Th2-type Immune Reactions Research Articles

Eosinophilic Gastrointestinal Diseases: The Pathogenesis, Diagnosis, and Treatment.

Eosinophilic gastrointestinal diseases are delayed-type chronic allergic disorders that show gastrointestinal eosinophil dense infiltration, with an exaggerated Th2-type immune reaction considered to be an important mechanism. These diseases can be roughly divided into two types: eosinophilic esophagitis, mainly found in young and middle-aged men, and eosinophilic gastroenteritis, which is found in both genders equally. A diagnosis of eosinophilic esophagitis is suspected when characteristic endoscopic findings, including longitudinal furrows and rings, are noted. However, characteristic endoscopic abnormalities are rarely found in cases with eosinophilic gastroenteritis, so multiple biopsy sampling from the apparently normal gastrointestinal mucosal surface is important for making an accurate diagnosis. The administration of systemic glucocorticoid is the standard treatment for eosinophilic gastroenteritis, while acid inhibitors and topical glucocorticoid swallowing therapy are effective for eosinophilic esophagitis. Anti-cytokine therapies for eosinophilic gastrointestinal diseases are currently under development.

Influence of <i>Helicobacter pylori</i> on cytokine regulation in chronic atrophic gastritis

At present, the level of Helicobacter pylori infection is determined by geographic area, gender and age of the examined individuals, and can reach up to 95% of the total population. Environmental adaptation of H. pylori is exhibited in its ability to adhere to the gastric mucosal epithelium and modulated expression of its own virulent factors. Current concepts implicate that H. pylori can survive inside epithelial cells, evading host immune response. Cytokines are produced by immune cells and act to regulate its major stages. A cytokine cascade launched after Helicobacter pylori infection triggers immune reactions, progression of chronic inflammatory and destructive processes in the gastric mucosa. The role of cytokines in precancerous diseases of the stomach is ambiguous because, on the one hand, they activate immune response aimed at eliminating the pathogen, whereas on the other hand, they do contribute to the disease progression. The aim of our study was to examine profile of some cytokines and features of cytokine regulation in H. pylori-infected middle-aged males with chronic gastritis (CG) as well as chronic atrophic gastritis (CAG). In patients with CG with H. pylori, CAG and CAG with H. pylori, an increase in the cytokine IL-2 was observed that might contribute to augmented damaging effect of cytotoxic lymphocytes, as well as implementation of antitumor effect. CAG with H. pylori was featured with IL-8 hyperproduction, which resulted in increased absolute numbers of band neutrophils in peripheral blood and their decreased phagocytic activity evidencing about altered host defense mechanisms. There was increased amount of IFNy involved in recognition of malignantly transformed cells and upregulated expression of the major histocompatibility complex molecules on antigen-presenting cells. In patients with CG with H. pylori and CAG with H. pylori, production of IL-4 was increased, which might serve as a contributing factor to the chronicity of H. pylori-associated diseases. Overproduction of type 1 and type 2 cytokines indicates about activated Th1 and Th2 type immune reactions in H. pylori-associat-ed CG. A potent pro-inflammatory cytokine cascade triggers inflammatory changes in gastric mucosa with developing neutrophil infiltration and lymphocyte activation. Damage and death of epithelial cells upon inflammation form erosive and ulcerative defects, or changes manifested as gastric mucosal atrophy, metaplasia and neoplasia. The data obtained may be used as additional diagnostic criteria in early diagnostics of precancerous stomach diseases.

Allergy in an Evolutionary Framework.

Respiratory allergy including bronchial asthma and food allergy have gained epidemic character in the last decades in industrialized countries. Much has been learned with respect to the pathophysiology of allergic disease and this has facilitated specific therapies. Allergy is a chronic disease, and being so prevalent claims to search for evolutionary causes of the general susceptibility of humans as a species to react to environmental antigens in a Th2 type immune reaction with IgE production. In an evolutionary analysis of Allergy, necessary questions addressed in this review are "Why does IgE exist or why did IgE evolve?" as well as from the point of view of the mismatch hypothesis, "Why is there an Allergy epidemic?" Recent studies on the possible biological and protective role of IgE against parasites, arthropods, venoms or toxins are challenging the widely accepted definition of allergens as generally innocuous antigens. Combining the immunologic danger model and the toxin hypothesis for allergies, the allergic response could have evolved with an adaptive value and allergens could be proxies for other putative noxious agents. The last decades yielded with vast molecular data of allergens. With available bioinformatics tools, we therefore also describe that evolutionary theory could be applied to prevent allergy, estimate cross-reactivity, to design allergen-specific immunotherapy and to assess the risks of novel foods.

