Browsing by Subject "IgE"

Now showing 1 - 6 of 6
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    Airway exposure initiates peanut allergy by involving the IL-1 pathway and T follicular helper cells in mice
    (Elsevier, 2018-10) Dolence, Joseph J.; Kobayashi, Takao; Iijima, Koji; Krempski, James; Drake, Li Y.; Dent, Alexander L.; Kita, Hirohito; Microbiology and Immunology, School of Medicine
    BACKGROUND: Little is currently known regarding the immunologic mechanism(s) that initiate peanut allergy. Notably, peanut proteins have been detected in house dust, and their levels correlate with peanut allergy prevalence. OBJECTIVE: This study aimed to develop a new mouse model for peanut allergy and to investigate the immunologic mechanisms involved in peanut allergen sensitization. METHODS: To mimic environmental exposure, naive mice were exposed to peanut flour by inhalation for up to 4 weeks. We then analyzed serum levels of IgE antibody and challenged mice with peanut proteins. Immunological mechanisms involved in sensitization were analyzed using cytokine reporter mice, an adoptive cell transfer model, and gene knockout mice. RESULTS: When exposed to peanut flour by inhalation, both BALB/c and C57BL/6 mice developed peanut allergy, as demonstrated by the presence of peanut-specific IgE antibodies and manifestation of acute anaphylaxis on challenge. A large number of follicular helper T (Tfh) cells were also detected in draining lymph nodes of allergic mice. These cells produced IL-4 and IL-21, and they more robustly promoted peanut-specific IgE production than Th2 cells did. Genetic depletion of Tfh cells decreased IgE antibody levels and protected mice from anaphylaxis, without affecting Th2 cells. Furthermore, peanut flour exposure increased lung levels of IL-1α and IL-1β, and mice deficient in the receptor for these cytokines showed a significant decrease in Tfh cells compared with in wild-type mice. CONCLUSIONS: Tfh cells play a key role in peanut allergy, and the IL-1 pathway is involved in the Tfh response to peanut allergen exposure.
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    Designer covalent heterobivalent inhibitors prevent IgE-dependent responses to peanut allergen
    (National Academy of Sciences, 2019-04-30) Deak, Peter E.; Kim, Baksun; Qayum, Amina Abdul; Shin, Jaeho; Vitalpur, Girish; Kloepfer, Kirsten M.; Turner, Matthew J.; Smith, Neal; Shreffler, Wayne G.; Kiziltepe, Tanyel; Kaplan, Mark H.; Bilgicer, Basar; Pediatrics, School of Medicine
    Allergies are a result of allergen proteins cross-linking allergen-specific IgE (sIgE) on the surface of mast cells and basophils. The diversity and complexity of allergen epitopes, and high-affinity of the sIgE-allergen interaction have impaired the development of allergen-specific inhibitors of allergic responses. This study presents a design of food allergen-specific sIgE inhibitors named covalent heterobivalent inhibitors (cHBIs) that selectively form covalent bonds to only sIgEs, thereby permanently inhibiting them. Using screening reagents termed nanoallergens, we identified two immunodominant epitopes in peanuts that were common in a population of 16 allergic patients. Two cHBIs designed to inhibit only these two epitopes completely abrogated the allergic response in 14 of the 16 patients in an in vitro assay and inhibited basophil activation in an allergic patient ex vivo analysis. The efficacy of the cHBI design has valuable clinical implications for many allergen-specific responses and more broadly for any antibody-based disease.
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    Evidence that High Affinity IgE Can Develop in the Germinal Center in the Absence of an IgG1-switched Intermediate
    (American Association of Immunologists, 2023) Chen, Qiang; Liu, Hong; Luling, Noelle; Reinke, Julia; Dent, Alexander L.; Microbiology and Immunology, School of Medicine
    High affinity allergen-specific IgE is essential for the severe allergic anaphylaxis response. High affinity antibodies (Abs) are formed by successive rounds of selection of Ag-specific B cells in the germinal center (GC), however several studies have shown that IgE+ GC B cells are impaired in their ability to undergo selection in the GC. A pathway, known as the “indirect switching pathway” for IgE, has been described whereby Ag-specific B cells initially switch to the IgG1 isotype and undergo affinity selection in the GC, with a secondary switch to the IgE isotype after affinity selection. In previous work, using a food allergy model in mice, we investigated how high affinity IgE develops in the GC but we did not test the indirect switching model. Here we analyzed the importance of the indirect switching pathway by constructing IgG1-cre Bcl6-fl/fl mice. In these mice, once B cells switch to IgG1, they delete Bcl6 and thus cannot enter or persist in the GC. When we tested IgG1-cre Bcl6-fl/fl mice with our food allergy model, we found that as expected, IgG1 Abs had decreased affinity, but unexpectedly the affinity of IgE for allergen was unchanged. IgG1-cre Bcl6-fl/fl mice underwent anaphylaxis in response to allergen, consistent with the formation of high affinity IgE. Thus, in a food allergy response, high affinity IgE can be efficiently formed in the absence of indirect switching to IgG1, either by direct selection of IgE+ GC B cells or indirect selection of IgM+ GC B cells that later switch to IgE.
