Astrocytes and Inflammatory T Helper Cells: A Dangerous Liaison in Multiple Sclerosis.

Multiple Sclerosis (MS) is a neurodegenerative autoimmune disorder of the central nervous system (CNS) characterized by the recruitment of self-reactive T lymphocytes, mainly inflammatory T helper (Th) cell subsets. Once recruited within the CNS, inflammatory Th cells produce several inflammatory cytokines and chemokines that activate resident glial cells, thus contributing to the breakdown of blood-brain barrier (BBB), demyelination and axonal loss. Astrocytes are recognized as key players of MS immunopathology, which respond to Th cell-defining cytokines by acquiring a reactive phenotype that amplify neuroinflammation into the CNS and contribute to MS progression. In this review, we summarize current knowledge of the astrocytic changes and behaviour in both MS and experimental autoimmune encephalomyelitis (EAE), and the contribution of pathogenic Th1, Th17 and Th1-like Th17 cell subsets, and CD8+ T cells to the morphological and functional modifications occurring in astrocytes and their pathological outcomes.

Inhibiting OX40 Restores Regulatory T-Cell Function and Suppresses Inflammation in Pulmonary Sarcoidosis.

BACKGROUND: Pulmonary sarcoidosis (PS) is a noncaseating granulomatous disease of unknown origin. Despite conflicting reports, it is considered that the regulatory T (Treg) cells are functionally impaired in PS, but the underlying mechanisms remain unclear. OX40, a pivotal costimulatory molecule, is essential for T-cell functions and memory development, but its impact on Treg cells is ambiguous. RESEARCH QUESTION: Does the OX40 pathway influence the suppressive functions of Treg cells in PS? STUDY DESIGN AND METHODS: Fifty treatment-naïve patients with PS and 30 healthy control participants were recruited for this study. Polychromatic flow cytometry-based immunologic assays were performed to enumerate effector T helper (Th) cells and Treg cells along with their functions. Using real-time polymerase chain reaction analysis, small interfering RNA, and pharmacologic inhibitors, the impact of OX40 on Treg cell function was investigated. RESULTS: We observed enrichment of Th-9 cells perhaps for the first time along with Th-1, Th-17, and Treg cells in patients' BAL fluid (BALF) compared with peripheral blood. However, Treg cells were observed to be functionally defective at the pathological site. We observed higher expression of OX40 on both T effector (CD4+Foxp3-) and Treg (CD4+Foxp3+) cells obtained from the BALF of patients with PS. However, OX40 exerted contrasting impact on these T-cell subsets, enhancing effector T-cell functions (interferon γ, tumor necrosis factor α) while inhibiting Treg cell function (IL-10, transforming growth factor ß). OX40 silencing or blocking on Treg cells resulted in restoration of their impaired functions. INTERPRETATION: We propose that inhibiting the OX40 pathway may constitute a therapeutic strategy for controlling inflammatory T cells by restoring Treg cell functions in patients with PS.

Characterizing the immune responses of those who survived or succumbed to COVID-19: Can immunological signatures predict outcome?

BACKGROUND: Immunodeficiency has pivotal role in the pathogenesis of coronavirus disease 2019 (COVID-19). Several studies have indicated defects in the immune system of COVID-19 patients at different disease stages. Therefore, this study investigated whether alters in immune responses of COVID-19 patients may be considered as predicting factors for disease outcome. METHODS: The percentages of innate and adoptive immune cells in the recovered and dead patients with COVID-19, and healthy subjects were determined by flow cytometry. The levels of pro- and anti-inflammatory cytokines and other immune factors were also measured by enzyme-linked immunosorbent assay. RESULTS: At the first day of hospitalization, the frequencies of CD56dim CD16+ NK cells and CD56bright CD16dim/- NK cells in patients who died during treatment were significantly increased compared to recovered and healthy individuals (P < 0.0001). The recovered and dead patients had a significant increase in monocyte number in comparison with healthy subjects (P < 0.05). No significant change was observed in Th1 cell numbers between the recovered and dead patients while Th2, Th17 cell, and Treg percentages in death cases were significantly lower than healthy control and those recovered, unlike exhausted CD4 + and CD8 + T cells and activated CD4 + T cells (P < 0.0001-0.05). The activated CD8 + T cell was significantly higher in the recovered patients than healthy individuals (P < 0.0001-0.05). IL-1α, IL-1ß, IL-6, and TNF-α levels in patients were significantly increased (P < 0.0001-0.01). However, there were no differences in TNF-α and IL-1ß levels between dead and recovered patients. Unlike TGF-ß1 level, IL-10 was significantly increased in recovered patients (P < 0.05). Lymphocyte numbers in recovered patients were significantly increased compared to dead patients, unlike ESR value (P < 0.001-0.01). CRP value in recovered patients significantly differed from dead patients (P < 0.001). CONCLUSION: Changes in frequencies of some immune cells and levels of some immune factors may be considered as predictors of mortality in COVID-19 patients.

