Sawada H: Delirium and high Fever are associated with subacute motor deterioration in Parkinson disease: A nested case-control study. PLOS One. 9:e949442014. View Article : Google Scholar : PubMed/NCBI
6	Noelker C, Morel L, Osterloh A, Alvarez-Fischer D, Lescot T, Breloer M, Gold M, Oertel WH, Henze C, Michel PP, et al: Heat shock protein 60: An endogenous inducer of dopaminergic cell death in Parkinson disease. J Neuroinflammation. 11:862014. View Article : Google Scholar : PubMed/NCBI
7	More SV, Kumar H, Kim IS, Song SY and Choi DK: Cellular and molecular mediators of neuroinflammation in the pathogenesis of Parkinson's disease. Mediators Inflamm. 2013:9523752013. View Article : Google Scholar : PubMed/NCBI
8	Bakay RA, Boyer KL, Freed CR and Ansari AA: Immunological responses to injury and grafting in the central nervous system of nonhuman primates. Cell Transplant. 7:109–120. 1998. View Article : Google Scholar : PubMed/NCBI
9	Luk KC, Kehm VM, Zhang B, O'Brien P, Trojanowski JQ and Lee VM: Intracerebral inoculation of pathological α-synuclein initiates a rapidly progressive neurodegenerative α-synucleinopathy in mice. J Exp Med. 209:975–986. 2012. View Article : Google Scholar : PubMed/NCBI
10	Maetzler W, Apel A, Langkamp M, Deuschle C, Dilger SS, Stirnkorb JG, Schulte C, Schleicher E, Gasser T and Berg D: Comparable autoantibody serum levels against amyloid- and inflammation-associated proteins in Parkinson's disease patients and controls. PLOS One. 9:e886042014. View Article : Google Scholar : PubMed/NCBI
11	Hamza TH, Zabetian CP, Tenesa A, Laederach A, Montimurro J, Yearout D, Kay DM, Doheny KF, Paschall J, Pugh E, et al: Common genetic variation in the HLA region is associated with late-onset sporadic Parkinson's disease. Nat Genet. 42:781–785. 2010. View Article : Google Scholar : PubMed/NCBI
12	Melief J, Koning N, Schuurman KG, Van De Garde MD, Smolders J, Hoek RM, Van Eijk M, Hamann J and Huitinga I: Phenotyping primary human microglia: Tight regulation of LPS responsiveness. Glia. 60:1506–1517. 2012. View Article : Google Scholar : PubMed/NCBI
13	Shannon KM, Keshavarzian A, Dodiya HB, Jakate S and Kordower JH: Is alpha-synuclein in the colon a biomarker for premotor Parkinson's disease? Evidence from 3 cases. Mov Disord. 27:716–719. 2012. View Article : Google Scholar : PubMed/NCBI
14	Hirsch EC and Hunot S: Neuroinflammation in Parkinson's disease: A target for neuroprotection? Lancet Neurol. 8:382–397. 2009. View Article : Google Scholar : PubMed/NCBI
15	Brochard V, Combadière B, Prigent A, Laouar Y, Perrin A, Beray-Berthat V, Bonduelle O, Alvarez-Fischer D, Callebert J, Launay JM, et al: Infiltration of CD4+lymphocytes into the brain contributes to neurodegeneration in a mouse model of Parkinson disease. J Clin Invest. 119:182–192. 2009.
16	González H, Contreras F, Prado C, Elgueta D, Franz D, Bernales S and Pacheco R: Dopamine receptor D3 expressed on CD4+ T cells favors neurodegeneration of dopaminergic neurons during Parkinson's disease. J Immunol. 190:5048–5056. 2013. View Article : Google Scholar : PubMed/NCBI
17	Zhou L, Chong MM and Littman DR: Plasticity of CD4+ T cell lineage differentiation. Immunity. 30:646–655. 2009. View Article : Google Scholar : PubMed/NCBI
18	Wan YY: Multi-tasking of helper T cells. Immunology. 130:166–171. 2010. View Article : Google Scholar : PubMed/NCBI
19	Mu L, Sun B, Kong Q, Wang J, Wang G, Zhang S, Wang D, Liu Y, Liu Y, An H, et al: Disequilibrium of T helper type 1, 2 and 17 cells and regulatory T cells during the development of experimental autoimmune myasthenia gravis. Immunology. 128:e826–e836. 2009. View Article : Google Scholar : PubMed/NCBI
20	Nie K, Zhang Y, Gan R and Wang L, Zhao J, Huang Z, Tang H and Wang L: Polymorphisms in immune/inflammatory cytokine genes are related to Parkinson's disease with cognitive impairment in the han chinese population. Neurosci Lett. 541:111–115. 2013. View Article : Google Scholar : PubMed/NCBI
21	Sanchez-Guajardo V, Annibali A, Jensen PH and Romero-Ramos M: α-Synuclein vaccination prevents the accumulation of parkinson disease-like pathologic inclusions in striatum in association with regulatory T cell recruitment in a rat model. J Neuropathol Exp Neurol. 72:624–645. 2013. View Article : Google Scholar : PubMed/NCBI
22	Saunders JA, Estes KA, Kosloski LM, Allen HE, Dempsey KM, Torres-Russotto DR, Meza JL, Santamaria PM, Bertoni JM, Murman DL, et al: CD4+ regulatory and effector/memory T cell subsets profile motor dysfunction in Parkinson's disease. J Neuroimmune Pharmacol. 7:927–738. 2012. View Article : Google Scholar : PubMed/NCBI
