Type 1 and Type 2 cytokines imbalance in adult male C57BL/6 mice following a 7-day oral exposure to perfluorooctanesulfonate (PFOS)

Previous studies indicate that exposure to perfluorooctanesulfonate (PFOS), a ubiquitous and highly persistent environmental contaminant induces immunotoxicity in mice. However, clear mechanisms to explain any PFOS-induced immunotoxicity are still unknown. The study here sought to examine the ability of PFOS to potentially perturb T-helper (T_H)-1 and -2 cell cytokine secreting activities, as well as to cause shifts in antibody isotype levels, as possible mechanisms involved in PFOS-induced immunotoxicity. Adult male C57BL/6 mice were given by gavage 0, 5, or 20?mg PFOS/kg/d for 7 days. One day after the final exposure, spleens from these hosts were isolated and used for analyses of the ex vivo production of T_H1-type (interleukin-2 (IL-2), interferon-γ (IFNγ)), T_H2-type (IL-4), and IL-10 cytokines by isolated splenocytes. In addition, serum was isolated from these mice in order to assess their levels of immunoglobulin M (IgM) and IgG antibodies. In all studies, levels of the cytokines of the antibodies were quantified via enzyme-linked immunosorbent assay or enzyme-linked immunosorbent spot. The results here showed that IL-2 and IFNγ formation was reduced, but that IL-4 production increased by the 5 and 20?mg PFOS/kg/d treatments. Serum IgM levels decreased significantly (in dose-related manner) as a result of the PFOS exposures; serum IgG levels increased markedly with 5?mg PFOS/kg/d, but decreased slightly with the 20 mg PFOS/kg/d regimens PFOS exposure increased serum corticosterone levels in a dose-dependent manner. These results indicated that, after a high-dose short-term exposure to PFOS, a host’s immune state is likely to be characterized by a shift toward a more T_H2-like state that, in turn, may lead to suppression of their cellular response and enhancement of their humoral response.     

TH17 (and TH1) signatures of intestinal biopsies of CD patients in response to gliadin

Celiac disease (CD) is an immunological disorder caused by intolerance to ingested gliadin and other cereal prolamins that has been included in the T_H1-dominated group of diseases, where IL-12 induced IFNγ is the major proinflamatory signal. Recently, another linage of T cells has been described, namely T_H17, characterized by production of IL-17, that differentiate in response to TGFβ and IL-6 and participate in the pathogenesis of several autoimmune diseases. Using RT-PCR analysis of gene expression, we analyzed the presence of T_H1 (IL-12 and IFNγ) and T_H17 (TGFβ, IL-6, IL-17A, IL-17F and IL-23) related cytokines in intestinal biopsies from CD patients with active disease compared to remission and from treated patients after acute, in vitro re-exposure to gliadin. Potent T_H1 and T_H17 responses were present in the active stage of the disease, whereas short incubation of normalized biopsies with gliadin did not increase the expression of the effector cytokines, although a tendency of upregulation for both T_H1 and T_H17 promoting factors was observed, suggestive of a reactivation of proinflammatory pathways. These results place CD into the group of autoimmune disorders in which T_H17 cells also participate, although the relative importance of each T cell response and their role in the initial events of the disease need further investigation.     

The hair dyes PPD and PTD fail to induce a TH2 immune response following repeated topical application in BALB/c mice