T Helper Cells: The Modulators of Inflammation in Multiple Sclerosis.

Multiple sclerosis (MS) is a chronic neurodegenerative disease characterized by the progressive loss of axonal myelin in several areas of the central nervous system (CNS) that is responsible for clinical symptoms such as muscle spasms, optic neuritis, and paralysis. The progress made in more than one decade of research in animal models of MS for clarifying the pathophysiology of MS disease validated the concept that MS is an autoimmune inflammatory disorder caused by the recruitment in the CNS of self-reactive lymphocytes, mainly CD4+ T cells. Indeed, high levels of T helper (Th) cells and related cytokines and chemokines have been found in CNS lesions and in cerebrospinal fluid (CSF) of MS patients, thus contributing to the breakdown of the blood-brain barrier (BBB), the activation of resident astrocytes and microglia, and finally the outcome of neuroinflammation. To date, several types of Th cells have been discovered and designated according to the secreted lineage-defining cytokines. Interestingly, Th1, Th17, Th1-like Th17, Th9, and Th22 have been associated with MS. In this review, we discuss the role and interplay of different Th cell subpopulations and their lineage-defining cytokines in modulating the inflammatory responses in MS and the approved as well as the novel therapeutic approaches targeting T lymphocytes in the treatment of the disease.

IL-9 and Th9 Cells in Tumor Immunity.

T cells can be categorized into functionally diverse subpopulations, which include Th1, Th2, Th9, Th17, Th22, and Tfh cells and Foxp3+ Tregs, based on their role in maintaining normal immune homeostasis and affecting pathological immune-associated diseases. Among these subpopulations, Th9 cells are relatively new, and less is known about their signaling and effects on tumor immunity. Recently, some studies have focused on regulation of the IL-9/IL-9R signaling pathway and Th9 cell differentiation and their roles in tumor environments. Herein, we summarize recent progress in understanding the regulatory signaling of IL-9 and Th9 cells and their critical roles and mechanisms in antitumor immunity.

Follicular helper T cells in type 1 diabetes.

Type 1 diabetes (T1D) is an autoimmune disease caused by the dysfunction of immune system and consequently the destruction of insulin-producing ß cells. In past decades, numerous studies have uncovered that CD4+ T cell subsets are critical in the pathogenesis of T1D, manifesting that type 1 T helper (Th1) and Th17 cells are pathogenic, while regulatory T (Treg) cells and Th2 cells are protective. More recently, the pathogenic role of another subset, follicular helper T (Tfh) cells that essentially regulate germinal center (GC) formation and humoral responses, has also been demonstrated in T1D and many other autoimmune diseases. In this review, we summarize the evidence for the aberrant differentiation and function of Tfh cells in T1D, and also discuss the underlying mechanisms. A better understanding on the pathogenic role of Tfh cells in T1D will inspire the design of potential therapeutic strategies to target this subset in the future.

Distribution of distinct subsets of circulating T follicular helper cells in Kawasaki disease.

