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Guo C, Yuan H, Wang Y, Feng Y, Zhang Y, Yin T, He H, Gou J, Tang X. The interplay between PEGylated nanoparticles and blood immune system. Adv Drug Deliv Rev 2023; 200:115044. [PMID: 37541623 DOI: 10.1016/j.addr.2023.115044] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2023] [Revised: 07/11/2023] [Accepted: 07/31/2023] [Indexed: 08/06/2023]
Abstract
During the last two decades, an increasing number of reports have pointed out that the immunogenicity of polyethylene glycol (PEG) may trigger accelerated blood clearance (ABC) and hypersensitivity reaction (HSR) to PEGylated nanoparticles, which could make PEG modification counterproductive. These phenomena would be detrimental to the efficacy of the load and even life-threatening to patients. Consequently, further elucidation of the interplay between PEGylated nanoparticles and the blood immune system will be beneficial to developing and applying related formulations. Many groups have worked to unveil the relevance of structural factors, dosing schedule, and other factors to the ABC phenomenon and hypersensitivity reaction. Interestingly, the results of some reports seem to be difficult to interpret or contradict with other reports. In this review, we summarize the physiological mechanisms of PEG-specific immune response. Moreover, we speculate on the potential relationship between the induction phase and the effectuation phase to explain the divergent results in published reports. In addition, the role of nanoparticle-associated factors is discussed based on the classification of the action phase. This review may help researchers to develop PEGylated nanoparticles to avoid unfavorable immune responses based on the underlying mechanism.
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Affiliation(s)
- Chen Guo
- Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, Liaoning, PR China
| | - Haoyang Yuan
- Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, Liaoning, PR China
| | - Yuxiu Wang
- Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, Liaoning, PR China
| | - Yupeng Feng
- Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, Liaoning, PR China
| | - Yu Zhang
- Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, Liaoning, PR China
| | - Tian Yin
- School of Functional Food and Wine, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, Liaoning, PR China
| | - Haibing He
- Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, Liaoning, PR China
| | - Jingxin Gou
- Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, Liaoning, PR China.
| | - Xing Tang
- Department of Pharmaceutics, School of Pharmacy, Shenyang Pharmaceutical University, 103 Wenhua Road, Shenyang 110016, Liaoning, PR China.
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Liang X, Wang Z, Yang H, Luo X, Sun J, Yang M, Shi X, Yue X, Zheng Y. Evaluation of allergenicity of cow milk treated with enzymatic hydrolysis through a mouse model of allergy. J Dairy Sci 2022; 105:1039-1050. [PMID: 34955271 DOI: 10.3168/jds.2021-20686] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2021] [Accepted: 10/08/2021] [Indexed: 01/09/2023]
Abstract
Cow milk (CM) allergy is a worldwide concern. Currently, few studies have been performed on the immunoreactivity of CM and fewer still on the antigenicity of CM in vivo and in vitro. In this study, we assessed the potential allergenicity of enzymatically hydrolyzed CM using in vitro ELISA and oral sensitization and challenge of BALB/c mice. Alcalase-, Protamex-, and Flavourzyme-treated CM (all from Novozymes) diminished IgE binding capacity, with greatest reductions of 56.31%, 50.62%, and 56.45%, respectively. Allergic symptoms and levels of total IgG1 were reduced, and allergic inflammation of the lung, jejunum, and spleen was relieved. Moreover, the numbers of CD8+ T and B220+ cells decreased, and the balance of CD4+ T/CD8+ T cells was effectively regulated. These findings suggest that the potential allergenicity of CM was reduced by enzymatic hydrolysis, and our research will lay a solid foundation for developing high-quality hypoallergenic CM products.
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Affiliation(s)
- Xiaona Liang
- College of Food Science, Shenyang Agricultural University, Shenyang 100866, P. R. China
| | - Zongzhou Wang
- College of Food Science, Shenyang Agricultural University, Shenyang 100866, P. R. China
| | - Hui Yang
- College of Food Science, Shenyang Agricultural University, Shenyang 100866, P. R. China
| | - Xue Luo
- College of Food Science, Shenyang Agricultural University, Shenyang 100866, P. R. China
| | - Jing Sun
- College of Food Science, Shenyang Agricultural University, Shenyang 100866, P. R. China
| | - Mei Yang
- College of Food Science, Shenyang Agricultural University, Shenyang 100866, P. R. China
| | - Xinyang Shi
- College of Food Science, Shenyang Agricultural University, Shenyang 100866, P. R. China
| | - Xiqing Yue
- College of Food Science, Shenyang Agricultural University, Shenyang 100866, P. R. China.
| | - Yan Zheng
- College of Food Science, Shenyang Agricultural University, Shenyang 100866, P. R. China.