1,4-Phenylenediamine (PPD) and the structurally-related 1,4-toluenediamine (PTD) are frequently used oxidative hair dye precursors that can induce a delayed-type hypersensitivity reaction known as contact allergy. Very rare cases of Type 1 (IgE-mediated) allergic responses associated with PPD or PTD have been reported among hair dye users. As part of an effort to determine if repeated dermal exposure to the dyes could induce a T-helper-2 (T_H2) response, we used a dermal exposure regimen in mice reported to identify a T_H2 response. Ear swelling was evident at post-final exposure to PPD and PTD, indicating that an immune response was observed. However, cytokine mRNA after repeated topical exposure to these two chemicals showed no shift in the expression toward the typical T_H2 cytokines interleukin (IL)-4 and IL-10 compared to the T_H1 cytokine interferon (IFN)-γ. Consistent with these cytokine profiles, no concomitant increase in total serum IgE antibody titer or in B220⁺IgE⁺ lymphocytes in lymph nodes and skin application site skin was detected. In contrast, using an identical exposure regimen, animals topically exposed to the known respiratory (Type 1) allergen toluene 2,4-diisocyanate (TDI) showed significant expression of IL-4 and IL-10 mRNA compared to IFNγ as well as an increase in total serum IgE and in B220⁺IgE⁺ cells in lymph nodes and skin application site. The data generated are consistent with the pattern of adverse reactions to hair dyes seen clinically, which overwhelmingly is of delayed rather than immediate-type hypersensitivity. Although current animal models have a limited ability to detect rare T_H2 responses to contact allergens, the present study results support the view that exposure to hair dyes is not associated with relevant T_H2 induction.     

Amorphous nanosilica particles block induction of oral tolerance in mice

The mucosal immune system is exposed to non-self antigens in food and the gut microbiota. Therefore, the recognition of orally ingested non-self antigens is suppressed in healthy individuals to avoid excessive immune responses in a process called “oral tolerance”. The breakdown of oral tolerance has been cited as a possible cause of food allergy, and amorphous silica nanoparticles (nSP) have been implicated in this breakdown. As nSP are widely used in foodstuffs and other products, exposure to them is increasing; thus, investigations of any effects of nSP on oral tolerance are urgent. This study evaluated the effects of nSP30 (particle diameter =?39?nm) on immunological unresponsiveness induced in mice with oral ovalbumin (OVA). Specifically, production of OVA-specific antibodies, splenocyte proliferation in response to OVA, and effects on T-helper (T_H)-1, T_H2, and T_H17 responses (in terms of cytokine and IgG/IgE subclass expression) were evaluated. nSP30 increased the levels of OVA-specific IgG in OVA-tolerized mice and induced the proliferation of OVA-immunized splenocytes in response to OVA in a dose-related manner. nSP30 also increased the expression of OVA-specific IgG₁, IgE, and IgG_2a, indicating stimulation of the T_H1 and T_H2 responses. The expression of interferon (IFN)-γ (T_H1), interleukin (IL)-4 and IL-5 (T_H2), and IL-17 (T_H17) was also stimulated in a dose-related manner by nSP30 in splenocytes stimulated ex vivo with OVA. The induction of tolerance by OVA, the production of anti-OVA IgG antibodies, and proliferation of splenocytes in response to OVA was inhibited by nSP30 in conjunction with OVA and was dose-related. The nSP30 enhanced T_H1 and T_H2 responses that might prevent the induction of oral tolerance. Overall, this study showed that the abrogation of OVA-induced oral tolerance in mice by exposure to nSP30 was dose-related and that nSP30 stimulated T_H1, T_H2, and T_H17 responses.     

Is TGFβ as an anti-inflammatory cytokine required for differentiation of inflammatory TH17 cells?