BACKGROUND: Kawasaki disease (KD) is an acute febrile vasculitis that primarily affects children. Previous studies have shown that both innate and adapt immune systems are involved in the immunopathogenesis of KD. The following study analyzes the distribution of the subsets of Circulating T follicular helper cells (cTfh cells) in KD patients with and without coronary artery lesions (CALs). METHODS: Twenty KD patients and fifteen healthy sex- and age- matched children were enrolled. Patients were divided into two groups depending on CALs. Blood samples were collected respectively before and after intravenous immunoglobulin (IVIG) administration. Circulating Tfh cells were categorized into three subsets by flow cytometry including cTfh1 (CXCR3 + CCR6-), cTfh2 (CXCR3-CCX6-) and cTfh17 (CXCR3-CCR6+) cells in circulating CD3 + CD4 + CXCR5 + CD45RA- T cells. Cytometric bead arrays were used to analyze the level of IFN-γ, IL-4 and IL-17A. RESULTS: We found that frequency of cTfh2 cells was significantly elevated in KD patients before IVIG administration with low expression of cTfh1 cells, where the ratio of cTfh2 + cTfh17/cTfh1 significantly increased. Levels of IFN-γ, IL-4 and IL-17A in KD were significantly higher compared to controls. Further analysis showed that cTfh1 cells were negatively correlated with serum CRP, whereas cTfh2 cells were positively correlated with serum CRP and ESR. Comparison of different groups showed that frequency of cTfh1 cells in CALs+ group were significantly lower compared to CALs- group. In contrast, cTfh2 cells in CALs+ group significantly increased. After IVIG administration, frequency of cTfh2 cells and the ratio significantly decreased while the frequency of cTfh1 cells significantly increased. Meanwhile, all levels of cytokines decreased. CONCLUSIONS: Our data demonstrated that cTfh1 and cTfh2 cells participate in the pathogenesis of KD, and that the two subsets might be associated with CALs.

Formalizing and enriching phenotype signatures using Boolean networks.

In order to predict the behavior of a biological system, one common approach is to perform a simulation on a dynamic model. Boolean networks allow to analyze the qualitative aspects of the model by identifying its steady states and attractors. Each of them, when possible, is associated with a phenotype which conveys a biological interpretation. Phenotypes are characterized by their signatures, provided by domain experts. The number of steady states tends to increase with the network size and the number of simulation conditions, which makes the biological interpretation difficult. As a first step, we explore the use of Formal Concept Analysis as a symbolic bi-clustering technics to classify and sort the steady states of a Boolean network according to biological signatures based on the hierarchy of the roles the network components play in the phenotypes. FCA generates a lattice structure describing the dependencies between proteins in the signature and steady-states of the Boolean network. We use this lattice (i) to enrich the biological signatures according to the dependencies carried by the network dynamics, (ii) to identify variants to the phenotypes and (iii) to characterize hybrid phenotypes. We applied our approach on a T helper lymphocyte (Th) differentiation network with a set of signatures corresponding to the sub-types of Th. Our method generated the same classification as a manual analysis performed by experts in the field, and was also able to work under extended simulation conditions. This led to the identification and prediction of a new hybrid sub-type later confirmed by the literature.

Altered immune cell follicular dynamics in HIV infection following influenza vaccination.

HIV infection changes the lymph node (LN) tissue architecture, potentially impairing the immunologic response to antigenic challenge. The tissue-resident immune cell dynamics in virologically suppressed HIV+ patients on combination antiretroviral therapy (cART) are not clear. We obtained LN biopsies before and 10 to 14 days after trivalent seasonal influenza immunization from healthy controls (HCs) and HIV+ volunteers on cART to investigate CD4+ T follicular helper (Tfh) and B cell dynamics by flow cytometry and quantitative imaging analysis. Prior to vaccination, compared with those in HCs, HIV+ LNs exhibited an altered follicular architecture, but harbored higher numbers of Tfh cells and increased IgG+ follicular memory B cells. Moreover, Tfh cell numbers were dependent upon preservation of the follicular dendritic cell (FDC) network and were predictive of the magnitude of the vaccine-induced IgG responses. Interestingly, postvaccination LN samples in HIV+ participants had significantly (P = 0.0179) reduced Tfh cell numbers compared with prevaccination samples, without evidence for peripheral Tfh (pTfh) cell reduction. We conclude that influenza vaccination alters the cellularity of draining LNs of HIV+ persons in conjunction with development of antigen-specific humoral responses. The underlying mechanism of Tfh cell decline warrants further investigation, as it could bear implications for the rational design of HIV vaccines.