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    Follicular helper T cells mediate IgE antibody response to airborne allergens
    (Elsevier, 2017-01) Kobayashi, Takao; Iijima, Koji; Dent, Alexander L.; Kita, Hirohito; Microbiology and Immunology, School of Medicine
    BACKGROUND: TH2 cells have long been believed to play a pivotal role in allergic immune responses, including IgE antibody production and type 2 cytokine-mediated inflammation and pathology. A new T-cell subset, follicular helper T (TFH) cells, is specialized in supporting B-cell maturation and antibody production. OBJECTIVE: We sought to investigate the roles of TFH cells in allergic immune responses. METHODS: Naive mice were exposed to cytokines or natural allergens through the airways. Development of allergic immune responses was analyzed by collecting draining lymph nodes and sera and by challenging the animals. Cytokine reporter mice and gene-deficient mice were used to dissect the immunologic mechanisms. RESULTS: We observed the development of IL-4-producing TFH cells and TH2 cells in draining lymph nodes after airway exposure to IL-1 family cytokines or natural allergens. TFH and TH2 cells demonstrated unique phenotypes, tissue localization, and cytokine responses. TFH cells supported the sustained production of IgE antibody in vivo in the absence of other T-cell subsets or even when TH2 cell functions were severely compromised. Conversely, conditional deficiency of the master regulator Bcl6 in CD4+ T cells resulted in a marked reduction in TFH cell numbers and IgE antibody levels, but type 2 cytokine responses and eosinophilic inflammation in the airways remained unaffected. CONCLUSION: TFH cells play critical roles in the regulation of IgE antibody production. Allergic immune responses to airborne allergens likely involve 2 distinct subsets of IL-4-producing CD4+ T cells, namely TFH and Th2 cells.
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    Follicular regulatory T cells produce neuritin to regulate B cells
    (Elsevier, 2021) Gonzalez-Figueroa, Paula; Roco, Jonathan A.; Papa, Ilenia; Núñez Villacís, Lorena; Stanley, Maurice; Linterman, Michelle A.; Dent, Alexander; Canete, Pablo F.; Vinuesa, Carola G.; Microbiology and Immunology, School of Medicine
    Regulatory T cells prevent the emergence of autoantibodies and excessive IgE, but the precise mechanisms are unclear. Here, we show that BCL6-expressing Tregs, known as follicular regulatory T (Tfr) cells, produce abundant neuritin protein that targets B cells. Mice lacking Tfr cells or neuritin in Foxp3-expressing cells accumulated early plasma cells in germinal centers (GCs) and developed autoantibodies against histones and tissue-specific self-antigens. Upon immunization, these mice also produced increased plasma IgE and IgG1. We show that neuritin is taken up by B cells, causes phosphorylation of numerous proteins, and dampens IgE class switching. Neuritin reduced differentiation of mouse and human GC B cells into plasma cells, downregulated BLIMP-1, and upregulated BCL6. Administration of neuritin to Tfr-deficient mice prevented the accumulation of early plasma cells in GCs. Production of neuritin by Tfr cells emerges as a central mechanism to suppress B cell-driven autoimmunity and IgE-mediated allergies.
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    T Follicular Regulatory Cells Promote the Germinal Center Reaction and Allergic IgE Response While Repressing Abnormal Differentiation of T Follicular Helper Cells
    (2019-05) Xie, Ming; Dent, Alexander L.; Dong, X. Charlie; Kaplan, Mark H.; Zhou, Baohua
    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.