Research article

Histamine suppresses T helper 17 responses mediated by transforming growth factor-β1 in murine chronic allergic contact dermatitis

  • Received: 27 September 2018 Accepted: 05 December 2018 Published: 07 December 2018
  • Allergic skin diseases are caused by the introduction of antigen into the skin. Repeated application of antigens prompts the development of atopic dermatitis (AD) and chronic allergic contact dermatitis (CACD). Histamine facilitates the development of chronic lesions in CACD. T helper (Th)17 cells are less prevalent in the chronic lesional skin compared to acute lesional skin in AD and CACD. The present experiment determined the effects of histamine in regulating Th17 in a murine model of CACD. CACD was induced by repeated epicutaneous challenge of 2,4,6-trinitro-1-chlorobenzene in histidine decarboxylase (HDC) (-/-) mice. Th17 response were analyzed by transforming growth factor (TGF)-β1, interleukin (IL)-17 and IL-22 levels in lesional skin. TGF-β1 was injected into the dermis of CACD-developing mice. Histamine H1 or H4 receptor antagonist were orally administrated in CACD-developing mice. IL-17 and IL-22 levels were lower in HDC (+/+) mice compared to HDC (-/-) mice. TGF-β1 levels were also lower in HDC (+/+) mice compared to HDC (-/-) mice. TGF-β1 injection increased IL-17 and IL-22 levels in the lesional skin of HDC (+/+) mice. Histamine H1 or H4 receptor antagonist administration also increased TGF-β1, IL-17 and IL-22 levels in the lesional skin of HDC (+/+) mice. In conclusion, histamine suppresses Th17 function in murine CACD. This effect was induced by the down-regulation of TGF-β1 through histamine H1 and H4 receptors.

    Citation: Masahiro Seike. Histamine suppresses T helper 17 responses mediated by transforming growth factor-β1 in murine chronic allergic contact dermatitis[J]. AIMS Allergy and Immunology, 2018, 2(4): 180-189. doi: 10.3934/Allergy.2018.4.180

    Related Papers:

    [1] Nikolay Kalaydzhiev, Elena Zlatareva, Dessislava Bogdanova, Svetozar Stoichev, Avgustina Danailova . Changes in biophysical properties and behavior of aging human erythrocytes treated with natural polyelectrolytes. AIMS Biophysics, 2025, 12(1): 14-28. doi: 10.3934/biophy.2025002
    [2] Lajevardipour Alireza, W. M. Chon James, H. A. Clayton Andrew . Determining complex aggregate distributions of macromolecules using photobleaching image correlation microscopy. AIMS Biophysics, 2015, 2(1): 1-7. doi: 10.3934/biophy.2015.1.1
    [3] Claudia Tanja Mierke . Physical role of nuclear and cytoskeletal confinements in cell migration mode selection and switching. AIMS Biophysics, 2017, 4(4): 615-658. doi: 10.3934/biophy.2017.4.615
    [4] Nily Dan . Membrane-induced interactions between curvature-generating protein domains: the role of area perturbation. AIMS Biophysics, 2017, 4(1): 107-120. doi: 10.3934/biophy.2017.1.107
    [5] Klemen Bohinc, Leo Lue . On the electrostatics of DNA in chromatin. AIMS Biophysics, 2016, 3(1): 75-87. doi: 10.3934/biophy.2016.1.75
    [6] Piotr H. Pawłowski . Charged amino acids may promote coronavirus SARS-CoV-2 fusion with the host cell. AIMS Biophysics, 2021, 8(1): 111-120. doi: 10.3934/biophy.2021008
    [7] Andrew H.A. Clayton . Cell Surface Receptors in the 21st Century. AIMS Biophysics, 2014, 1(1): 51-52. doi: 10.3934/biophy.2014.1.51
    [8] István P. Sugár . Density of electric field energy around two surface-charged spheres surrounded by electrolyte I. The spheres are separated from each other. AIMS Biophysics, 2022, 9(2): 86-95. doi: 10.3934/biophy.2022008
    [9] Michelle de Medeiros Aires, Janine Treter, Antônio Nunes Filho, Igor Oliveira Nascimento, Alexandre José Macedo, Clodomiro Alves Júnior . Minimizing Pseudomonas aeruginosa adhesion to titanium surfaces by a plasma nitriding process. AIMS Biophysics, 2017, 4(1): 19-32. doi: 10.3934/biophy.2017.1.19
    [10] Arjun Acharya, Madan Khanal, Rajesh Maharjan, Kalpana Gyawali, Bhoj Raj Luitel, Rameshwar Adhikari, Deependra Das Mulmi, Tika Ram Lamichhane, Hari Prasad Lamichhane . Quantum chemical calculations on calcium oxalate and dolichin A and their binding efficacy to lactoferrin: An in silico study using DFT, molecular docking, and molecular dynamics simulations. AIMS Biophysics, 2024, 11(2): 142-165. doi: 10.3934/biophy.2024010
  • Allergic skin diseases are caused by the introduction of antigen into the skin. Repeated application of antigens prompts the development of atopic dermatitis (AD) and chronic allergic contact dermatitis (CACD). Histamine facilitates the development of chronic lesions in CACD. T helper (Th)17 cells are less prevalent in the chronic lesional skin compared to acute lesional skin in AD and CACD. The present experiment determined the effects of histamine in regulating Th17 in a murine model of CACD. CACD was induced by repeated epicutaneous challenge of 2,4,6-trinitro-1-chlorobenzene in histidine decarboxylase (HDC) (-/-) mice. Th17 response were analyzed by transforming growth factor (TGF)-β1, interleukin (IL)-17 and IL-22 levels in lesional skin. TGF-β1 was injected into the dermis of CACD-developing mice. Histamine H1 or H4 receptor antagonist were orally administrated in CACD-developing mice. IL-17 and IL-22 levels were lower in HDC (+/+) mice compared to HDC (-/-) mice. TGF-β1 levels were also lower in HDC (+/+) mice compared to HDC (-/-) mice. TGF-β1 injection increased IL-17 and IL-22 levels in the lesional skin of HDC (+/+) mice. Histamine H1 or H4 receptor antagonist administration also increased TGF-β1, IL-17 and IL-22 levels in the lesional skin of HDC (+/+) mice. In conclusion, histamine suppresses Th17 function in murine CACD. This effect was induced by the down-regulation of TGF-β1 through histamine H1 and H4 receptors.