Constitutive Changes in Circulating Follicular Helper T Cells and Their Subsets in Patients with Graves' Disease.

BACKGROUND: Follicular helper T (Tfh) cells are critical for high-affinity antibody generation and B cell maturation and differentiation, which play important roles in autoimmune diseases. Graves' disease (GD) is one prototype of common organ-specific autoimmune thyroid diseases (AITD) characterized by autoreactive antibodies, suggesting a possible role for Tfh cells in the pathogenesis of GD. Our objective was to explore the role of circulating Tfh cell subsets and associated plasma cells (PCs) in patients with GD. METHODS: Thirty-six patients with GD and 20 healthy controls (HC) were enrolled in this study. The frequencies of circulating Tfh cell subsets and PCs were determined by flow cytometry, and plasma cytokines, including interleukin- (IL-) 21, IL-4, IL-17A, and interferon- (IFN-) γ, were measured using an enzyme-linked immunosorbent assay (ELISA). The mRNA expression of transcription factors (Bcl-6, T-bet, GATA-3, and RORγt) in peripheral blood mononuclear cells (PBMCs) was evaluated by real-time quantitative PCR. Results. Compared with HC, the frequencies of circulating CD4+CXCR5+CD45RA-Tfh (cTfh) cells with ICOS and PD-1 expression, the Tfh2 subset (CXCR3-CCR6-Tfh) cells, and PCs (CD19+CD27highCD38high) were significantly increased in the GD patients, but the frequencies of Tfh1 (CXCR3+CCR6-Tfh) and Tfh17 (CXCR3-CCR6+Tfh) subset cells among CD4+T cells were significantly decreased in GD patients. The plasma concentrations of IL-21, IL-4, and IL-17A were elevated in GD patients. Additionally, a positive correlation was found between the frequency of PD-1+Tfh cells (Tfh2 or PCs) and plasma IL-21 concentration (or serum TPO-Ab levels). The mRNA levels of transcription factors (GATA-3 and RORγt) were significantly increased, but T-bet and Bcl-6 mRNA expression was not obviously varied in PBMCs from GD patients. Interestingly, Tfh cell subsets and PCs from GD patients were partly normalized by treatment. CONCLUSION: Circulating Tfh cell subsets and PCs might play an important role in the pathogenesis of GD, which are potential clues for GD patients' interventions.

T Helper Cell Differentiation, Heterogeneity, and Plasticity.

Naïve CD4 T cells, on activation, differentiate into distinct T helper (Th) subsets that produce lineage-specific cytokines. By producing unique sets of cytokines, effector Th subsets play critical roles in orchestrating immune responses to a variety of infections and are involved in the pathogenesis of many inflammatory diseases including autoimmunity, allergy, and asthma. The differentiation of Th cells relies on the strength of T-cell receptor (TCR) signaling and signals triggered by polarizing cytokines that activate and/or up-regulate particular transcription factors. Several lineage-specific master transcription factors dictate Th cell fates and functions. Although these master regulators cross-regulate each other, their expression can be dynamic. Sometimes, they are even coexpressed, resulting in massive Th-cell heterogeneity and plasticity. Similar regulation mediated by these master regulators is also found in innate lymphoid cells (ILCs) that are innate counterparts of Th cells.

Do infections with disseminated Mycobacterium avium complex precede sweet's syndrome? A case report and literature review.