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Shao J, Yin Z, Wang Y, Yang Y, Tang Q, Zhang M, Jiao J, Liu C, Yang M, Zhen L, Hassouna A, White WL, Lu J. Effects of Different Doses of Eucalyptus Oil From Eucalyptus globulus Labill on Respiratory Tract Immunity and Immune Function in Healthy Rats. Front Pharmacol 2020; 11:1287. [PMID: 32973518 PMCID: PMC7472567 DOI: 10.3389/fphar.2020.01287] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Accepted: 08/03/2020] [Indexed: 12/12/2022] Open
Abstract
Eucalyptol (1,8-cineole), the major constituent of eucalyptus oil (EO), was used in traditional medicine as a remedy for colds and bronchitis. This study aimed at clarifying the effect of eucalyptol on respiratory immune function of CD8 and CD4 cells, and alveolar macrophages (AM). Thirty male Sprague-Dawley rats were divided into experimental and control groups. The drug was given once a day for 3 weeks and the experimental group was divided according to the eucalyptol dose into: 30, 100, and 300 mg·kg-1 groups. Flow cytometry was used to detect the phagocytic function of CD4, CD8 cells, and AM in the bronchopulmonary lavage fluid. The 30 and 100 mg·kg-1 groups had an up-regulation effect on CD8 (p < 0.05), with no significant effect on macrophage phagocytosis. The 300 mg·kg-1 group had an inhibitory effect on CD8 and macrophage phagocytosis (p < 0.05), with no significant difference in CD4 between groups. Further investigation was conducted to evaluate the effect of EO on immune function in rats by detecting blood T, B, and NK cells using flow cytometry, and blood IgA, IgG, IgM, and IFN-γ levels by ELISA. High dosage of eucalyptol significantly reduced the proportion of blood B and NK cells (p < 0.05). IgA was decreased in the 100 and 300 mg·kg-1 groups (p < 0.05). There are no significant differences between the number of T cells and the IgG, IgM, and IFN-γ levels between experimental and control groups. Rational use of EO containing eucalyptol can improve the immune function of the respiratory tract and the body immunity, while high dose could have damaging effects, through modifying the phagocytic function of CD8 cells and reducing the proportion of blood B cells, NK cells, and IgA.
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Affiliation(s)
- Jie Shao
- 521 Hospital of Norinco Group, Xi'an, China
| | | | - Yaqin Wang
- 521 Hospital of Norinco Group, Xi'an, China
| | | | - Qing Tang
- 521 Hospital of Norinco Group, Xi'an, China
| | | | | | | | | | | | - Amira Hassouna
- School of Public Health and Interdisciplinary Studies, Faculty of Health and Environmental Sciences, Auckland University of Technology, Auckland, New Zealand.,Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - William Lindsey White
- School of Science, Faculty of Health and Environmental Sciences, Auckland University of Technology, Auckland, New Zealand
| | - Jun Lu
- School of Public Health and Interdisciplinary Studies, Faculty of Health and Environmental Sciences, Auckland University of Technology, Auckland, New Zealand.,School of Science, Faculty of Health and Environmental Sciences, Auckland University of Technology, Auckland, New Zealand.,College of Food Engineering and Nutritional Science, Shaanxi Normal University, Xi'an, China.,Maurice Wilkins Centre for Molecular Biodiscovery, Auckland, New Zealand
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Kalli F, Cioni M, Parodi A, Altosole T, Ferrera F, Barra G, De Palma R, Fenoglio D, Filaci G, Rongioletti F. Increased frequency of interleukin-4 and reduced frequency of interferon-γ and IL-17-producing CD4+ and CD8+ cells in scleromyxedema. J Eur Acad Dermatol Venereol 2020; 34:1092-1097. [PMID: 31912592 DOI: 10.1111/jdv.16136] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2019] [Accepted: 11/12/2019] [Indexed: 11/27/2022]
Abstract
BACKGROUND Little is known about the pathogenesis of scleromyxedema, a life-threatening fibromucinosis disease with immunological dysregulation. OBJECTIVES To investigate on T-cell phenotype, function and cytokine biology in search of new insights supporting the immunopathogenesis of the disease. METHODS We analysed the frequency of circulating lymphocyte subsets, the T-cell maturation stage, the generation of antigen-specific T-cell lines and T-cell cytokine secretion. RESULTS The analysis of T-cell maturation stage and the TCR spectratyping findings revealed that scleromyxedema patients showed clear immunological signs of long-lasting immune system activation and stimulation leading to a skewed T-cell repertoire. Moreover, these analyses showed that both CD4+ and CD8+ T cells from scleromyxedema patients have a profound deficiency (even after stimulation) relatively to the production of IFN-γ and IL17 with respect to healthy donor control cells, while they are massively skewed towards IL4 secretion after stimulation. CONCLUSIONS Our data indicate that a chronic Th2-skewed T-cell response against an unknown target antigen leading to abnormally high IL4 secretion, a pro-fibrotic cytokine, is a main immunological hallmark of scleromyxedema patients. These results, never reported before, may have a translational therapeutic value due to the availability of anti-IL4 agents such as dupilumab.