    1. Introduction

    Big Data brings many problems to the general attention of physicists, mathematicians, social scientists, biologists, etc. [18,1]. A first attempt to categorize them into major groups runs into the problem of choosing a criterion of classification among many available ones. Differentiation of Big Data operates through their types (complex data structures) and the relationships that can be established between them (complex data patterns). Knowing Big Data distributional laws might simplify the task of understanding the essential characteristics (sufficient statistics) of their complexities through newly designed sampling techniques, fast data mining methods and efficient algorithmic processing.


    1.1. Data dominium and statistical complexity

    Let us consider three features or attributes of data complexity destined to change due to the effect of size or bigness: dimensionality, heterogeneity and uncertainty (Figure 1). Let us also assume that Big Data uncertainty requires almost axiomatic solutions (say, cross-validation), ranging across a myriad of statistical model selection methods suitably adapted. In general, uncertainty can be associated to entropy and considering a fluctuation theorem for networks, changes in entropy reflect positive changes in resilience against perturbations [6]. In particular, bigger average shortest path lengths in resilient networks mitigate node removal effects, inducing slower network disintegration.

    Figure 1. Big Data complexities: Uncertainty, Dimensionality, Heterogeneity.

    Among the challenges, the one coming from imbalanced data classification and incompleteness, is inherently data dependent. In general, given data with a stratified structure, a lack of balance exists when the classes are not equally represented in the data, which might reflect the sparseness of features rather than the class definition itself [5]. Thus, a class of interest could be the one addressing treated patients, and presenting few instances compared to a more largely represented class of control patients. Moving to a larger dataset is the most immediate solution towards the goal of rebalancing the classes. Sampling is also a strategy that can augment the poorer class (over-sampling) or diminish the richer one (under-sampling). The common aspect is ending up in both scenarios with synthetic samples. Importing a penalization strategy into the model is another possible route aimed to discount classification mistakes. By bringing penalties into the model, the latter can rebalance the over- and under-represented classes.


    1.2.