Sweet's syndrome is reportedly associated with preceding nontuberculous mycobacterial infections (NTMIs). Here, we report on a systemic Mycobacterium intracellulare infection in a patient on corticoid therapy for Sweet's syndrome. Literature searches show that 69.1% of patients with Sweet's syndrome and NTMIs developed this syndrome later than NTMIs and 89.3% of them developed during the clinical course of a rapidly growing mycobacterial infection. The residual cases were associated with slow-growing mycobacteria (14.3%), but only three cases of Mycobacterium avium complex (MAC) infections before the onset of Sweet's syndrome have been reported, and all of them were caused by disseminated MAC disease. One of these cases developed during corticoid therapy for Sweet's syndrome, while another case had underlying diabetes mellitus. Hence, the occurrence of systemic MAC disease may be an inevitable consequence of long-term steroid use and underlying diseases. Literature searches also show that cervical lymphadenitis was a predominant symptom in NTMIs (90.5%). The present case did not have cervical lymphadenitis although the previously reported MAC cases did experience it. Therefore, lymphadenitis from NTMIs may be related to the pathogenesis of Sweet's syndrome. Hence, should a patient have systemic infection without lymphadenitis, it will be more difficult to clinically confirm that MAC disease is a predisposing factor for Sweet's syndrome.

siRNA­mediated knockdown of T­bet and RORγt contributes to decreased inflammation in pre­eclampsia.

Abnormal immune response resulting from disordered T helper (Th)1/Th2 and Th17/regulatory T cells (Treg) cytokine expression has been demonstrated to serve an important role in the pathogenesis of preeclampsia (PE). However, the role of transcription factors regulating Th cell differentiation contributing to PE remain unclear. To determine whether a decrease in the expression of the T cell lineage transcription factor T­bet can restore immune balance and alleviate the systemic inflammatory response present in PE, 30 patients diagnosed with PE were assessed and compared with healthy pregnant controls. The expression of the transcription factors T­bet and retinoic acid receptor­related orphan receptor (ROR)γt were increased in the peripheral blood mononuclear cells of PE patients compared with controls, consistent with the presence of abnormally high T­bet:GATA3 and RORγt:forkhead box (FOX) P3 ratios. The present study additionally identified a high­efficiency, specific small interfering (si)RNA that can downregulate RORγt and T­bet mRNA levels and inhibit protein expression. This effective siRNA was transfected into activated CD4+ T cells derived from patients with PE to observe the changes to transcription factor expression and attempt to elucidate the regulatory mechanism of T cell subsets. It was identified that knockdown of RORγt induced increased expression of FOXP3 and that the ratios of RORγt:FOXP3 and interleukin (IL)­17A:IL­10 were subsequently decreased. The results suggested that siRNA­mediated knockdown of T­bet regulated the immune balance of Th17/Tregs via changes to RORγt and FOXP3. When siRNA against RORγt and T­bet were used in combination, a stronger ability to regulate immune balance was observed. These results imply that Th1­ and Th17­type immunity is dominant in PE and that the siRNA­mediated knockdown of certain Th1 and Th17 cell transcription factors may be an effective therapeutic target for promoting immune balance in CD4+ T cell subgroups and ameliorating local and generalized inflammation in PE.

IL-9 and Th9 cells in health and diseases-From tolerance to immunopathology.

CD4+ T cells have the capacity to differentiate into various T helper (Th) cell subsets after activation, and by acquiring distinct cytokine profiles and effector functions, they regulate the nature as well as the outcomes of immune responses. Th9 cells are a relatively new member in the Th cell family. The signature cytokine for Th9 cells is IL-9, a cytokine in the IL-2Rγc-chain family. Over the past few years, there has been an explosion of knowledge on the roles of Th9 cells in immunity and immunopathology, but the exact mechanisms in the control of Th9 cells remain poorly defined. This apparent paradox presents both challenges and opportunities. Here we review recent advances in our understanding of the fundamental biology of IL-9 and Th9 cells, highlighting the challenges and unanswered questions in the field. We also discuss potential opportunities in targeting Th9 cells for therapeutic purposes in the clinic.

The predominance of a naive T helper cell subset in the immune response of experimental acute pancreatitis.