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Affiliation(s)
- F Kalli
- Centre of Excellence for Biomedical Research, University of Genoa, Genoa, Italy
| | - M Cioni
- Section of Dermatology, DISSAL, University of Genoa, Genoa, Italy.,Section of Pathology, Department of Surgical and Morphological Sciences, University of Genoa, Genoa, Italy
| | - A Parodi
- Centre of Excellence for Biomedical Research, University of Genoa, Genoa, Italy
| | - T Altosole
- Centre of Excellence for Biomedical Research, University of Genoa, Genoa, Italy
| | - F Ferrera
- Centre of Excellence for Biomedical Research, University of Genoa, Genoa, Italy
| | - G Barra
- Department of Precision Medicine, Università della Campania "L. Vanvitelli", Napoli, Italy
| | - R De Palma
- Institute of Protein Biochemistry, CNR, Napoli, Italy.,Department of Internal Medicine, University of Genoa- IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - D Fenoglio
- Centre of Excellence for Biomedical Research, University of Genoa, Genoa, Italy.,Department of Internal Medicine, University of Genoa- IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - G Filaci
- Department of Internal Medicine and Centre of Excellence for Biomedical Research, University of Genoa, Genoa, Italy.,Bioterapy Unit, IRCCS Ospedale Policlinico San Martino, Genoa, Italy
| | - F Rongioletti
- Section of Pathology, Department of Surgical and Morphological Sciences, University of Genoa, Genoa, Italy.,Department of Medical Science and Public Health, Unit of Dermatology, University of Cagliari, Cagliari, Italy
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Zhang X, Fujii T, Ogata H, Yamasaki R, Masaki K, Cui Y, Matsushita T, Isobe N, Kira JI. Cerebrospinal fluid cytokine/chemokine/growth factor profiles in idiopathic hypertrophic pachymeningitis. J Neuroimmunol 2019; 330:38-43. [PMID: 30784775 DOI: 10.1016/j.jneuroim.2019.01.010] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2018] [Revised: 01/17/2019] [Accepted: 01/17/2019] [Indexed: 02/06/2023]
Abstract
Hypertrophic pachymeningitis (HP) is a rare neurologic disease causing inflammatory fibrous thickening of the brain and spinal dura mater. We investigated the cerebrospinal fluid cytokine profile of HP by measuring 28 cytokines/chemokines/growth factors with a multiplexed fluorescent immunoassay in 8 patients with HP (6 idiopathic, 1 IgG4-related, 1 anti-neutrophil cytoplasmic antibody-related), and 11 with other non-inflammatory neurologic diseases (OND). Interleukin (IL)-4, IL-5, IL-9, IL-10, TNF-α, and CXCL8/IL-8 levels were significantly higher in idiopathic HP (IHP) than OND. Cluster analyses disclosed two major clusters: one mainly consisted of IHP and the other of OND, suggesting a unique cytokine profile in IHP.
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Affiliation(s)
- Xu Zhang
- Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan; Department of Neurology and Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China. shu-@neuro.med.kyushu-u.ac.jp
| | - Takayuki Fujii
- Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
| | - Hidenori Ogata
- Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
| | - Ryo Yamasaki
- Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
| | - Katsuhisa Masaki
- Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yiwen Cui
- Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
| | - Takuya Matsushita
- Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
| | - Noriko Isobe
- Department of Neurological Therapeutics, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
| | - Jun-Ichi Kira
- Department of Neurology, Neurological Institute, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
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Fonteh P, Smith M, Brand M. Adaptive Immune Cell Dysregulation and Role in Acute Pancreatitis Disease Progression and Treatment. Arch Immunol Ther Exp (Warsz) 2018; 66:199-209. [PMID: 29189884 DOI: 10.1007/s00005-017-0495-1] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2017] [Accepted: 08/31/2017] [Indexed: 12/18/2022]
Abstract
Acute pancreatitis (AP) is an inflammation of the pancreas caused by various stimuli including excessive alcohol consumption, gallstone disease and certain viral infections. Managing specifically the severe form of AP is limited due to lack of an understanding of the complex immune events that occur during AP involving immune cells and inflammatory molecules such as cytokines. The relative abundance of various immune cells resulting from the immune dysregulation drives disease progression. In this review, we examine the literature on the adaptive immune cells in AP, the prognostic value of these cells in stratifying patients into appropriate care and treatment strategies based on cell frequency in different AP severities are discussed.
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Affiliation(s)
- Pascaline Fonteh
- Department of Surgery, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown, Johannesburg, 2193, South Africa.
| | - Martin Smith
- Department of Surgery, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown, Johannesburg, 2193, South Africa
| | - Martin Brand
- Department of Surgery, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown, Johannesburg, 2193, South Africa
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7
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He SH, Zhang HY, Zeng XN, Chen D, Yang PC. Mast cells and basophils are essential for allergies: mechanisms of allergic inflammation and a proposed procedure for diagnosis. Acta Pharmacol Sin 2013; 34:1270-83. [PMID: 23974516 DOI: 10.1038/aps.2013.88] [Citation(s) in RCA: 71] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2013] [Accepted: 06/12/2013] [Indexed: 02/06/2023]
Abstract
The current definition of allergy is a group of IgE-mediated diseases. However, a large portion of patients with clinical manifestations of allergies do not exhibit elevated serum levels of IgE (sIgEs). In this article, three key factors, ie soluble allergens, sIgEs and mast cells or basophils, representing the causative factors, messengers and primary effector cells in allergic inflammation, respectively, were discussed. Based on current knowledge on allergic diseases, we propose that allergic diseases are a group of diseases mediated through activated mast cells and/or basophils in sensitive individuals, and allergic diseases include four subgroups: (1) IgE dependent; (2) other immunoglobulin dependent; (3) non-immunoglobulin mediated; (4) mixture of the first three subgroups. According to our proposed definition, pseudo-allergic-reactions, in which mast cell or basophil activation is not mediated via IgE, or to a lesser extent via IgG or IgM, should be non-IgE-mediated allergic diseases. Specific allergen challenge tests (SACTs) are gold standard tests for diagnosing allergies in vivo, but risky. The identification of surface membrane activation markers of mast cells and basophils (CD203c, CCR3, CD63, etc) has led to development of the basophil activation test (BAT), an in vitro specific allergen challenge test (SACT). Based on currently available laboratory allergy tests, we here propose a laboratory examination procedure for allergy.