Canine macrophages can like human macrophages be in vitro activated toward the M2a subtype relevant in allergy

The M2a subtype of macrophages plays an important role in human immunoglobulin E (IgE-mediated allergies) and other Th2 type immune reactions. In contrast, very little is known about these cells in the dog. Here we describe an in vitro method to activate canine histiocytic DH82 cells and primary canine monocyte-derived macrophages (MDMs) toward the M2a macrophages using human cytokines. For a side-by-side comparison, we compared the canine cells to human MDMs, and the human monocytic cell line U937 activated towards M1 and M2a cells on the cellular and molecular level. In analogy to activated human M2a cells, canine M2a, differentiated from both DH82 and MDMs, showed an increase in CD206 surface receptor expression compared to M1. Interestingly, canine M2a, but not M1 derived from MDM, upregulated the high-affinity IgE receptor (FcεRI). Transcription levels of M2a-associated genes (IL10, CCL22, TGFβ, CD163) showed a diverse pattern between the human and dog species, whereas M1 genes (IDO1, CXCL11, IL6, TNF-α) were similarly upregulated in canine and human M1 cells (cell lines and MDMs). We suggest that our novel in vitro method will be suitable in comparative allergology studies focussing on macrophages.

Serum TARC levels are strongly correlated with blood eosinophil count in patients with drug eruptions

BackgroundThis study aims to evaluate the relationship between serum thymus and activation-regulated chemokine (TARC) levels with various clinicopathological conditions in patients with drug eruptions. The value of TARC in diagnosing drug-induced hypersensitivity syndrome (DIHS) was also examined. MethodsStudy participants included 84 patients who presented with generalized eruptions suspected to be drug-related, including DIHS, Stevens-Johnson syndrome (SJS)/toxic epidermal necrolysis (TEN), maculopapular exanthema (MPE), erythema multiforme (EM), erythroderma, and toxicoderma. The correlation coefficients between serum TARC levels and clinical parameters in peripheral blood samples were calculated. ResultsSerum TARC levels in patients with DIHS were higher than those found in patients with SJS/TEN, MPE, EM, and toxicoderma. TARC levels had 100% sensitivity and 92.3% specificity in diagnosing DIHS, with a threshold value of 13,900 pg/mL. Serum TARC levels positively correlated with age, white blood cell (WBC) count, neutrophil count, eosinophil count, monocyte count, atypical lymphocyte (Aty-ly) count, serum blood urea nitrogen (BUN) levels, and creatinine (Cr) levels. It negatively correlated with serum total protein (TP), albumin (Alb), and estimated glomerular filtration rate (eGFR). Among these clinical parameters, blood eosinophil counts were most strongly correlated with serum TARC levels, with a correlation coefficient of 0.53. ConclusionsSerum TARC levels are well correlated with blood eosinophil counts in patients with generalized drug eruptions, indicating that Th2-type immune reactions underlie TARC production. Serum TARC measurements also have potent diagnostic value for DIHS, with high sensitivity and specificity.

IL-4 mediates dicloxacillin-induced liver injury in mice

Drug-induced liver injury (DILI) is a major problem in drug development and clinical drug therapy. In most cases, the mechanisms are still unknown. It is difficult to predict DILI in humans due to the lack of experimental animal models. Dicloxacillin, penicillinase-sensitive penicillin, rarely causes cholestatic or mixed liver injury, and there is some evidence for immunoallergic idiosyncratic reaction in human. In this study, we investigated the mechanisms of dicloxacillin-induced liver injury. Plasma ALT and total-bilirubin (T-Bil) levels were significantly increased in dicloxacillin-administered (600 mg/kg, i.p.) mice. Dicloxacillin administration induced Th2 (helper T cells)-mediated factors and increased the plasma interleukin (IL)-4 level. Neutralization of IL-4 suppressed the hepatotoxicity of dicloxacillin, and recombinant mouse IL-4 administration (0.5 or 2.0 μg/mouse, i.p.) exacerbated it. Chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTh2) is a cognate receptor for prostaglandin (PG) D 2, and is suggested to be involved in Th2-dependent allergic inflammation. We investigated the effect of 13,14-Dihydro-15-keto-PGD 2 (DK-PGD 2; 10 μg/mouse, i.p.) administration on dicloxacillin-induced liver injury. DK-PGD 2/dicloxacillin coadministration resulted in a significant increase of alanine aminotransferases and a remarkable increase of macrophage inflammatory protein 2 expression. In conclusion, to the best of our knowledge, this is the first report to demonstrate that dicloxacillin-induced liver injury is mediated by a Th2-type immune reaction and exacerbated by DK-PGD 2.