INTRODUCTION: In necrotizing acute pancreatitis (NAP), systemic inflammatory response syndrome (SIRS) and the compensatory anti-inflammatory response syndrome (CARS) decide overall outcome and mortality. In patients, low lymphocyte counts were found, but T-helper cells seemed to conversely increase. Our aim was to further categorize T-helper cells within the context of NAP induced SIRS and CARS. METHODS: NAP was induced by injection of sodium-taurocholate into the common bile duct of male BALB/c mice; sham treated animals received saline infusion. The animals were sacrificed at 6, 12, 24 and 48 h later. Lymphocytes from blood, liver and spleen were isolated and examined by flow cytometry. Staining was performed for CD4, CD8, CD19, CD45RB, CD25, CD69, and CD152. CD4+ cells were sorted for their CD45RB expression and sought for gene regulation associated to TH1/TH2 cells by quantitative RT-PCR. RESULTS: In NAP, CD4+ was solely increased in all compartments. CD8+ remained without substantial alterations. CD45RB showed significant expression in RBhigh in T-helper cells, confirmed by the CD45RBhigh/low ratio (Liver, 24 h: NAP 2.2, SHAM 0.6; p < 0.001). CD45RBhigh and -low cells were not associated to patterns of TH1/TH2 expression. In NAP, CCR4 expression was significantly decreased within RBhigh cells (fold change: 0.04, p < 0.05), while TLR6 showed significant overexpression (fold change: 2.36, p < 0.05). CONCLUSION: T-helper cells increase in NAP, leaning towards CD45RBhigh expression. They resemble naive T-cells, in which NAP leads to expression profiles associated with an innate immune response. This suggests new findings in immunological pathomechanisms of NAP.

An increased expression profile of Th9/IL-9 correlated with Th17/IL-17 in patients with immune thrombocytopenia.

Immune thrombocytopenia (ITP) is a heterogeneous autoimmune disease, characterized by dysregulation of cellular immunity. Th9 cells were recently identified as a new subtype of Th cells, characterized by preferential production of IL-9. Given the pleiotropic function of IL-9, Th9 cells are demonstrated to be involved in various autoimmune diseases. However, whether Th9 cells are involved in the pathogenesis of ITP remains unclear. In this study, 49 active ITP patients, 39 ITP with remission and 20 healthy controls were included. Peripheral blood mononuclear cells (PBMCs) were isolated from ITP and controls for measuring Th9 and Th17 cells by flow cytometry. Meanwhile, RNA was isolated from PBMCs for the measurement of the mRNA level of PU.1, IRF4, BATF, and RORγt by quantitative real-time PCR. Plasma levels of IL-9 and IL-17 were detected by ELISA. Our results showed that higher expressions of Th9, IL-9, and associated transcription factors (PU.1, IRF4, and BATF) were found in active ITP patients and restored to the normal level (except IL-9) in patients in remission. Meanwhile, Th9 cells and the IL-9 plasma level were positively correlated with Th17 cells and the IL-17 level in ITP patients, respectively. Moreover, a positive correlation of IRF4 or BATF with RORγt was found. In conclusion, an aberrant expression profile of Th9/IL-9 was associated with pathogenesis of ITP possibly through cooperatively working with Th17/IL-17 and therapeutically targeting Th9/IL-9 might be a novel approach in the treatment of ITP.

Tracking global gene expression responses in T cell differentiation.

Upon receiving antigens from the innate immune cells, CD4(+) T cells differentiate into distinct effector cells. To probe the global responses of distinct effector cells, we analyzed transcriptome-wide expressions of Th1, Th2, Treg and Th17 using Pearson correlation, entropy and principal component analyses, with Th0 as a control. Although the global response of Th0 was quite distinct from Th17, surprisingly, it was highly similar to Th1, Th2 and Treg. Moreover, 8 major temporal groups consisting of 5704 differentially expressed genes were revealed for both Th0 and Th17. Gene functional enrichment analysis showed immune responses and metabolic processes were mainly activated between Th0 and Th17, while genes related to cell cycle and replication were differentially regulated. Moreover, we found the upregulation of several novel genes for Th0 and Th17. Overall, we deduce that Th0 is globally similar to Th1, Th2 and Treg. Our results indicate that Th0 is a differentiated state and, therefore, may not be used as a control cell type.