T-Helper 17 (T_H17) cells are a CD4⁺ T_H subset that plays a critical role in the pathophysiology of inflammatory disorders, especially chronic forms. It seems that the derivation of T_H17 cells from their precursors take place in inflammatory microenvironment. The role of transforming growth factor (TGF)-β as an anti-inflammatory cytokine in T_H17 cell differentiation is controversial. To address some of the discrepancies that exist among different studies, this study was undertaken to more clarify the TGFβ role in human T_H17 cell differentiation. Here, CD4⁺ T-cells were isolated from peripheral blood samples and cultured in X-VIVO 15 serum-free medium. Purified cells were then treated with different combinations of polarizing cytokines (interleukin [IL]1-β, -6, and -23, with or without TGFβ), neutralizing anti-interferon (IFN)-γ and anti-IL-4 antibodies and polyclonal stimulators anti-CD3 and -CD28 antibodies, and then analyzed for IL-17, IFNγ, Foxp3, and CD25 expression by flow cytometry and for release of IL-17, -21, -22, and -10 into culture media by ELISA. The effects of selective inhibition of TGFβ signaling pathway on T_H17 cell polarization were also determined by using small molecules SB-431542 and A83-01. The current study found that a combination of pro-inflammatory cytokines, including IL-1β, -6, and -23, but not TGFβ, could be used as a cytokine combination to induce development of human T_H17 cells. It was also shown that TGFβ acted as a negative regulator in this regard and also led to reduced IL-17 and IL-22 production while inducing Foxp3 expression. Indeed, blocking of TGFβ signaling pathways by selective inhibitors up-regulated T_H17 cell differentiation. From the data here, we concluded that TGFβ down-regulates human T_H17 cell differentiation and that a presence of pro-inflammatory cytokines (along with IFNγ and IL-4 neutralizing antibodies) is sufficient for optimal differentiation of human T_H17 cells.     

Treg cells may regulate interlukin-17 production by modulating TH1 responses in 1,3-β-glucan-induced lung inflammation in mice

1,3-β-glucan is considered a fungal biomarker and exposure to this agent can induce lung inflammation. Complement activation plays an important role in early immune responses to β-glucan. Previous studies showed that T-regulatory cells (T_regs) regulated 1,3-β-glucan-induced lung inflammation by modulating the maintenance of immune homeostasis in the lung. Both interleukin (IL)-17 and T_H17 cells play pivotal roles in inflammation associated with lung disease and share reciprocal developmental pathways with T_regs. However, the effect of T_regs on IL-17 and T_H17 responses in 1,3-β-glucan-induced lung inflammation remains unclear. In this study, mice were exposed to 1,3-β-glucan by intratracheal instillation. To investigate the effects of T_regs on IL-17 and T_H17 cells in the induced lung inflammation, a T_reg-depleted mice model was generated by administration of anti-CD25 mAb. The results indicated that T_reg-depleted mice showed more severe pathological inflammatory changes in lung tissues. T_regs depletion reduced IL-17 expression in these tissues, and increased those of T_H1 cytokines. The expression of IL-17 increased at the early phase of the inflammation response. There were no significant effects of the T_regs on expression of RORγt and IL-6 or the amount of CD4⁺IL-17⁺ cells in the lungs. When taken together, the late phase of the 1,3-β-glucan-induced inflammatory response in the mice was primarily mediated by T_H1 cytokines rather than IL-17. In contrast, the early phase of the inflammatory response might be mediated in part by IL-17 along with activated complement. T_regs might be required for IL-17 expression during the late phase inflammatory response in mice. The increased IL-17 mRNA observed during the 1,3-β-glucan induced inflammatory response were attributed to cells other than T_H17 cells.     

Involvement of TH1/TH2 Cytokines in the Pathogenesis of Autoimmune Skin Disease—Pemphigus Vulgaris

