Rheumatoid arthritis is a chronic disease that affects multiple joints. It is considered to be an autoimmune disease in which a T helper (Th)-1 type response has been implicated to play an important pathogenetic role. As osteoclasts, cells that resorb bone, play a crucial part in the bone destruction that occurs in RA, we and others have investigated the pathophysiology of these cells. The findings that interferon (IFN)-γ strongly inhibits osteoclastogenesis and that interleukin (IL)-17 has the ability to enhance osteoclast differentiation have cast doubt on the hypothesis that RA is a Th1 disease. In this review, I describe the relationship between Th cells, the so-called "commander" of the immune response, and RA, mainly from the viewpoint of the environments Th cells create for the excessive differentiation and function of osteoclasts, resulting in the destruction of bone.

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Multiple sclerosis (MS) is a CD4⁺ T cell-mediated autoimmune disease affecting the central nervous system. It was largely accepted that Th1 cells driven by IL-12 were pathogenic T cells in human MS and experimental autoimmune encephalomyelitis, an animal model of MS. Recent data have established that IL-17-producing CD4⁺ T cells, driven by IL-23 and referred to as Th17 cells, play a pivotal role in the pathogenesis of EAE. A combination of TGF-β and IL-6 induce Th17 cell lineage commitment via expression of transcription factor RORγt. Th17 cells and induced Foxp3⁺ T regulatory cells are in reciprocal position in the T cell lineage commitment governed by TGF-β and IL-6. The vitamin A metabolite retinoic acid is involved in this process via TGF-β dependent induction of Foxp3. We have demonstrated that human Th17 cells could be identified as CCR2⁺ CCR5^- memory CD4⁺ T cells. It is becoming clear that IL-23/Th17 axis also plays an important role in the pathogenesis of various human autoimmune diseases including MS. Additionally, accumulating evidences raise a possibility that CCR2 on Th17 cells may be a therapeutic target in MS.

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The identification of novel helper T (Th) cell subsets, i.e., IL-17-producing Th cells (Th17 cells) and regulatory T cells (Treg cells), provided new insight into our understanding of the molecular mechanisms involved in the development of infectious and autoimmune diseases as well as immune responses, and thus led to revision of the classic Th1/Th2 paradigm. Several current lines of evidence from gene-deficient mice indicate that IL-17 and Th17 cells, but not IFN-γ and Th1 cells, are responsible for the development of autoimmune diseases such as murine arthritis and encephalomyelitis, which have classically been considered to be Th1-mediated disorders. Th17 cells may also contribute to the pathogenesis of classically recognized Th2-mediated allergic disorders. In this review, we summarize the current knowledge regarding IL-17 and Th17 cells and discuss their potential roles in the pathogenesis of allergic disorders.

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Immunomodulators such as lipopolysaccharides (LPS) and forskolin change the nature of dendritic cells (DCs) to induce Th1 and Th2 cells, respectively, thereby designated Th1 or Th2 adjuvants. Recent studies showed that Th17-inducing activity can be carried by certain polysaccharides such as β-glucan derived from Candia albicans. Such activities can be scrutinized by using MLR, cAMP and possibly, differential expression of Notch ligand isoforms. In this review article, we also introduce an effective method to establish human Th17 cell clones and a transcriptome analysis using human Th subpopulations. In vivo relevance to human Th17 responses is discussed.

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Background: Eosinophils play a pivotal role in allergic inflammation. Recent evidence suggests that they not only function as terminal effector cells but have potential to interact with allergen and initiate immune responses. We investigated cytokine production from eosinophils through direct interaction with a major allergen, house dust mite (HDM).
Methods: Purified eosinophils from HDM-sensitized or non-sensitized donors were cultured with HDM extract or lipopolysaccharide (LPS) for 18 or 40 h. A panel of cytokine gene expression in eosinophils was examined by means of real-time RT-PCR. Released cytokines in the culture supernatants were assessed with a specific ELISA. In some experiments, HDM was pretreated with protease inhibitors, then added to the culture. Cytokines tested for gene expression were interleukin (IL)-2, 4, 6, 7, 8, 9, 10, 11, 12, 13, 16,17, 18, TGF-β1 and GM-CSF,.
Results: LPS induced small enhancement of GM-CSF gene expression at 18 h. At 40 h, HDM induced about 60-fold enhancement of IL-9 gene expression. IL-9 protein was also detected in the culture supernatants at 60h. Those reactions were observed regardless of HDM sensitization status of the donors. HDM-induced IL-9 expression was completely inhibited with a serine protease inhibitor, AEBSF, not with a cysteine protease inhibitor, E-64.
Conclusions: Accumulated eosinophils in the airways in asthma may directly react with HDM and produce IL-9 to further promote Th2-type immune responses. Protease-activated receptor 2, a ligand for serine proteases, which contained in HDM, may be involved in the reaction.

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Background: IgE antibodies against Japanese cedar pollen (JCP) play an important role for the pathogenesis of the cedar pollinosis, but the mechanism of their production has been unclear. We explored the capacity of peripheral blood B cells from pollinosis patients to produce anti-JCP specific IgE.
Methods: Peripheral blood B cells from 16 pollinosis patients and 9 normal subjects were cultured with mitomycin-C treated T cells with immobilized anti-CD3 for 10 days.
Results: B cells from pollinosis patients produced higher amounts of anti-JCP specific IgE than those from normal subjects upon stimulation with immobilized anti-CD3 activated autologous T cell, whereas the production of anti-JCP specific IgM were comparable between normal subjects and patients. Exogenous IL-4/IL-5 or anti-CD3 stimulated patients' T cells could not induce the production of anti-JCP specific IgE from normal B cells.
Conclusions: These results indicate that B cells from normal individuals contain comparable numbers of precursors that are committed to produce anti-JCP specific IgM to patients' B cells. Moreover, the data confirm that the class switching of IgM to IgE within anti-JCP specific B cells contributes to development of Japanese cedar pollinosis.