    Interestingly, with Big Data one turns from the usual curse of dimensionality (large $p$, small $n$, with $p$ number of measurements, and $n$ the number of samples) also to a curse of heterogeneity (Figure 1) [28]. Here, a data generation mixture processing could be conceivable as an underlying Big Data mechanism through which the emergence of sub-populations may be observed [9,16]. Simply speaking, the data mixture would mirror a variety of heterogeneous groups, say $k$, and considering $y$ as our response, $X$ as our covariate vector, $\Theta$ as a parameter vector, and $d(.)$ as density functions, a possible Big Data Generating Process might be associated with the mixture probability density function D as follows:

    $ D_{\pi}(y, X, \Theta) = \pi_{1} d_{1}(y, X, \Theta_{1}) + \pi_{2}d_{2}(y, X, \Theta_{2}) + \ldots + \pi_{k} d_{k}(y, X, \Theta_{k}) $ (1)

    Several interdependent influences need to be considered for model selection purposes in an attempt to improve analyses and inference: additional dimensions or further stratifications in data are expected to weaken the ratio between systematic versus erratic systems characterization. Nevertheless, major problems are most likely coming from:

    ● Mismatch between dimensions (typically, sample size and characterizing variables), requiring regularized solutions;

    ● Existence of inherent but latent stratifications, inducing clusters or communities;

    ● Influence of stochastic components (only in part observable)

    Superior precision of estimates and stabilization of variability are expected with Big Data, but the complexity increases too, due to novel classifications and sampling rates, both becoming sub-optimal at aggregate level. With regard to the latter aspect, an important question is: how likely is the chance of operating at under-sampled data conditions with Big Data? Then, how to recover a correct sampling rate in such a context, a problem related to the so-called Nyquist rate? An associated problem is aliasing, which arises when a signal is discretely sampled at a rate that does not allow to capture the changes in the signal. To avoid aliasing, the sampling frequency should be at least twice the highest frequency contained in the signal [12,24,4]. With a plethora of measurements coming from heterogeneous digital instruments and sensors, the sampling rate from corresponding signals is necessarily different at individual source and most likely largely undetermined at the aggregate level. The challenge is that of identifying specific data stratifications and segmentations, at the cost of relatively heavy computations.

    With Big Data, not only the likely increase of dimensionality might augment the general complexity (spurious correlations, error propagation etc.) and affect the confidence in models, but in many cases the original data comes unstructured or based on a huge number of primitives, and in both cases either transformations or reductions are pursued. In general, the patterns at individual and population levels may differ substantially, and thus be hardly summarized by some statistics or predicted with some confidence.

    It is expected that by integrating information from a variety of sources, the assimilation of the whole data spectrum could not incur in significant loss of information (a good example might be again a subset of patients responding to the same treatment). Therefore, big data in medicine, for instance, would benefit from the ability to recognize disease heterogeneity and to stratify even further in order to be more accurate in the assessment of therapies [2]. In such regards, we might thus consider the blessing of Big Data.

    Finally, Figure 1 implies a key role for sufficient statistics, supposed to simplify statistical analysis [20]. A crucial question is: what is a sufficient statistics in Big Data? Can we achieve full information about the data from only a reduced set of it, considering that we only have a partial knowledge of the granularity of the original $\Theta$? In turn, how measurable and reliable can be other statistics (say, necessary statistics) that are computed from the previous one? Moving from data to graphs can elucidate further this matter.


    2. All-connected systems complexity

    Despite data liquidity flows fast and abundantly, Big Data does not represent a self-organized space, say $\Theta$. Observable connections co-exist with many false signals (false positives) and latent connections (false negatives). Linked, and even more linkable data, are destined to become crucial domains, once features are identified (Figure 2). In parallel with Eq. (1), networks too encompass latent structures and stochastic aspects, under the hypothesis of an average network connectivity degree fluctuating according to some probability law.

    Figure 2. Interoperability between two big spaces, Data and Graphs, through features.

    Therefore, hidden networks can depend on a network generator mechanism subject to some level of unknown uncertainty. Mixture mechanisms enable network approximation by a superposition of random networks (Poisson type, for large N) multiplied by the hidden variable distribution (HVD) [22,19]. Thus, given a Poisson-like $p(k)$, an observed network degree distribution is possibly represented as

    $ p(k) = \int \pi(\lambda) p(k|\lambda) d\lambda $ (2)

    More in general, there exists an interplay between information and disequilibrium in a system, which can represent complexity $C$ according to: $C = U D$, with $U$ as the uncertainty measure (such as Shannon Information or entropy), and $D$ as the disequilibrium (distance form equilibrium or equipartition of the probability distribution between states) [17]. Complexity grows or attenuates depending on both information and disequilibrium. Notably, while the former factor refers to the probability distribution of accessible states of a system in equilibrium (inference principle of maximum entropy), no methods in disequilibrium can deliver the probability distribution, i.e. we cannot predict the system's behavior.