Pemphigus vulgaris (PV) is classical example of antigen-driven severe autoimmune bullous skin disorder. Auto reactive T cells are critical for the induction and regulation of antibody production. With regard to cytokine production profiles, it has been reported that qualitative as well as quantitative alterations in cytokine production can result in activation of inefficacious effector mechanisms and therefore, complex and severe impairment in immune functions. The purpose of this study was to observe the alterations in the levels of T_H1 [Interleukin-2 (IL-2), Interferon-gamma (IFN-γ)] and T_H2 (IL-4 and IL-10) cytokines in the sera from patients affected with PV and compared with Pemphigus foliaceus and healthy subjects. This work is aimed to comprehend the involvement of T_H1 and T_H2 cells as inflammatory infiltrate in the modulation of acantholysis and production of pemphigus lesions. Seventy PV, 13 PF and 50 healthy, age-matched individuals without any generalized skin diseases were included in this study. The diagnosis of PV and PF patients was confirmed by histopathology (hematoxylin and eosin) and / direct immunofluorescence. The levels of T_H1 cytokines (IL-2 and IFN-γ) and T_H2 cytokine markers (IL-4 and IL-10) were estimated by high sensitivity ELISA kits. All patients with PV and PF showed significantly (p < 0.000) elevated levels of T_H2 cytokines (IL-10 and IL-4) as compared with healthy controls. However, the mean concentration of T_H1 cytokines (IL-2 and IFN-γ) was significantly decreased in patients as compared to healthy individuals. Both T_H1 and T_H2 cytokines did not show any significant difference between PV and PF cases. Current concepts support the idea that PV, induced by autoantibodies against Dsg3, is the consequence of an imbalance between Dsg3-reactive T_H2 and T_H1 cells that may be critical for the maintenance of tolerance against Dsg3. Cytokine profile for confirmed PV cases showed direct evidences for involvement of T cell responses. Increase in IL-4 and IL-10 shows induction of T_H2 cells in the pathogenesis of autoimmune disorders Pemphigus vulgaris. The decreased levels of IL-2 and IFN-γ might demonstrate the inhibitory effects by IL-4 and IL-10, which suppress the expansion of T_H1 population.     

Immune impairments and antibodies to HTL VIII/LAV in asymptomatic male homosexuals in Israel: Relevance to the risk of acquired immune deficiency syndrome (AIDS)

We have studied 288 Israeli asymptomatic male homosexuals (MHS) to determine the prevalence of antibodies to HTLVI and HTLVIII and their correlation with impairments of the immune system and serum interferon (IFN). Seropositivity for HTLVI, HTLVIII, or both was found in 1.4, 8.3, and 0%, respectively. Significant decreases in the total peripheral T cells, T_H cells, and T_H/T_S ratio as well as elevated IFN serum levels were found in the MHS group in comparison with normal controls. Although no difference in the prevalence of either immune derangements or elevated serum IFN was observed between HTLVIII/LAV-seropositive and HTLVIII/LAV-seronegative MHS, the decreases in total T cells, T_H cells, and T_H/T_S ratios were significantly greater in the seropositive MHS. These results indicate that (a) immune impairments and IFN system activation occur commonly in homosexuals, precede their exposure to HTLVIII/LAV, and probably reflect this group's increased risk for AIDS and (b) HTLVIII/LAV infection of MHS aggravates further their preexisting immune impairments.     

TH17 cells express ST2 and are controlled by the alarmin IL-33 in the small intestine

T_H17 cells are major drivers of inflammation and involved in several autoimmune diseases. Tissue inflammation is a beneficial host response to infection, but it can also contribute to autoimmunity. The crosstalk between a tissue and the immune system during an inflammatory response is key for preserving tissue integrity and restoring physiological processes. However, how the inflamed tissue regulates the magnitude of an immune response by controlling pro-inflammatory T cells is not well characterized so far. Here we show that T_H17 cells accumulating in the small intestine upon inflammation express the IL-33 receptor (ST2) and intestinal epithelial cells (IEC) are the main source of the alarmin interleukin-33 (IL-33). We show that pro-inflammatory T_H17 cells acquire a regulatory phenotype with immunosuppressive properties in response to IL-33. Absence of ST2 signaling promotes the secretion of pro-inflammatory cytokines by T_H17 cells and dampens the secretion of IL-10. Our results provide new insights into the mechanisms by which IEC, via IL-33/ST2 axis, may control pro-inflammatory T_H17 cells in the small intestine to sustain homeostasis.     