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8
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Yang GY, Chen X, Sun YC, Ma CL, Qian G. Chemokine-like factor 1 (CLFK1) is over-expressed in patients with atopic dermatitis. Int J Biol Sci 2013; 9:759-65. [PMID: 23983609 PMCID: PMC3753440 DOI: 10.7150/ijbs.6291] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2013] [Accepted: 07/24/2013] [Indexed: 12/31/2022] Open
Abstract
Background: Human chemokine-like factor 1 (CKLF1), a recently discovered chemokine, has a broad spectrum of biological functions in immune-mediated diseases. It is highly expressed on Th2 lymphocytes and is a functional ligand for human CCR4. CKLF1 has a major role in the recruitment and activation of leucocytes, which plays an important role in the pathogenesis of allergic diseases. The present study was designed to determine the expression of CKLF1 in skin and serum in patients with atopic dermatitis (AD). Methods: The CKLF1 protein expression in skin lesion was analyzed by immunohistochemistry and ELISA. The mRNA expression of CKLF1 in skin lesion was detected by Real-time PCR. The serum levels of CKLF1, IgE, eotaxin, IL-4, IL-5, and IL-13 were measured by ELISA. Results: Histopathological changes in the skin of AD patients showed local inflammation with epidermal thickening and significant inflammatory cellular infiltration. Immunohistochemistry results demonstrated that CKLF1-staining positive cells were located in the epidermal and dermis, and that the CKLF1 expression in AD patients was significantly higher than that in normal control. The CKLF1 mRNA expression in AD patients was significantly higher than that in healthy controls. Serum CKLF1 and IgE levels were significantly increased in AD patients, as were the serum levels of IL-4, IL-5, IL-13 and eotaxin. Conclusions: Both CKLF1 protien and mRNA levels are overexpressed in the skin lesion of AD patients, along with an increase in serum CKLF1 level, indicating that CKLF1 may play an important role in the development of atopic dermatitis.
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Affiliation(s)
- Gao-Yun Yang
- Department of Dermatology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, China.
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Serum Interleukin-4 and Total Immunoglobulin E in Nonatopic Alopecia Areata Patients and HLA-DRB1 Typing. Dermatol Res Pract 2010; 2010:503587. [PMID: 20671941 PMCID: PMC2910459 DOI: 10.1155/2010/503587] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2010] [Accepted: 06/01/2010] [Indexed: 02/07/2023] Open
Abstract
Background. Interleukin-4 (IL-4), a Th2 cytokine, can stimulate immunoglobulin E (IgE) transcription. No previous studies evaluated the genetic mechanisms in nonatopic AA patients with elevated serum IgE.
Objective. To compare serum IL-4 and total IgE levels between Egyptian nonatopic AA patients and healthy subjects and to investigate a possible relation to HLA-DRB1 alleles. Results. Serum IL-4 and total IgE were measured by ELISA in 40 controls and 54 nonatopic AA patients. Patients' HLA-DRB1 typing by sequence specific oligonucleotide probe technique was compared to normal Egyptian population. We found significantly elevated serum IL-4 and total IgE in AA patients (particularly alopecia universalis, AU, and chronic patients) (P < .01). HLA-DRB1*11 is a general susceptibility/chronicity allele. DRB1*13 is a protective allele. DRB1*01 and DRB1*07 are linked to chronicity. Localized AA showed decreased DRB1*03 and DRB1*07. Extensive forms showed increased DRB1*08 and decreased DRB1*04. Elevated IL4 and IgE were observed in patients with DRB1*07 and DRB1*11 not DRB1*04.
Conclusion. Serum IL-4 and IgE are elevated in nonatopic AA patients, particularly AU and chronic disease. Relevant susceptibility, chronicity, and severity HLADRB1 alleles may have a role in determining type, magnitude, and duration of immune response in AA favouring increased IL4 and IgE.