    When we consider the space $\Theta$, its expansion occurs because both $U$ and $D$ may grow. Instead, joint consideration of Big Graph space, say $\Psi$, suggests reduction of complexity by reconciling single node dynamics within entangled entities of a more complex nature but undergoing a common probability law, thus a different behavior and state of equilibrium. The representation property of networks can also take advantage from tensors (multidimensional arrays), in which each dimension is a mode. Let us name $T$ a $n$-node tensor with $n = 1 \ldots, N$, and $N$ big, which is $T \in R^{(I_{1}x I_{2}x \ldots x I_{N})}$. Some tensors would involve modes embedding node features. This way, tensor networks can enable multidimensional intra-an inter-modularization interactive dynamics according to various degrees of features interdependence.

    The context built through $F$ possibly mitigates data information gaps, but likely does not compensate for them. Indeed, $F$ needs to be well designed to parallel the role played by a set of sufficient statistics as a coarse representation of data useful to identify good statistical estimation procedures, say. Data gaps that do not convey information about the underlying distribution, would have effects balanced by sufficient statistics replacing the sample information without any loss. Because of missing data, inhomogeneous measurements, different scales, etc., it is likely that Big Data would exacerbate such gaps and the corresponding information loss could be harder to contrast or not even recoverable by sufficient statistics. Without measuring the latter, we cannot determine its distribution either. Mapping data to features becomes almost a necessity, and many projective techniques allow such step. Among the most popular approaches, compressive sensing is the one looking at the signals/data structure to represent them with minimal measurements/features [3,7,8].

    In $\Psi$, two main properties are key. One is multiplexing, which addresses the fact that multiple layers of complex interactions interplay among network nodes, such that the latter are interconnected via multiple types of links [14]. The other is modularization, which delivers a community map from the initial network, thus dealing naturally with heterogeneity.

    As said earlier with tensor networks, nodes are particularly interesting when their feature contents are considered, say a certain function $\beta (f \in F)$ may be applied to them. This is to say that the connectivity patterns obtained from $\beta (f_{n}, f_{m})$, given two features $f_{n}$ and $f_{m}$, would constrain the adjacency matrix to the form $A_{n, m} = \beta(f_{n}, f_{m})$, thus qualitatively enriching the network [26]. Back to modularization, the more complex appears the structure of the feature patterns and the harder becomes to partition the network into modules or communities. The latter would usually require some kind of algorithmic search (greedy-like) [21], but may also involve further pre-processing steps, for instance the elimination of problematic nodes like hubs. Then, it might be facilitating random walk switching between modules, thus better conductance property and in turn goodness of community structure [15]. It is known that conductance of scale-free networks is a very heterogeneous property that depends on the node degrees [13].


    3. Entanglement

    It is important to note that tensor networks recall a rich architecture of interconnected nodes whose glue is due to entanglement, telling about the underlying information [25]. Many topological measures provide information on network structures, including entropic ones. Mutual information can be for instance computed between two network modules, say $I$ and $J$, so as to measure their correlation by $MI = S(I) + S(J) - S(IJ)$, in which both individual (first two terms) and combined (third term) entropies are considered. However, also entanglement is a quantum measure of correlation that can be put in relationships with topology, thus associating graphs to quantum states [10].

    In general, quantum entanglement occurs when for interacting particles their quantum state cannot be described independently but only as a system. When such system interplays with the environment, a loss of information occurs, something generally called decoherence. In isomorphic graphs, defined by having adjacency matrix unique up to permutations of rows and columns, the same entanglement entropy is reflected into equivalent network states. The presence of synchronization [23] (say, nodes pulsing at the same frequency and thus representing a synchronized state) somehow ensures about the existence of entanglement between nodes, and protects the network from decoherence effects.


    4. Symmetries

    Network hubs are good candidate nodes to analyze node and edge dynamics. They have been the first object of network control, for instance. And it turns out they are not categorized as drivers due to the fact that due to their nature, the relatively large interconnected network regions receive similar signals through them, leaving unexplored many other regions which are possible targets. This is an effect of the presence of symmetries induced by the hubs, which reduce the number of nodes to be controlled but at the same time expand the number of edges through which the control signals flow [27].