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Background: Despite the difference in geographical dominance of certain grasses, a high degree of allergenic similarity or cross-reactivity between Bermuda grass pollen (BGP) and timothy grass pollen (TGP) has been previously demonstrated.
The aim of the present study was to ascertain the sensitisation to TGP in 411 patients known for their reactivity to BGP extracts by analysing their reactivity to crude timothy pollen extract and timothy pollen purified allergens, establishing their specific IgE-profiles.
Methods: Using the immunoenzymatic CAP method we evaluated IgE-specific antibodies for BGP- and TGP- extracts and the timothy recombinant (r) and natural (n) allergens rPhl p 1, rPhl p 2, nPhl p 4, rPhl p 5, rPhl p 6, rPhl p 7, rPhl p 11, and rPhl p 12.
Results: BGP-IgE positive patients (median = 8.0kUA/l, 2.8-22.2kUA/l 25^th-75^th percentile) simultaneously had IgE positive results for TGP (100% of subjects) (median = 48.9kUA/l, 19.8- > 100kUA/l 25^th-75^th percentile) and high prevalence of sensitization to 6/8 Phleum pratense allergens (Phl p 1, 2, 4, 5, 6, 11, markers of genuine sensitisation to TGP) other than profilin and calcium binding protein. More than 72% of BGP allergic patients were co-sensitised to rPhl p 1, rPhl p 2, nPhl p 4, rPhl p 5, rPhl p 6. A decrease of total and specific IgE with patients' age was observed.
Conclusions: Our data show that all BGP-allergic patients simultaneously exhibit higher IgE antibody levels to recombinant and natural P. pratense allergens as well as to crude TGP extract. This suggests that when choosing an immunotherapeutic regimen for BGP-sensitised patients (after establishing their IgE profile via purified TGP-allergens), subcutaneous or sublingual TGP-extract vaccines in appropriate doses, in order to influence T epitope specificity, might be beneficial. Though extremely uncommon, in cases where a patient is exclusively BGP allergen-sensitised, BGP-extract therapy is the appropriate therapeutic response.

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Background: We previously reported the phenotypic distribution patterns of airway smooth muscles in fatal asthmatics; Type I asthmatics with smooth muscle bundle thickening only in large airways and Type II in whole airways. We hypothesized that increased smooth muscle bundles in the airway walls would disrupt airway lymphatics to impair airway clearance in these fatal asthmatics.
Methods: The autopsy lungs of seven fatal asthmatics (three Type I, four Type II asthmatics) and five controls were examined by immunohistochemistry to reveal the lymphatics distributed in the airway walls. The total area of lymphatics around each cross-sectioned airway was measured and its airway radius was calculated using an image analyzer system. Finally, the distribution areas of lymphatics in the same level of airways of bronchial trees were compared among Type I, Type II asthmatics and controls.
Results: The total area of airway lymphatics in each lung was found to be positively correlated with the airway radius (R). The distribution areas of lymphatics in larger airways (1.5 < R < 2.0mm) of both types of asthmatics were significantly decreased than controls, and Type I asthmatics contained much less lymphatics than Type II asthmatics in these airways. The lymphatics around smaller airways (0.5 < R < 1.0mm) were also reduced in both phenotypes of asthmatics without statistic difference between them. The airway lymphatics of these fatal asthmatics were observed to be interrupted by thickened muscle bundle layers, and by fibrotic tissues developed around these airways as well.
Conclusions: These results indicate that distribution of lymphatics were decreased in the airway walls of fatal asthmatics which contained muscle bundles and fibro-connective tissues both of which were augmented in these airway walls to disrupt lymphatics, impair airway clearance and accelerate mucosal edema which would cause refractory status of these patients.

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Background: Japanese cedar pollen (JCP) sensitization and Japanese cedar pollinosis (JCPS) appear to be increasingly prevalent in younger children. The present study investigated factors affecting JCP sensitization and JCPS development in school children.
Methods: In May or June each year from 1994 to 2006, 275-510 children were assessed for serum JCP-IgE and house dust mite (HDM)-IgE levels, and surveyed regarding rhinoconjunctival symptoms.
Results: Strong JCP sensitization (IgE ≥ 17.5U_A/ml) was associated with age (odds ratio (OR) = 2.65), the amount of dispersed pollen in the observed year (OR = 2.03) and in the year following birth (OR = 1.51), the month of birth (OR = 2.18), and the recent birth cohort (OR = 1.96). Symptoms were negatively correlated with the recent birth cohort (OR = 0.69) after adjusting for JCP-IgE levels. Strong HDM sensitization was associated with gender (OR = 0.65 for girls) and the recent birth cohort (OR = 1.76).
Conclusions: JCP sensitization appeared to be associated with the recent birth cohort and to increases in dispersed pollen just after birth and in the observed season. Although the recent birth cohort was more easily sensitized, they were not more likely to develop symptoms. In contrast to JCP sensitization, strong HDM sensitization appeared to develop prior to commencement of primary school and was more likely to affect boys.

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