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Suzuki M, Zheng X, Zhang X, Ichim TE, Beduhn ME, Min W. Oligonucleotide based-strategies for allergy with special reference to siRNA. Expert Opin Biol Ther 2010; 9:441-50. [PMID: 19344281 DOI: 10.1517/14712590902841924] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022]
Abstract
BACKGROUND Allergic diseases are a significant global health care problem. Current pharmacological approaches address symptoms but do not alter the underlying immune dysregulation. Current allergen-specific immunotherapy has several drawbacks. Therefore, approaches that attenuate allergic responses safely and effectively at the level of upstream causative events are desirable. Oligonuleotide-based therapies [CpG DNA, antisense oligonucleotides, and small interfering RNA (siRNA)] are promising approaches. OBJECTIVE/METHODS We review developments in oligonucleotide-based therapies and the potential of siRNA for treating allergy. RESULTS/CONCLUSIONS Strategies with oligonucleotides basically aim to reduce T helper type 2 (Th2) responses. It is controversial whether the reduction of Th2 responses does, in fact, attenuate allergic diseases. Increased understanding of allergic mechanisms will enhance the efficacy of oligonucleotide-based therapy.
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Affiliation(s)
- Motohiko Suzuki
- University of Western Ontario, University Hospital C9 - 136, Department of Surgery, London, Ontario, N6A 5A5, Canada
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11
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Suzuki M, Zheng X, Zhang X, Li M, Vladau C, Ichim TE, Sun H, Min LR, Garcia B, Min WP. Novel vaccination for allergy through gene silencing of CD40 using small interfering RNA. THE JOURNAL OF IMMUNOLOGY 2008; 180:8461-9. [PMID: 18523314 DOI: 10.4049/jimmunol.180.12.8461] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
Small interfering RNA (siRNA) is a potent means of inducing gene-specific silencing. Gene silencing strategies using siRNA have demonstrated therapeutic benefits in animal models of various diseases, and are currently in clinical trials. However, the utility of gene silencing as a treatment for allergic diseases has not yet been reported. In this study, we report a novel therapy for allergy through gene silencing of CD40, a critical costimulatory molecule and a key factor in allergic immune responses. Silencing CD40 resulted in generation of immunoregulatory dendritic cells (DCs). Administration of CD40 siRNA remarkably reduced nasal allergic symptoms and local eosinophil accumulation in the OVA-induced allergic mice. The OVA-specific T cell response was inhibited after the CD40 siRNA treatment. Additionally, anti-OVA specific IgE and production of IL-4 and IL-5 of T cells stimulated by OVA were significantly decreased in CD40 siRNA-treated mice. Furthermore, we demonstrated that the therapeutic effects by CD40 siRNA were associated with impaired Ag-presenting functions of DCs and B cells, and generation of regulatory T cells. The present study highlights a therapeutic potential of siRNA-based treatment for allergic diseases.
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Affiliation(s)
- Motohiko Suzuki
- Department of Surgery, University of Western Ontario, London, ON, Canada
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12
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Pietruczuk M, Dabrowska MI, Wereszczynska-Siemiatkowska U, Dabrowski A. Alteration of peripheral blood lymphocyte subsets in acute pancreatitis. World J Gastroenterol 2006; 12:5344-5351. [PMID: 16981265 PMCID: PMC4088202 DOI: 10.3748/wjg.v12.i33.5344] [Citation(s) in RCA: 65] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2006] [Revised: 05/28/2006] [Accepted: 06/15/2006] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate peripheral blood lymphocyte subsets in patients with acute pancreatitis (AP). METHODS Twenty patients with mild AP (M-AP) and 15 with severe AP (S-AP) were included in our study. Peripheral blood lymphocytes were examined at d 1-3, 5, 10 and 30 by means of flow cytometry. RESULTS A significant depletion of circulating lymphocytes was found in AP. In the early AP, the magnitude of depletion was similar for T- and B- lymphocytes. In the late course of S-AP, B-lymphocytes were much more depleted than T-lymphocytes. At d 10, strong shift in the CD7+/CD19+ ratio implicating predominance of T- over B-lymphocytes in S-AP was found. Among T-lymphocytes, the significant depletion of the CD4+ population was observed in M-AP and S-AP, while CD8+ cells were in the normal range. Lymphocytes were found to strongly express activation markers: CD69, CD25, CD28, CD38 and CD122. Serum interleukin-2 (IL-2), IL-4, IL-5, IL-10, interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) levels were significantly increased in both forms of AP. The magnitude of elevation of cytokines known to be produced by Th2 was much higher than cytokines produced by Th1 cells. CONCLUSION AP in humans is characterized by significant reduction of peripheral blood T- and B-lymphocytes.
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Affiliation(s)
- Miroslawa Pietruczuk
- Department of Gastroenterology and Internal Medicine, Medical University of Bialystok, Sklodowska-Curie 24A, Bialystok 15-276, Poland.
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Abstract
Atopic dermatitis (AD) is commonly associated with immunoglobulin E (IgE) antibody-related mechanisms, which are the focus of this article. The vast majority of patients with AD exhibit hyperproduction of IgE, particularly during disease onset or flare. IgE-dependent late-phase reactions may influence the chronic inflammatory response in AD. Clearly, genetics plays a major role in determining who develops AD. However, the recent increase in AD prevalence suggests that a complex interaction between environmental factors and susceptibility genes results in clinical expression of the disorder. These immunologic "triggers" differ among individuals and include various foods, airborne allergens, irritants and contactants, hormones, stress, climate, and microorganisms. Although much about AD remains to be elucidated, our current understanding of its pathophysiology has provided clinicians with the ability to construct more rational therapeutic interventions, including multiple-agent regimens that provide both immediate relief and effective long-term management. Future advances will come from identification of the genes causing this disease and further elucidation of the immunoregulatory mechanisms involved in the pathogenesis of AD.