Effects of lactational exposure to low-dose BaP on allergic and non-allergic immune responses in mice offspring

Benzo[a]pyrene (BaP) can induce developmental and reproductive toxicity; however, the full scope of its immunotoxic effects remains unknown. This study aimed to assess effects of lactational exposure to low-dose BaP (comparable to human exposure) on potential allergic\non-allergic immune responses in murine offspring. Lactating C3H/HeJ dams were orally dosed with BaP at 0, 0.25, 5.0, or 100?pmol/animal/week) at post-natal days [PND] 1, 8, and 15. Five-weeks-old pups then received intratracheally ovalbumin (OVA) every 2 weeks for 6 weeks. Following the final exposure, mice were processed to permit analyses of bronchoalveolar lavage (BAL) fluid cell profiles as well as levels of lung inflammatory cytokines and chemokines, serum OVA-specific immunoglobulin, and mediastinal lymph node (MLN) cell activation/proliferation. In OVA-sensitized male offspring, lactational low-dose BaP exposure led to enhanced (albeit not significantly) macrophage, neutrophil, and eosinophil infiltration to, and increased T-helper (T_H)-2 cytokine production in, the lungs. In females, BaP exposure, regardless of dose, led to slightly enhanced lung levels of macrophages and eosinophils, and of inflammatory molecules. Protein levels of interleukin (IL)-33 in the OVA?+?BaP (middle dose) group, and interferon (IFN)-γ in the OVA?+?BaP (low dose) group, were higher than that of the OVA (no BaP) group. Ex vivo studies showed lactational exposure to BaP partially induced activation of T-cells and antigen-presenting cells (APCs) in the MLN cells of both male and female offspring, with or without OVA sensitization. Further, IL-4 and IFNγ levels in MLN culture supernatants were elevated even without OVA-re-stimulation in OVA?+?BaP groups. In conclusion, lactational exposure to low-dose BaP appeared to exert slight effects on later allergic and non-allergic immune responses in offspring by facilitating development of modest T_H2 responses and activating MLN cells. In addition, lactational exposures to BaP might give rise to gender differences in allergic/non-allergic immune responses of offspring.     

Hypomethylation of Notch1 DNA is associated with the occurrence of uveitis

Uveitis is a serious intra-ocular inflammatory disease that can lead to visual impairment even blindness worldwide. Notch signaling can regulate the differentiation of naive CD4⁺ T cells, influencing the development of uveitis. DNA methylation is closely related to the autoimmune diseases. In this study, we measured the Notch1 DNA methylation level, determined the Notch1 and related DNA methylases mRNA expression and evaluated the ratio of T helper type 17 regulatory T cell (Th17/T_reg) in peripheral blood mononuclear cells (PBMCs) from uveitis patients and normal control subjects; we also tested the levels of relevant inflammatory cytokines in serum from the participants. Results indicated that compared with those in normal control individuals, the expression of ten–eleven translocation 2 (TET2) and Notch1 mRNA is elevated in uveitis patients, whereas the methylation level in Notch1 DNA promotor region [−842 ~ −646 base pairs (bp)] is down-regulated, and is unrelated to anatomical location. Moreover, the Th17/T_reg ratio is up-regulated in PBMCs from uveitis patients, accompanied by the elevated levels of proinflammatory cytokines [e.g. interleukin (IL)-2, IL-6, IL-17 and interferon (IFN)-γ] in serum from uveitis patients. These findings suggest that the over-expression of TET2 DNA demethylase may lead to hypomethylation of Notch1, activate the Notch1 signaling, induce naive CD4⁺ T cells to differentiate theTh17 subset and thus disturb the balance of the Th17/T_reg ratio in uveitis patients. Overall, hypomethylation of Notch1 DNA is closely associated with the occurrence of uveitis. Our study preliminarily reveals the underlying mechanism for the occurrence of uveitis related to the hypomethylation of Notch1 DNA, providing a novel therapeutic strategy against uveitis in clinical practice.     

