While food hypersensitivity can be a life-threatening problem, its scope is yet to be fully developed. More work is needed to further define its parameters but basic food hypersensitivity has been significantly clarified in the decade of the 80's to become standard practice for most updated allergists. Studies related to inhalation of food antigens remains within the purview of research centers as does other immunologic processes. The diagnosis of food hypersensitivity remains dependent on the medical history with test like elimination diets, skin testing, and RAST. Double-blind, placebo-controlled, food challenges (DBPCFC) provide the most definitive support for the association between certain symptoms and a specific food.

Indiana University-Purdue University Indianapolis (IUPUI) / Follicular T helper (TFH) and regulatory (TFR) cells are two key classes of CD4+ T cells found in germinal centers (GCs). The primary role of TFH cells is to help B cells form GCs to produce high-affinity antibodies during an infection while the role of TFR cells remains controversial. The transcriptional repressor Bcl6 is essential for the differentiation of TFH, TFR and GCB cells and understanding signaling pathways that induce Bcl6 and TFH cell differentiation are important. We observed that Bcl6 is highly up-regulated in activated CD4 T cells following glucose deprivation by a pathway involving the metabolic sensor AMP kinase. The transcription factor Blimp1 represses both TFH cell differentiation and Bcl6 expression, and we show the major role of Blimp1 on TFH cell differentiation is to repress Bcl6 expression and not other genes in the TFH differentiation pathway. We also found Bcl6 positively regulates expression of the key TFH cell receptor PD-1 by inhibiting the repression of PD-1 by the transcription factor Tbet. The roles of TFH and TFR cells in controlling allergen-specific IgE were investigated using a peanut allergy model and strains of mice with alterations in the TFH and TFR pathways. We found TFR cells unexpectedly play an essential role in promoting and maintaining IgE production and anaphylaxis, as well as the GC reaction. Compared to control mice, TFR-deficient mice lacked circulating peanut-specific IgE and anaphylactic responses were significantly weakened. Mechanistically, TFR cells require Blimp1 controlled IL-10 to promote GCB cell survival and IgE production. Blocking IL-10 signals mimicked the loss of IgE levels in TFR-deficient mice and rescued mice from anaphylaxis. Overall, these studies have defined novel roles of Bcl6, TFH and TFR cells in regulating antibody production by the GC reaction, and provide greater understanding of how allergic immune responses are controlled. / 2019-11-21

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Thymic stromal lymphopoietin (TSLP), an epithelial-derived cytokine, has a critical role in the development of allergic inflammatory responses and have been implicated in type 2 allergic disease, including asthma, allergic rhinitis, and atopic dermatitis. Genetic polymorphisms in the TSLP gene are among the most commonly cited variants associated with asthma and allergic disease, however, the functional effects of these polymorphism are not fully understood. The objective of this study was to investigate the role of a TSLP polymorphism in the Th2 inflammatory responses of the nasal epithelium, as well as in responding to nasal allergen provocation and intranasal corticosteroid treatment. We cultured nasal epithelial cells from allergic asthmatic subjects and examined cytokine and chemokine secretions and gene expression profiles in response to polyinosinic:polycytidylic acid treatment. To explore the functional consequences of the rs1837253 polymorphism we analyzed the two TSLP gene isoforms, as they have shown dichotomous effects, however, no associations were found between rs1837253 genotype and the expression of TSLP and gene isoforms. We did not find any associations of TSLP or cytokine production between genotypes, or in relation to response to nasal allergen challenge or corticosteroid treatment. Exploration of local and systemic effects of the rs1837253 SNP did not show any differences in response to INCS treatment in vitro or ex vivo. We did demonstrate that nasal epithelial cell-derived factors are capable of stimulating eosinophil/basophil colony forming units in the absence and presence of exogenous IL-3. Overall, the results indicate a role of the nasal epithelium in driving eosinophil/basophil differentiation and highlight the complexity of gene-environment interactions and the mechanisms of asthma and allergic inflammation. / Thesis / Master of Science (MSc)