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Li M, Messaddeq N, Teletin M, Pasquali JL, Metzger D, Chambon P. Retinoid X receptor ablation in adult mouse keratinocytes generates an atopic dermatitis triggered by thymic stromal lymphopoietin. Proc Natl Acad Sci U S A 2005; 102:14795-800. [PMID: 16199515 PMCID: PMC1253602 DOI: 10.1073/pnas.0507385102] [Citation(s) in RCA: 165] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/03/2023] Open
Abstract
To investigate the role of retinoid X receptors (RXRs) in epidermal homeostasis, we generated RXRalphabeta(ep-/-) somatic mutants in which both RXRalpha and RXRbeta are selectively ablated in epidermal keratinocytes of adult mice. These mice develop a chronic dermatitis mimicking that observed in atopic dermatitis (AD) patients. In addition, they exhibit immunological abnormalities including elevated serum levels of IgE and IgG, associated with blood and tissue eosinophilia, indicating that keratinocyte-selective ablation of RXRs also generates a systemic syndrome similar to that found in AD patients. Furthermore, the profile of increased expression of cytokines and chemokines in skin of keratinocyte-selective RXRalphabeta-ablated mutants was typical of a T helper 2-type inflammation, known to be crucially involved in human AD pathogenesis. Finally, we demonstrate that thymic stromal lymphopoietin, whose expression is rapidly and strongly induced in RXRalphabeta-ablated keratinocytes, plays a key role in initiating the skin and systemic AD-like pathologies.
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Affiliation(s)
- Mei Li
- Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Institut Clinique de la Souris (ICS), Collège de France, BP10142, 1 Rue Laurent Fries, Illkirch 67404, CU de Strasbourg, France
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15
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Loza MJ, Luppi P, Kiefer K, Martin ES, Szczytkowski JL, Perussia B. Human peripheral CD2−/lo T cells: an extrathymic population of early differentiated, developing T cells. Int Immunol 2005; 17:1213-25. [PMID: 16027135 DOI: 10.1093/intimm/dxh298] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
We previously reported that a subset of human peripheral blood CD3+ T cells expresses low-to-null CD2 levels (CD2-/lo), produces type 2 cytokines and is inducible to differentiate to functionally mature IFN-gamma+ cells. Multiple-color immunofluorescence analysis indicated that this population, representing <0.1% of the T cells in fresh lymphocytes, contains subsets that are phenotypically immature, including CD4-CD8- and CD3+TCR- cells. Ex vivo, the CD2-/lo cells can proliferate (carboxyfluorescein diacetate succinimidyl ester analysis) independently from exogenous stimulation, respond to CD3-mediated stimulation with significantly greater proliferation than the autologous mature cells and their subsets are inducible to undergo in vitro a developmental sequence similar to that reported for the phenotypically similar thymic populations. This is especially evident for the CD4+CD8+ subset. CD2-/lo T-cell populations exhibit a TCR repertoire (Vbeta chain distribution) that is complete but different (complementarity determining region R3 analysis) from that of the autologous CD2+ T cells. These characteristics distinguish peripheral CD2-/lo T cells as possible early differentiated T cells that may undergo extrathymic maturation, and potentially contribute to maintain the peripheral naive T-cell pool. These findings define the existence of phenotypically immature T cells in the periphery. Also, given the high numbers of CD2-/lo T cells generated, upon ex vivo culture, from peripheral lymphocytes of all adult and neonatal individuals tested, they have relevance to clinical applications for immune reconstitution of T cells, as well as myeloid cells, via myeloid colony-stimulating factors and type 2 cytokines.
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Affiliation(s)
- Matthew J Loza
- Department of Microbiology and Immunology, Kimmel Cancer Center, Jefferson Medical College, Thomas Jefferson University, BLSB 750, 233 South, 10th Street, Philadelphia, PA 19107, USA
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16
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Ostrowska E, Knowles A, Muralitharan M, Cross RF, Bauman DE, Dunshea FR. Effects of dietary conjugated linoleic acid on haematological and humoral responses in the grower pig. ACTA ACUST UNITED AC 2004. [DOI: 10.1071/ar04002] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
The effects of conjugated linoleic acid (CLA) on the levels of total serum leucocytes, granulocytes including neutrophils, basophils, and eosinophils, as well as on monocytes and leucocytes were measured in pigs selected from a clean (minimal disease) herd. Thirty pigs were fed different rates of dietary CLA (0, 1.25, 2.5, 5.0, 7.5, and 10.0 g CLA-55/kg diet) for 8 weeks. Blood samples were collected at the end of the study for assessment of haematological and humoral responses to CLA supplementation. No difference in total white blood cells including the neutrophil, monocyte, and lymphocyte counts was observed among different dietary groups. A dose-dependent reduction (P = 0.02) in eosinophil concentrations suggests that CLA exerts anti-inflammatory activities. A 2-fold increase in the level of basophils was recorded in pigs fed lower levels of CLA (1.25 and 2.5 g CLA/kg diet) but the levels decreased gradually (P = 0.05) and were below the detection limit at the highest rate (10 g/kg) of CLA supplementation. The level of IgG was reduced by over 50% in CLA-fed pigs (P < 0.001), although the response was quadratic in nature (P < 0.001). T-cell population analysis showed that CD4+ cells tended (P = 0.06) to be reduced linearly with increasing inclusion of CLA in the diet. Our results suggest that dietary CLA modulates haematological and humoral responses in a dose-dependent manner.