Oxidative induction of pro-inflammatory cytokine formation by human monocyte-derived macrophages following exposure to manganese in vitro

Abstract

Manganese (as Mn²⁺), a superoxide dismutase mimetic, catalyzes the formation of the relatively stable membrane-permeable reactive oxygen species (ROS) hydrogen peroxide (H₂O₂), a mediator of intracellular redox signaling in immune and inflammatory cells. The goal of this study was to investigate the potential for Mn²⁺, via its pro-oxidative properties, to activate production of pro-inflammatory cytokines/chemokines IL-1β, IL-6, IL-8, IFNγ, TNFα, and G-CSF by human monocyte-derived macrophages in vitro. For these studies, the cells were isolated from peripheral blood mononuclear leukocytes and matured to generate a population of large CD14/CD16 co-expressing cells. The monocyte-derived macrophages were then exposed to bacterial lipopolysaccharide (LPS, 1?μg/ml) or MnCl₂ (25–100?μM)—alone or in combination—for 24?h at 37?°C, after which cell-free supernatants were analyzed using a multiplex cytokine assay procedure. Exposure of the cells to LPS caused modest statistically insignificant increases in cytokine production; MnCl₂ caused dose-related increases in production of all six cytokines (achieving statistical significance of p?<?0.0171–?<?0.0005 for IL-1β, IL-6, IL-8, IFNγ, and TNFα). In the case of LPS and MnCl₂ combinations, the observed increases in production of IL-1β, IL-6, IL-8, IFNγ, and G-CSF were greater than those seen with cells exposed to the individual agents. The Mn²⁺-mediated induction of cytokine production was associated with increased production of H₂O₂ and completely attenuated by inclusion of the H₂O₂-scavenger dithiothreitol, and partially by inhibitors of NF-κB and p38MAP kinase. The findings from the studies here help to further characterize the pro-inflammatory mechanisms that may underpin clinical disorders associated with excess exposure to Mn²⁺, particularly those disorders seen in the central nervous and respiratory systems.     

Aspergillus fumigatus conidia stimulate lung epithelial cells (TC-1 JHU-1) to produce IL-12, IFNγ, IL-13 and IL-17 cytokines: Modulatory effect of propolis extract

Aspergillus fumigatus conidia are the most prevalent indoors fungal allergens. The interaction between Aspergillus antigens and lung epithelial cells (LECs) result in innate immune functions. The association between Aspergillus conidia and allergic reactions, like allergic bronchopulmonary aspergillosis (ABPA) and asthma have been repeatedly reported. Since conventional therapies for allergy and asthma are limited, finding new promising treatments are inevitable. This study was designed to evaluate the effect of A. fumigatus conidia on IL-12, IFNγ, IL-13 and IL-17 release from mouse LECs and to investigate the effect of propolis on cytokines modulation. Cells were divided to two groups, one was exposed to 3 × 10⁴ conidia of Aspergillus fumigatus and another group was treated by propolis (25 μg/mL) as well as exposed to A. fumigatus conidia. Cytokines IL-13, IL-12, IFNγ and IL-17 were measured at times 0, 6 and 12 hours after exposure using ELISA assay. The results indicated that A. fumigatus could increase the release of the cytokines with IL-13 and IL-17 being the most affected ones whilst treatment with propolis decreased the effects of A. fumigatus on IL-13 and IL-17 production. The results showed that propolis has down regulatory effects on Th2 cytokine, IL-13, and IL-17 production, whereas it caused a significant induction of IL-12, as an important Th1 cytokines by LECs. With respect to the obtained results, propolis extract might be contributed to decrease Th2 responses in allergic asthma phenomenon. However more investigations must be done in future to fully understand its efficacy.     