    In general, symmetries in a network induce, through some transformations, the invariance in its elements. This holds for transformations leaving the network s properties unchanged. Network invariant is called any property that is preserved under any of its possible isomorphisms, thus independently of its representation. A symmetry group $S_{g}$ acting on a set of nodes $N$ of a network defines for each node $n \in N$ an orbit, $O_{x} = \{s * x: s \in S_{g}\}$ [11]. The symmetry group partitions the sets of nodes into unique orbits, thus reducing the redundancy. If we consider the stochastic nature of networks, and the relevance of network ensembles, these objects call for further analysis under the lens of symmetries.


    [1] Kim H, Kim JR, Kang H, et al. (2014) 7,8,4'-Trihyroxyisoflavone attenuates DNCB-induced atopic dermatitis-like symptoms in NC/Nga mice. PLoS One 29: e104938.
    [2] Kitagaki H, Fujisawa S, Watanabe K, et al. (1995) Immediate-type hypersensitivity response followed by a late reaction is induced by repeated epicutaneous application of contact sensitizing agents in mice. J Invest Dermatol 105: 749–755. doi: 10.1111/1523-1747.ep12325538
    [3] Yamaura K, Shimada M, Ueno K (2011) Anthocyanins from bilberry (Vaccinium myrtillus L.) alleviate pruritus in a mouse model of chronic allergic contact dermatitis. Pharmacognosy Res 3: 173–177.
    [4] Boothe WD, Tarbox JA, Tarbox MB (2017) Atopic dermatitis: Pathophysiology. Adv Exp Med Biol 1027: 21–37. doi: 10.1007/978-3-319-64804-0_3
    [5] Lin L, Xie M, Chen X, et al. (2018) Toll-like receptor 4 attenuates a murine model of atopic dermatitis through inhibition of langerin-positive DCs migration. Exp Dermatol 27: 1015–1022. doi: 10.1111/exd.13698
    [6] Liu L, Guo D, Liang Q, et al. (2015) The efficacy of sublingual immunotherapy with Dermatophagoides farinae vaccine in a murine atopic dermatitis model. Clin Exp Allergy 45: 815–822. doi: 10.1111/cea.12417
    [7] Stander S, Steinhoff M (2002) Pathophysiology of pruritus in atopic dermatitis: An overview. Exp Dermatol 11: 12–24. doi: 10.1034/j.1600-0625.2002.110102.x
    [8] Seike M, Takata T, Ikeda M, et al. (2005) Histamine helps development of eczematous lesions in experimental contact dermatitis in mice. Arch Dermatol Res 297: 68–74. doi: 10.1007/s00403-005-0569-5
    [9] Seike M, Furuya K, Omura M, et al. (2010) Histamine H4 receptor antagonist ameliorates chronic allergic contact dermatitis induced by repeated challenge. Allergy 65: 319–326. doi: 10.1111/j.1398-9995.2009.02240.x
    [10] Matsushita A, Seike M, Okawa H, et al. (2012) Advantage of histamine H4 receptor antagonist usage with H1 receptor antagonist for the treatment of murine allergic contact dermatitis. Exp Dermatol 21: 714–715. doi: 10.1111/j.1600-0625.2012.01559.x
    [11] Ohsawa Y, Hirasawa N (2012) The antagonism of histamine H1 and H4 receptors ameliorates chronic allergic dermatitis via anti-pruritic and anti-inflammatory effects in NC/Nga mice. Allergy 67: 1014–1022. doi: 10.1111/j.1398-9995.2012.02854.x
    [12] Liang SC, Tan X, Luxenberg DP, et al. (2006) Interleukin (IL)-22 and IL-17 are coexpressed by Th17 cells and cooperatively enhance expression of antimicrobial peptides. J Exp Med 203: 2271–2279. doi: 10.1084/jem.20061308
    [13] Yi T, Chen Y, Wang L, et al. (2009) Reciprocal differentiation and tissue-specific pathogenesis of Th1, Th2 and Th17 cells in graft-versus-host disease. Blood 114: 3101–3112. doi: 10.1182/blood-2009-05-219402
    [14] Koga C, Kabashima K, Shiraishi N, et al. (2008) Possible pathogenic role of Th17 cells for atopic dermatitis. J Invest Dermatol 128: 2625–2630. doi: 10.1038/jid.2008.111