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17
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Abstract
The diagnosis of human allergic diseases involves the combined use of a careful clinical history, physical examination, and in vitro and in vivo assay methods for the detection of IgE antibodies of defined allergen specificities. In vivo (skin testing) and in vitro (measurement of specific IgE in serum) techniques cannot be considered interchangeable, the former reflecting not only the presence of IgE but also mast cell integrity, vascular and neural responsiveness. Both techniques have similarities and differences, advantages and disadvantages. Recently introduced "second generation" immunoassays have continued to improve the analytical sensitivity and reproducibility thanks to automation and improved reagent quality. Quantitative assays may allow the use of specific clinical thresholds able to differentiate symptomatic from asymptomatic patients. False-negative and false-positive results should derive from lability of some major extracts, and from possible cross-reactivities, respectively. Characterization of allergens at a molecular and submolecular level and, where necessary, the use of recombinant allergens can reduce cross-reactions and further improve the quality of immunoassays.
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Affiliation(s)
- Mario Plebani
- Department of Laboratory Medicine, University-Hospital of Padova, and Centre for Biomedical Research, Castelfranco, Veneto, Italy.
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18
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Walker JK, Fong AM, Lawson BL, Savov JD, Patel DD, Schwartz DA, Lefkowitz RJ. β-Arrestin-2 regulates the development of allergic asthma. J Clin Invest 2003. [DOI: 10.1172/jci200317265] [Citation(s) in RCA: 149] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
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19
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Walker JKL, Fong AM, Lawson BL, Savov JD, Patel DD, Schwartz DA, Lefkowitz RJ. Beta-arrestin-2 regulates the development of allergic asthma. J Clin Invest 2003; 112:566-74. [PMID: 12925697 PMCID: PMC171386 DOI: 10.1172/jci17265] [Citation(s) in RCA: 85] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023] Open
Abstract
Asthma is a chronic inflammatory disorder of the airways that is coordinated by Th2 cells in both human asthmatics and animal models of allergic asthma. Migration of Th2 cells to the lung is key to their inflammatory function and is regulated in large part by chemokine receptors, members of the seven-membrane-spanning receptor family. It has been reported recently that T cells lacking beta-arrestin-2, a G protein-coupled receptor regulatory protein, demonstrate impaired migration in vitro. Here we show that allergen-sensitized mice having a targeted deletion of the beta-arrestin-2 gene do not accumulate T lymphocytes in their airways, nor do they demonstrate other physiological and inflammatory features characteristic of asthma. In contrast, the airway inflammatory response to LPS, an event not coordinated by Th2 cells, is fully functional in mice lacking beta-arrestin-2. beta-arrestin-2-deficient mice demonstrate OVA-specific IgE responses, but have defective macrophage-derived chemokine-mediated CD4+ T cell migration to the lung. This report provides the first evidence that beta-arrestin-2 is required for the manifestation of allergic asthma. Because beta-arrestin-2 regulates the development of allergic inflammation at a proximal step in the inflammatory cascade, novel therapies focused on this protein may prove useful in the treatment of asthma.
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Affiliation(s)
- Julia K L Walker
- Department of Medicine, Duke University Medical Center, Box 3821, Durham, North Carolina 27710, USA
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20
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Tsapogas P, Breslin T, Bilke S, Lagergren A, Månsson R, Liberg D, Peterson C, Sigvardsson M. RNA analysis of B cell lines arrested at defined stages of differentiation allows for an approximation of gene expression patterns during B cell development. J Leukoc Biol 2003; 74:102-10. [PMID: 12832448 DOI: 10.1189/jlb.0103008] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
The development of a mature B lymphocyte from a bone marrow stem cell is a highly ordered process involving stages with defined features and gene expression patterns. To obtain a deeper understanding of the molecular genetics of this process, we have performed RNA expression analysis of a set of mouse B lineage cell lines representing defined stages of B cell development using Affymetrix microarrays. The cells were grouped based on their previously defined phenotypic features, and a gene expression pattern for each group of cell lines was established. The data indicated that the cell lines representing a defined stage generally presented a high similarity in overall expression profiles. Numerous genes could be identified as expressed with a restricted pattern using dCHIP-based, quantitative comparisons or presence/absence-based, probabilistic state analysis. These experiments provide a model for gene expression during B cell development, and the correctly identified expression patterns of a number of control genes suggest that a series of cell lines can be useful tools in the elucidation of the molecular genetics of a complex differentiation process.