Th2 Immune Response Plays a Critical Role in the Development of Nickel-Induced Allergic Contact Dermatitis

Background:The precise roles of T helper (Th)1-type and Th2-type cytokine responses in nickel (Ni)-induced allergic contact dermatitis have not yet been clearly defined. We investigated the involvement of Th2 cytokines in Ni-induced contact hypersensitivity reaction using GATA-3 transgenic (Tg) mice. Methods: A Ni-titanium (Ti) alloy was implanted under the skin of GATA-3 Tg mice. A Ni solution was then injected 1 month after sensitization. The ear swelling response was measured at several time points after the injection; the cytokine levels in the skin were measured at 48 h after injection, and the serum levels of IgE were measured 1 month after injection. In addition, purified CD4+ splenic cells obtained from the GATA-3 Tg mice sensitized with the Ni-Ti alloy were infused into Rag-2^–/– mice, and the ear swelling response of these mice after a further challenge with Ni solution was also measured. Results:Marked ear swelling and elevated serum IgE levels and skin tissue levels of IL-4 were observed in Ni-Ti-sensitized GATA-3 Tg mice. The Rag-2^–/– mice transfused with the CD4+ splenic cells from the Ni-Ti alloy sensitized GATA-3 Tg mice showed a significantly more pronounced ear swelling response than the control mice. Conclusion: We confirmed the participation of Th2-type immune reactions in Ni-induced allergy using GATA-3 Tg mice.

Aspergillus 단백분해효소 알러젠에 의해 유도된 Th2 관련 기도염증반응에서 protease activated receptor 2 (PAR2)의 역할

Most allergens have protease activities, suggesting that proteases may be a key link between Th2-type immune reactions in allergic responses. Protease activated receptor (PAR) 2 is activated via the proteolytic cleavage of its N-terminal domain by proteinases. To know the role of PAR2 in Aspergillus protease allergen activated Th2 immune responses in airway epithelial cells, we investigated and compared immune cell recruitment and level of chemokines and cytokines between PAR2 knock out (KO) mice and wild type (WT) mice. There were evident immune cell infiltrations into the bronchial alveolar lavage fluid (BALF) of WT mice, but the infiltrations in PAR2 KO mice were significantly lowered than those of WT mice. The IL-25, TSLP, and eotaxin gene expressions were profoundly increased after Aspergillus protease, but their expression was significantly lowered in PAR2 KO mice in this study. Compared to PAR2 KO mice, OVA specific IgE concentrations in serum of WT mice were quite increased; moreover, the IgE level of PAR2 KO mice was lower than in WT mice. The IL-25 expression by Aspergillus protease stimulation was significantly reduced by p38 specific inhibitor treatment. In this study, we determined that Th2 response was initiated with IL-25 and TSLP mRNA up-regulation in lung epithelial cells via PAR2 after Aspergillus protease allergen treatment.

Do hepatitis B virus carriers develop atopic diseases?

The prevalence of allergic disorders, such as asthma, hay fever, and atopic dermatitis, has increased dramatically over the past few decades. Although the important inherited component in these diseases is well established, the role of environmental factors in relation to allergic disorders has become increasingly topical in the last decade. Immunologic data show that different infections can either promote atopy (as in respiratory syncytial virus infections) or inhibit it (as in measles, hepatitis A, and tuberculosis). Although there are 400 million hepatitis B virus (HBV) carriers around the world, and asymptomatic HBV carriers with a high level of virus replication are characterized by Th2-type immune reactions, the relationship between HBV carriers and atopic disorders has not been studied.

Interleukin-4 and breast cancer.

IL-4 is a pleiotropic cytokine produced by T lymphocytes which acts on various cells of such as T and B lymphocytes, monocytes, fibroblast, endothelial cells, macrophages and some others. IL-4 was originally described as a B cell growth factor, and now known to provide potent anti-tumor activity against various tumors, including breast cancer. IL-4 can induce apoptosis in cultured breast cancer cells. In addition, it has been clarified that IL-4 plays an important role in the regulation of estrogen synthesis enzymes including 17beta-HSD and 3beta-HSD. These findings imply that IL-4 is a key enzyme not only for Th2 type immune reactions but also for tumor cell growth itself in human breast cancer.

Selective Expression of a Novel Surface Molecule by Human Th2 Cells In Vivo

The search for reliable marker molecules discriminating between human Th1 and Th2 cells identified a gene encoding a novel member of the G protein-coupled leukocyte chemoattractant receptor family, which is selectively expressed in Th2 but not Th1 lineage cells, thereby named CRTH2 (chemoattractant receptor-homologous molecule expressed on Th2 cells). Studies with anti-CRTH2 mAbs demonstrated that CRTH2 was expressed in a small population (0.4-6.5%) of CD4+ T cells in fresh PBMCs of healthy adults, but no remarkable expression was seen in B cells and NK cells. In some cases, CD8+ T cells ( approximately 3.5%) expressed CRTH2. Phenotypes of CD4+ T cells expressing CRTH2 were CD45RA-, CD45RO+, and CD25+, similar to those of Ag-activated effector/memory T cells. Freshly isolated CRTH2+ CD4+ T cells produced Th2- but little or no Th1-type cytokines upon stimulation with PMA and ionomycin. In addition, an allergen-induced proliferative response in fresh PBMCs was significantly and selectively reduced by subtracting CRTH2+ cells. Together, these results indicate that CRTH2 is selectively expressed in vivo in an activated state of Th2 cells including allergen-responsive Th2 cells, suggesting its pivotal roles in ongoing Th2-type immune reactions.