Different patterns of cytokine induction in cultures of respiratory syncytial (RS) virus-specific human TH cell lines following stimulation with RS virus and RS virus proteins

Human peripheral blood mononuclear cell (PBMC) proliferative responses to live respiratory syncytial (RS) virus, formalin-inactivated RS (FI-RS) virus, RS virus F (fusion) protein, and RS virus G (attachment) protein were assessed. All donors responded to challenge with whole RS virus antigens and F and G proteins. F protein responses elicited higher levels of response than equivalent concentrations of G protein in nine out of ten adult RS-seropositive donors. Stimulation of PBMC induced low levels of interleukin 2 (IL-2), interferon γ (IFN-γ), IL-4, and IL-10 production. Human RS virus-specific T cell lines were generated from peripheral blood cultures following in vitro stimulation with RS virus antigens. All lines generated were shown to be MHC class II restricted. Characterisation of the lines was carried out by determining the levels of IL-2, IFN-γ, IL-4, and IL-10 in culture supernatants. T cell lines enriched for RS virus-specific cells provided a more sensitive system than PBMC cultures for the detection of cytokines. The pattern of cytokine production varied for the individual lines, and the detection of T_H1 and T_H2 cytokines was dependent on the nature of the stimulating RS virus antigen. Live RS virus induced a T_H1 pattern of cytokines (IL-2 and IFN-γ), whereas FI-RS virus induced the production of both T_H1 and T_H2 cytokines. In addition, T_H lines specific for individual RS virus proteins produced different cytokine profiles. F protein-specific lines generated T_H1-type cytokines (IL-2 and IFN-γ), whereas G protein-specific lines generated T_H2-type cytokines (IL-4 and IL-10). © 1996 Wiley-Liss, Inc.     

A model of TH17-associated ileal hyperplasia that requires both IL-17A and IFNγ to generate self-tolerance and prevent colitis

Homeostasis in the ileum, which is commonly disrupted in patients with Crohn's disease, involves ongoing immune responses. To study how homeostatic processes of the ileum impact CD4⁺T cell responses, we used TCR transgenic tools to breed mice that spontaneously produced CD4⁺T cells reactive to an antigen expressed in the ileum. At an early age, the ilea of these mice exhibit crypt hyperplasia and accumulate increased numbers of T_H17 cells bearing non-transgenic clonotypes. Half of these mice subsequently developed colitis linked to broad mucosal infiltration by T_H17 and T_H1 cells expressing non-transgenic clonotypes, chronic wasting disease and loss of ileal crypt hyperplasia. By contrast, adult mice with normal growth continued to exhibit T_H17-associated ileal crypt hyperplasia and additionally accumulated ileal-reactive Treg cells. Both IL-17A and IFNγ were protective, as their deficiency precluded ileal-reactive Treg accumulation and exacerbated colitic disease. IL-23R blockade prevented progression to colitis, whereas nTreg cell transfers prevented colitic disease, ileal crypt hyperplasia and ileal-reactive Treg accumulation. Thus, our studies identify an IL-17A and IFNγ-dependent homeostatic process that mobilizes ileal-reactive Treg cells and is disrupted by IL-23.     

Contribution of interleukin 17A to the development and regulation of allergic inflammation in a murine allergic rhinitis model

BackgroundInterleukin (IL) 17A, a key cytokine of T_H17 cells, is a well-known proinflammatory cytokine. Despite the important role of T_H17 cells in acute airway inflammation, the role of IL-17A in allergic rhinitis (AR) remains unclear.ObjectiveTo investigate the role of IL-17A in the allergic response in AR.MethodsWild-type BALB/c and IL-17A–deficient mice were immunized intraperitoneally and were challenged intranasally with ovalbumin. Allergic symptom scores, eosinophil infiltration, serum IgE level, and the levels of several cytokines in nasal lavage fluid and splenocyte supernatants were analyzed.ResultsIL-17A levels increased significantly more in ovalbumin-sensitized wild-type mice than in the negative control group. IL-17A–deficient mice showed a significant decrease in allergic symptoms, serum IgE levels, and eosinophil infiltration into the nasal mucosa compared with wild-type mice. IL-17A–deficient mice also showed decreased histamine and cysteinyl leukotriene release. Bone marrow–derived mast cells from IL-17A–deficient mice showed significantly lower degranulation and secretion of tumor necrosis factor α. Moreover, IL-17A deficiency attenuated the IL-5 level in nasal lavage fluid and its production in response to ovalbumin but did not increase interferon γ production and its level in nasal lavage fluid. In addition, secretion of IL-17A from spleen cells induced the expression of proinflammatory cytokine messenger RNA in macrophages. The mean level of proinflammatory cytokines, including tumor necrosis factor α and IL-17, decreased in IL-17A–deficient mice.ConclusionThese results suggest that IL-17A may partly contribute to the development of nasal allergic inflammation in an AR animal model and regulate AR via the activation of proinflammatory cytokines and modulation of T_H2 cytokine.     