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Affiliation(s)
- Panagiotis Tsapogas
- Laboratory for Cellular Differentiation, Department for Stemcell Biology, Lund University, Sweden
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21
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Crosby JR, Shen HH, Borchers MT, Justice JP, Ansay T, Lee JJ, Lee NA. Ectopic expression of IL-5 identifies an additional CD4(+) T cell mechanism of airway eosinophil recruitment. Am J Physiol Lung Cell Mol Physiol 2002; 282:L99-108. [PMID: 11741821 DOI: 10.1152/ajplung.2002.282.1.l99] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
CD4(+) T cells have a critical role in the development of allergic pulmonary inflammation, including the recruitment of eosinophils to the airway lumen and interstitium. The expression of interleukin (IL)-5 by CD4(+) cells has, in particular, often been lionized as the central link between allergic inflammation and the concomitant expansion or recruitment of eosinophils. The mechanism(s) by which CD4(+) T cells mediates eosinophil recruitment was assessed with gene knockout mice deficient for T cells or T cell subtypes and a unique IL-5 transgenic mouse (line NJ.1726) that constitutively overexpresses this cytokine in the lung epithelium. Pulmonary IL-5 expression is significantly attenuated in T cell- and CD4(+) but not CD8(+) cell-deficient animals, suggesting an obvious explanation for the lack of eosinophils in the lungs of T cell-deficient and CD4(-/-) mice. However, although the constitutive expression of IL-5 in the lung epithelium of NJ.1726 mice elicited an eosinophilia in the airway lumen of both naive and ovalbumin-treated mice, in the absence of CD4(+) cells, allergen-mediated eosinophil recruitment to the bronchoalveolar lavage fluid was abolished. Moreover, intranasal instillation of the potent eosinophil-specific chemokine eotaxin-2 was incapable of eliciting eosinophil recruitment in naive and ovalbumin-treated NJ.1726 CD4(-/-) mice, suggesting that eosinophil trafficking during allergic inflammatory responses is a consequence of a CD4(+) cell-mediated event(s) in addition to IL-5 expression and the establishment of a pulmonary chemokine gradient.
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Affiliation(s)
- Jeffrey R Crosby
- Division of Hematology/Oncology, Department of Biochemistry and Molecular Biology, Mayo Clinic Scottsdale, Scottsdale, Arizona 85259, USA
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22
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Abstract
The interaction between CD40 and its cognate ligand, CD40 ligand, is a primary regulator of the peripheral immune response, including modulation of T lymphocyte activation, B lymphocyte differentiation and antibody secretion, and innate immune cell activation, maturation, and survival. Recently, we and others have identified CD40 expression on a variety of CNS cells, including endothelial cells, smooth muscle cells, astroglia and microglia, and have found that, on many of these cells, CD40 expression is enhanced by pro-inflammatory stimuli. Importantly, the CD40-CD40 ligand interaction on microglia triggers a series of intracellular signaling events that are discussed, beginning with Src-family kinase activation and culminating in microglial activation as evidenced by tumor necrosis factor-alpha secretion. Based on the involvement of microglial activation and brain inflammation in Alzheimer's disease pathogenesis, we have investigated co-stimulation of microglia, smooth muscle, and endothelial cells with CD40 ligand in the presence of low doses of freshly solubilized amyloid-beta peptides. Data reviewed herein show that CD40 ligand and amyloid-beta act synergistically to promote pro-inflammatory responses by these cells, including secretion of interleukin-1 beta by endothelial cells and tumor necrosis factor-alpha by microglia. As these cytokines have been implicated in neuronal injury, a comprehensive model of pro-inflammatory CD40 ligand and amyloid-beta initiated Alzheimer's disease pathogenesis (mediated by multiple CNS cells) is proposed.
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Affiliation(s)
- T Town
- Department of Psychiatry, Roskamp Institute, University of South Florida, 3515 E. Fletcher Avenue, Tampa, FL 33613, USA
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23
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Lee NA, Gelfand EW, Lee JJ. Pulmonary T cells and eosinophils: coconspirators or independent triggers of allergic respiratory pathology? J Allergy Clin Immunol 2001; 107:945-57. [PMID: 11398070 DOI: 10.1067/mai.2001.116002] [Citation(s) in RCA: 98] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Etiologic discussions of allergic respiratory pathology frequently engender rabid constituencies of pro-T cell or proeosinophil disciples, each claiming, often with religious fervor, the importance of their leukocyte. However, increasing evidence suggests that the exclusionary rhetoric from either camp is inadequate to explain many of the pathologic changes occurring in the lung. Data from both asthmatic patient and mouse models of allergic respiratory inflammation suggest that, in addition to cell-autonomous activities, T-cell and eosinophil interactions may be critical to the onset and progression of pulmonary pathology. These studies also suggest that T-lymphocyte subpopulations and eosinophils communicate by means of both direct cell-cell interactions and through the secretion of inflammatory signals. Collectively, the data support an expanded view of T-cell and eosinophil activities in the lung, including both immunoregulative activities and downstream effector functions impinging directly on lung function.
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Affiliation(s)
- N A Lee
- Division of Hematology/Oncology, Department of Biochemistry and Molecular Biology, Mayo Clinic Scottsdale, 13400 E. Shea Blvd., Scottsdale, AZ 85259, USA
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