The long-term goal of this project is to better understand the immunologic mechanisms of asthma and allergic diseases. These diseases are generally thought to result from dysregulated immune responses to environmental proteins and organisms, which are mediated by Th2 cells. However, several fundamental questions still remain. How do patients develop such maladaptive T cell responses? Why don't all patients who have detectable serum IgE antibodies (e.g. patients with allergic rhinoconjunctivitis) develop asthma? By using the Alternaria fungus, which has been implicated in human asthma, we have been studying how allergen-specific CD4+ T cells develop and which allergen molecules are critically involved. We now hypothesize that the so-called "Th2-type immune response" to airborne allergens is mediated by two distinct CD4+ T cell subsets, namely Th2 cells and follicular T (Tfh) cells, which are critically involved in eosinophilic inflammation and gE antibody production, respectively. We also hypothesize that exogenous and endogenous ribonucleases (RNases) are involved in development of pathologic Th2 cells.
In Aim 1, we will use mouse models and determine the roles of Th2 cells and Tfh cells in Th2-type airway immune responses to Alternaria and other airborne allergens. We will leverage cytokine reporter mice and gene-deficient mice and investigate the compartmentalized development of Th2 cells and Tfh cells.
In Aim 2, we will investigate the roles of Tfh cells in human airway disease. We will characterize blood CXCR5+CD4+ T cells, a human counterpart of Tfh cells, in a cohort of patients with short ragweed hay fever and examine the dynamic changes in these cells during the hay fever season.
In Aim 3, we will determine the roles of Alternaria-derived RNases and endogenous RNases, such as eosinophil-derived neurotoxin, in development and exacerbation of Th2 type immune responses. We will integrate data obtained from in vitro experiments and in vivo mouse models. Recombinant Alternaria RNases and the fungi deficient in these RNases will be examined. The technical expertise required for these three Aims is readily available in the laboratories of Dr. Kita and his collaborator, Dr. Lawrence, a fungal functional genomics expert. The proposed studies are likely to provide a better understanding of the fundamental mechanisms underlying the development of Th2-type immunity to airborne allergens and will provide an explanation for the dissociation between robust airway inflammation and IgE antibody production in certain patients with allergic airway disorders. The study will also likely identify potential key environmental and endogenous molecules that participate in the development of pathologic T cell responses in asthma. Ultimately, these studies will significantly enhance our understanding of the key cellular pathway(s) and molecule(s) involved in allergen- induced airway inflammation, allowing for identification of critical targets for development of novel therapeutic strategies to treat or to prevent asthma and related airway disorders.
|Hara, Kenichiro; Iijima, Koji; Elias, Martha K et al. (2014) Airway uric acid is a sensor of inhaled protease allergens and initiates type 2 immune responses in respiratory mucosa. J Immunol 192:4032-42|
|Wada, Kota; Kobayashi, Takao; Matsuwaki, Yoshinori et al. (2013) Alternaria inhibits double-stranded RNA-induced cytokine production through Toll-like receptor 3. Int Arch Allergy Immunol 161 Suppl 2:75-83|
|Bartemes, Kathleen R; Kita, Hirohito (2012) Dynamic role of epithelium-derived cytokines in asthma. Clin Immunol 143:222-35|
|Kouzaki, Hideaki; Iijima, Koji; Kobayashi, Takao et al. (2011) The danger signal, extracellular ATP, is a sensor for an airborne allergen and triggers IL-33 release and innate Th2-type responses. J Immunol 186:4375-87|
|Kobayashi, Takao; Iijima, Koji; Radhakrishnan, Suresh et al. (2009) Asthma-related environmental fungus, Alternaria, activates dendritic cells and produces potent Th2 adjuvant activity. J Immunol 182:2502-10|
|Rank, Matthew A; Kobayashi, Takao; Kozaki, Hideaki et al. (2009) IL-33-activated dendritic cells induce an atypical TH2-type response. J Allergy Clin Immunol 123:1047-54|
|Kouzaki, Hideaki; O'Grady, Scott M; Lawrence, Christopher B et al. (2009) Proteases induce production of thymic stromal lymphopoietin by airway epithelial cells through protease-activated receptor-2. J Immunol 183:1427-34|
|Kroening, Paula R; Barnes, Terrance W; Pease, Larry et al. (2008) Cigarette smoke-induced oxidative stress suppresses generation of dendritic cell IL-12 and IL-23 through ERK-dependent pathways. J Immunol 181:1536-47|
|Vassallo, Robert; Kroening, Paula R; Parambil, Joseph et al. (2008) Nicotine and oxidative cigarette smoke constituents induce immune-modulatory and pro-inflammatory dendritic cell responses. Mol Immunol 45:3321-9|