23	Niwa F, Kuriyama N, Nakagawa M and Imanishi J: Effects of peripheral lymphocyte subpopulations and the clinical correlation with Parkinson's disease. Geriatr Gerontol Int. 12:102–107. 2012. View Article : Google Scholar
24	Fazekas de St Groth B, Zhu E, Asad S and Lee L: Flow cytometric detection of human regulatory T cells. Methods Mol Biol. 707:263–279. 2011. View Article : Google Scholar : PubMed/NCBI
25	McClymont SA, Putnam AL, Lee MR, Esensten JH, Liu W, Hulme MA, Hoffmüller U, Baron U, Olek S, Bluestone JA, et al: Plasticity of human regulatory T cells in healthy subjects and patients with type 1 diabetes. J Immunol. 186:3918–3926. 2011. View Article : Google Scholar : PubMed/NCBI
26	Pott Godoy MC, Ferrari CC and Pitossi FJ: Nigral neurode-generation triggered by striatal AdIL-1 administration can be exacerbated by systemic IL-1 expression. J Neuroimmunol. 222:29–39. 2010. View Article : Google Scholar : PubMed/NCBI
27	Hasegawa Y, Inagaki T, Sawada M and Suzumura A: Impaired cytokine production by peripheral blood mononuclear cells and monocytes/macrophages in Parkinson's disease. Acta Neurol Scand. 101:159–164. 2000. View Article : Google Scholar : PubMed/NCBI
28	Brodacki B, Staszewski J, Toczyłowska B, Kozłowska E, Drela N, Chalimoniuk M and Stepien A: Serum interleukin (IL-2, IL-10, IL-6, IL-4), TNF alpha and INF gamma concentrations are elevated in patients with atypical and idiopathic parkinsonism. Neurosci Lett. 441:158–162. 2008. View Article : Google Scholar : PubMed/NCBI
29	Reale M, Iarlori C, Thomas A, Gambi D, Perfetti B, Di Nicola M and Onofrj M: Peripheral cytokines profile in Parkinson's disease. Brain Behav Immun. 23:55–63. 2009. View Article : Google Scholar
30	Mu L, Sun B, Kong Q, Wang J, Wang G, Zhang S, Wang D, Liu Y, Liu Y, An H, et al: Disequilibrium of T helper type 1, 2 and 17 cells and regulatory T cells during the development of experimental autoimmune myasthenia gravis. Immunology. 128(1 Suppl): e826–e836. 2009. View Article : Google Scholar : PubMed/NCBI
31	Hawkins RD, Larjo A, Tripathi SK, Wagner U, Luu Y, Lönnberg T, Raghav SK, Lee LK, Lund R, Ren B, Lähdesmäki H and Lahesmaa R: Global chromatin state analysis reveals lineage-specific enhancers during the initiation of human T helper 1 and T helper 2 cell polarization. Immunity. 38:1271–1284. 2013. View Article : Google Scholar : PubMed/NCBI
32	Olson NC, Sallam R, Doyle MF, Tracy RP and Huber SA: T helper cell polarization in healthy people: Implications for cardiovascular disease. J Cardiovasc Transl Res. 6:772–786. 2013. View Article : Google Scholar : PubMed/NCBI
33	Wan YY and Flavell RA: How diverse - CD4 effector T cells and their functions. J Mol Cell Biol. 1:20–36. 2009. View Article : Google Scholar : PubMed/NCBI
34	Homey B: After TH1/TH2 now comes Treg/TH17: Significance of T helper cells in immune response organization. Hautarzt. 57:730–732. 2006.In German. View Article : Google Scholar : PubMed/NCBI
35	Sakaguchi S, Ono M, Setoguchi R, Yagi H, Hori S, Fehervari Z, Shimizu J, Takahashi T and Nomura T: Foxp3+ CD25+ CD4+ natural regulatory T cells in dominant self-tolerance and autoimmune disease. Immunol Rev. 212:8–27. 2006. View Article : Google Scholar : PubMed/NCBI
36	Chen Z, Lin F, Gao Y, Li Z, Zhang J, Xing Y, Deng Z, Yao Z, Tsun A and Li B: FOXP3 and RORγt: Transcriptional regulation of Treg and Th17. Int Immunopharmacol. 11:536–542. 2011. View Article : Google Scholar
37	Charles PD, Esper GJ and Davis TL: A definition of “on”: Patient diaries compared to the UPDRS. Parkinsonism Relat Disord. 5:99–101. 1999. View Article : Google Scholar
38	Longhi M, Ricciardi G, Tommasi G, Nicolato A, Foroni R, Betrolasi L, Beltramello A, Moretto G, Tinazzi M and Gerosa M: The role of 3T magnetic resonance imaging for targeting the human subthalamic nucleus in deep brain stimulation for Parkinson Disease. J Neurol Surg A Cent Eur Neurosurg. 76:181–189. 2015. View Article : Google Scholar : PubMed/NCBI
39	Braak H, Sastre M, Bohl JR, de Vos RA and Del Tredici K: Parkinson's disease: Lesions in dorsal horn layer I, involvement of parasympathetic and sympathetic pre- and postganglionic neurons. Acta Neuropathol. 113:421–429. 2007. View Article : Google Scholar : PubMed/NCBI
40	Chen Y, Yu M, Liu X, Qu H, Chen Q, Qian W, Wei D, Xu W, Ma B and Wu W: Clinical characteristics and peripheral T cell subsets in Parkinson's disease patients with constipation. Int J Clin Exp Pathol. 8:2495–2504. 2015.PubMed/NCBI
41	Reynolds AD, Stone DK, Hutter JA, Benner EJ, Mosley RL and Gendelman HE: Regulatory T cells attenuate Th17 cell-mediated nigrostriatal dopaminergic neurodegeneration in a model of Parkinson's disease. J Immunol. 184:2261–2271. PubMed/NCBI
42	Appel SH: CD4+ T cells mediate cytotoxicity in neurodegenerative diseases. J Clin Invest. 119:13–15. 2009.