Mapping the Diversity of Follicular Helper T Cells in Human Blood and Tonsils Using High-Dimensional Mass Cytometry Analysis.

Single-cell analysis technologies such as mass cytometry allow for measurements of cellular heterogeneity with unprecedented dimensionality. Here, we applied dimensionality reduction and automated clustering methods on human T helper (T(H)) cells derived from peripheral blood and tonsils, which showed differential cell composition and extensive T(H) cell heterogeneity. Notably, this analysis revealed numerous subtypes of follicular helper T (T(FH)) cells that followed a continuum spanning both blood and tonsils. Furthermore, we identified tonsillar CXCR5(lo)PD-1(lo)CCR7(lo) T(FH) cells expressing interferon-γ (IFN-γ), interleukin-17 (IL-17), or Foxp3, indicating that T(FH) cells exhibit diverse functional capacities within extrafollicular stages. Regression analysis demonstrated that CXCR5(lo)PD-1(-) and CXCR5(lo)PD-1(lo) cells accumulate during childhood in secondary lymphoid organs, supporting previous findings that these subsets represent memory T(FH) cells. This study provides an in-depth comparison of human blood and tonsillar T(FH) cells and outlines a general approach for subset discovery and hypothesizing of cellular progressions.

Alteration of circulating type 2 follicular helper T cells and regulatory B cells underlies the comorbid association of allergic rhinitis with bronchial asthma.

Allergic rhinitis (AR), the most common allergic disorder of the airway, is often accompanied by bronchial asthma. However, little is known about the mechanism by which AR advances to AR comorbid with bronchial asthma (AR+Asthma). To determine the pathophysiologic features of AR and AR+Asthma, we examined subsets of follicular helper T (Tfh) cells and regulatory B (Breg) cells in peripheral blood from AR and AR+Asthma patients. The results showed polarization of Tfh2 cells within Tfh cell subsets in both AR and AR+Asthma cases. Interestingly, the %Breg cells in total B cells were decreased in AR cases and, more extensively, in AR+Asthma cases. Moreover, we found significant correlations of fractional exhaled nitric oxide and blood eosinophil levels with the index %Tfh2 cells per %Breg cells. Our findings indicate that relative decrease in Breg cells under the condition of Tfh2 cell skewing is a putative exaggerating factor of AR to bronchial asthma.

Review: Lymphocytes, cytokines, chemokines and the T-helper 1-T-helper 2 balance in canine atopic dermatitis.

BACKGROUND: The development of atopic dermatitis (AD) and other cutaneous hypersensitivities involves the activation and differentiation of allergen-specific lymphocytes. Although hypersensitivity is often considered to be a 'T-helper 2-polarized' lymphocyte response, recent evidence suggests that clinical disease is associated with the development of multiple lymphocyte phenotypes. OBJECTIVES: The purpose of this paper is to review recent advances in the understanding of the roles of lymphocytes, cytokines and noncytokine factors in the pathogenesis of canine AD. METHODS: Citation databases, abstracts and proceedings from international meetings published between 2001 and 2013 were reviewed in this update. Where necessary, older articles were included for background information. RESULTS: The development of canine AD is associated with changes in both cutaneous and circulating lymphocyte populations. These lymphocyte responses are characterized by the production of a complex variety of cytokines, including not only T-helper 2 but also T-helper 1, T-helper 17 and regulatory T-cell responses. In addition, microarray gene expression analysis has enabled the identification of a number of noncytokine factors that appear to be associated with atopic inflammation. These include the calcium-binding protein S100A8, serum amyloid A and a number of protease inhibitors, as well as genes involved in epidermal barrier formation, innate immunity receptors, cell cycle proteins and apoptosis. CONCLUSIONS: The development of AD in dogs is characterized by the development of a delicate balance between a variety of T-cell phenotypes and inflammatory mediators, including cytokines, chemokines and noncytokine factors.