    [15] Matsushita A, Seike M, Hagiwara T, et al. (2014) Close relationship between T helper (Th)17 and Th2 response in murine allergic contact dermatitis. Clin Exp Dermatol 39: 924–931. doi: 10.1111/ced.12425
    [16] Ohtsu H, Tanaka S, Terui T, et al. (2001) Mice lacking histidine decarboxylase exhibit abnormal mast cells. FEBS Lett 502: 53–56. doi: 10.1016/S0014-5793(01)02663-1
    [17] Tamura T, Matsubara M, Takada C (2004) Effects of olopatadine hydrochloride, antihistamine drug, on skin inflammation induced by repeated topical application of oxazolone in mice. Brit J Dermatol 151: 1133–1142. doi: 10.1111/j.1365-2133.2004.06172.x
    [18] Kim JY, Jeong MS, Park MK, et al. (2014) Time-dependent progression from the acute to chronic phases in atopic dermatitis induced by epicutaneous allergen stimulation in NC/Nga mice. Exp Dermatol 23: 53–57. doi: 10.1111/exd.12297
    [19] Ohtsu H, Kuramasu K, Tanaka S, et al. (2002) Plasma extravasation induced by dietary supplemented histamine in histamine-free mice. Eur J Immunol 32: 1698–1708. doi: 10.1002/1521-4141(200206)32:6<1698::AID-IMMU1698>3.0.CO;2-7
    [20] Hamada R, Seike M, Kamijima R, et al. (2006) Neuronal conditions of spinal cord in dermatitis are improved by olopatadine. Eur J Pharmacol 547: 45–51. doi: 10.1016/j.ejphar.2006.06.058
    [21] Tamaka K, Seike M, Hagiwara T, et al. (2015) Histamine suppresses regulatory T cells mediated by TGF-β in murine chronic contact dermatitis. Exp Dermatol 24: 280–284. doi: 10.1111/exd.12644
    [22] Nakae S, Komiyama Y, Nambu A, et al. (2002) Antigen-specific T cell sensitization is impaired in IL-17-deficient mice, causing suppression of allergic cellular and humoral responses. Immunity 17: 375–387. doi: 10.1016/S1074-7613(02)00391-6
    [23] Zhao Y, Balato A, Fishelevich R, et al. (2009) Th17/Tc17 infiltration and associated cytokine gene expression in elicitation phase of allergic contact dermatitis. Brit J Dermatol 161: 1301–1306. doi: 10.1111/j.1365-2133.2009.09400.x
    [24] Kim D, McAlees JW, Bischoff LJ, et al. (2018) Combined administration of anti-IL-13 and anti-IL-17A at individually sub-therapeutic doses limits asthma-like symptoms in a mouse model of Th2/Th17 high asthma. Clin Exp Allergy, 24.
    [25] Bian R, Tang J, Hu L, et al. (2018) (E)-phenethyl 3-(3,5-dihydroxy-4-isopropylphenyl) acrylate gel improves DNFB-induced allergic contact hypersensitivity via regulating the balance of Th1/Th2/T17/Treg cell subsets. Int Immunopharmacol 65: 8–15. doi: 10.1016/j.intimp.2018.09.032
    [26] Wu R, Zeng J, Yuan J, et al. (2018) MicroRNA-210 overexpression promotes psoriasis-like inflammation by inducing Th1 and Th17 cell differentiation. J Clin Invest 128: 2551–2568. doi: 10.1172/JCI97426
    [27] Orciani M, Campanati A, Caffarini M, et al. (2017) T helper (Th)1, Th17 and Th2 imbalance in mesenchymal stem cells of adult patients with atopic dermatitis: at the origin of the problem. Brit J Dermatol 176: 1569–1576. doi: 10.1111/bjd.15078
    [28] Harrington LE, Hatton RD, Mangan PR, et al. (2005) Interleukin 17-producing CD4+ effector T cells develop via a lineage distinct from the T helper type 1 and 2 lineage. Nat Immunol 6: 1123–1132. doi: 10.1038/ni1254
    [29] Mangan PR, Harrington LE, O'Quinn DB, et al. (2006) Transforming growth factor-beta induces development of the TH17 lineage. Nature 441: 231–234. doi: 10.1038/nature04754
  • Reader Comments
  • © 2018 the Author(s), licensee AIMS Press. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0)
通讯作者: 陈斌, bchen63@163.com
  • 1. 

    沈阳化工大学材料科学与工程学院 沈阳 110142

  1. 本站搜索
  2. 百度学术搜索
  3. 万方数据库搜索
  4. CNKI搜索

Metrics

Article views(6232) PDF downloads(1767) Cited by(0)

Article outline

Figures and Tables

Figures(5)

Other Articles By Authors

/

DownLoad:  Full-Size Img  PowerPoint
Return
Return

Catalog