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Indiana University-Purdue University Indianapolis (IUPUI) / CD4 T cells are critical regulators of inflammatory diseases and play an important role in allergic airway diseases (AAD) by producing type 2 cytokines including IL-4, IL- 13, IL-5 and IL-9. In chronic AAD models, IL-9 producing CD4 T-helper (TH9) cells lead to accumulation of eosinophils and mast cells in the airway, increase levels of type-2 cytokines, stimulate ILC2 cell proliferation, and induce mucus production from airway epithelium. However, the transcriptional network that governs the development of TH9 cells and their function during allergic responses is not clearly understood. Naïve CD4 T cells differentiate into TH9 cells in the presence of IL-2, IL-4 and TGFβ, activating a complex network of transcription factors that restricts their development to TH9 lineage. In this study a variety of approaches were utilized, including characterizing Il9 reporter mice, to identify an additional Ets-transcription factor termed ERG (Ets-related gene) that is expressed preferentially in the TH9 subset. Knock-down of Erg during TH9 polarization led to a decrease in IL-9 production in TH9 cells in vitro. Deletion of Erg at the later stage of TH9 induced pathogenesis resulted in reduced IL-9 production in the airways in chronic AAD. Chromatin immunoprecipitation assays revealed that ERG interaction at the Il9 promoter region is restricted to the TH9 lineage and is sustained during TH9 polarization. In the absence of PU.1 and ETV5, ERG regulated IL-9 production independent of other Ets-transcription factors and the deletion of Erg further lead to a decrease in IL-9 production by lung-derived CD4-T cells in chronic AAD model. Lastly, I also identified IL-9 secreting CD4 tissue resident memory cell population that play an instrumental role in allergic recall responses. In summary, in this study novel transcription factors were identified that can regulate TH9 function and the role of IL-9 in allergic airway recall responses. / 2022-12-28

LysM-domain containing (LysMD) proteins are widespread in nature and associated with host-pathogen interactions, often-binding peptidoglycan and chitin. However, the functions of mammalian LysMD proteins have not been fully defined. Chitin, a major component of fungal cell walls, has been associated with allergic disorders such as asthma. However, chitin recognition by mammals remains enigmatic at best. The principal receptor(s) on epithelial cells for chitin recognition remain to be determined. In this study, we demonstrate that LYSMD3 is expressed on the surface of human airway epithelial cells. Interestingly, LYSMD3 is able to bind chitin and β-glucan as well as fungal spores. Knockdown and knockout of LYSMD3 markedly impaired chitin and fungi-induced inflammatory cytokine production in lung epithelial cells. Antagonization of LYSMD3 ectodomain by soluble LYSMD3 protein, multiple ligands, or antibody against LYSMD3 all significantly blocked chitin signaling. Taken together our study identifies LYSMD3 as a mammalian pattern recognition receptor (PRR) for chitin and is required for the epithelial inflammatory response to chitin and fungal spores. / Doctor of Philosophy / Chitin is the main ingredient in the crustacean shells (e.g. crab, shrimp, lobster). It can also be found in fungal cell walls and insect exoskeletons like house dust mites and cockroaches. Many people are allergic to seafood, fungal spores, house dust mites, and cockroach. These allergies are thought to be driven at least partially by a response to chitin. However, how mammals sense and response to chitin is largely unknown. In plants, LysM-domain (LysMD, chitin binding domain) containing receptors are the primary receptors for chitin. These receptors can bind directly to chitin and/or mediate the innate immune response against chitin-containing pathogens such as fungi. Mammals also have LysMD containing proteins, but the functions of these proteins are unclear. In this study, we demonstrate that human LYSMD3 is a novel receptor for chitin. LYSMD3 is essential for chitin recognition and chitin induced inflammatory responses by airway epithelial cells. Our characterization of LYSMD3 as the elusive human epithelial cell receptor for chitin, resolves a long-standing mystery and provides a new insight into the context of innate immunity in mammals against chitin-containing organisms and allergic inflammation.

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