Modeling TH2 responses and airway inflammation to understand fundamental mechanisms regulating the pathogenesis of asthma

In this review, we highlight experiments conducted in our laboratories that have elucidated functional roles for CD4⁺ T-helper type-2 lymphocytes (T_H2 cells), their associated cytokines, and eosinophils in the regulation of hallmark features of allergic asthma. Notably, we consider the complexity of type-2 responses and studies that have explored integrated signaling among classical T_H2 cytokines (IL-4, IL-5, and IL-13), which together with CCL11 (eotaxin-1) regulate critical aspects of eosinophil recruitment, allergic inflammation, and airway hyper-responsiveness (AHR). Among our most important findings, we have provided evidence that the initiation of T_H2 responses is regulated by airway epithelial cell-derived factors, including TRAIL and MID1, which promote T_H2 cell development via STAT6-dependent pathways. Further, we highlight studies demonstrating that microRNAs are key regulators of allergic inflammation and potential targets for anti-inflammatory therapy. On the background of T_H2 inflammation, we have demonstrated that innate immune cells (notably, airway macrophages) play essential roles in the generation of steroid-resistant inflammation and AHR secondary to allergen- and pathogen-induced exacerbations. Our work clearly indicates that understanding the diversity and spatiotemporal role of the inflammatory response and its interactions with resident airway cells is critical to advancing knowledge on asthma pathogenesis and the development of new therapeutic approaches.     

Effects of environmental lead exposure on T-helper cell-specific cytokines in children

Lead (Pb) may alter T-lymphocyte reactivity in situ by preferentially enhancing the development of T-helper 2 (T_H2)- and inhibiting T_H1-lymphocyte development. These effects could result in dysregulation of the presence/availability of T_H1- and T_H2-associated cytokines. The aim of this study was two-fold, that is, to assess whole blood Pb levels in schoolchildren from Taiwanese communities that varied in degree of potential for Pb exposure and then ascertain if there were relationships between Pb exposure and changes in levels of key T_H1 and T_H2 cytokines. Grades 5 and 6 students were selected from four different community schools, i.e., one from: urban area with new homes; urban area with old homes; rural site with old homes; and area located near an oil refinery. Students at each site were further divided into healthy and respiratory allergy subgroups. Blood was collected and whole blood Pb levels and serum interferon (IFN)-γ, interleukin (IL)-12, -4, and -5 levels were determined. The results indicate no differences in whole blood Pb levels (<4 µg/dl) among students from urban and rural sites; these values were similar in the healthy and allergic subjects. Serum T_H1 and T_H2 cytokine levels also did not differ among/within the groups. In contrast, refinery children had significantly increased Pb levels (5.2–8.8 µg/dl) relative to any of the other sets’ levels. Of these, children with allergies had serum T_H2 cytokine levels significantly higher and T_H1 cytokine levels significantly lower than their healthy counterparts. Oddly, though having elevated Pb levels, healthy refinery students did not display altered T_H1 or T_H2 cytokine levels relative to control student values. From this, we conclude that substantively increased whole blood Pb levels may promote T_H cell dysregulation and alter the availability of key T_H1 and T_H2 cytokines, effects that could ultimately contribute to development of pulmonary allergic diseases.