CD33 recruitment inhibits IgE-mediated anaphylaxis and desensitizes mast cells to allergen

Duan, Shiteng; Koziol‐White, Cynthia; Jester, William F.; Nycholat, Corwin M.; Macauley, Matthew; Panettieri, Reynold A.; Paulson, James C.

doi:10.1172/jci125456

Cited by 82 publications

(93 citation statements)

References 65 publications

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“…Recently we described a mouse model in which the cDNA encoding the long isoform of hCD33 (hCD33M) was inserted into the Rosa26 locus under control of Cre recombinase 38 . This previous study investigated hCD33 in mast cells, but here we took advantage of Cx 3 cr1 cre mice to enable expression of hCD33M in microglia 39 .…”

Section: Resultsmentioning

confidence: 99%

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Repression of phagocytosis by human CD33 is not conserved with mouse CD33

et al. 2019

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CD33 is an immunomodulatory receptor linked to Alzheimer’s disease (AD) susceptibility via regulation of phagocytosis in microglia. Divergent features between human CD33 (hCD33) and murine CD33 (mCD33) include a unique transmembrane lysine in mCD33 and cytoplasmic tyrosine in hCD33. The functional consequences of these differences in restraining phagocytosis remains poorly understood. Using a new αmCD33 monoclonal antibody, we show that mCD33 is expressed at high levels on neutrophils and low levels on microglia. Notably, cell surface expression of mCD33 is entirely dependent on Dap12 due to an interaction with the transmembrane lysine in mCD33. In RAW264.7 cultured macrophages, BV-2 cultured microglia, primary neonatal and adult microglia, uptake of cargo — including aggregated Aβ1–42 — is not altered upon genetic ablation of mCD33. Alternatively, deletion of hCD33 in monocytic cell lines increased cargo uptake. Moreover, transgenic mice expressing hCD33 in the microglial cell lineage showed repressed cargo uptake in primary microglia. Therefore, mCD33 and hCD33 have divergent roles in regulating phagocytosis, highlighting the importance of studying hCD33 in AD susceptibility.

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Section: Resultsmentioning

confidence: 99%

“…WT, CD45.1 +/+ , Cx 3 cr1 Cre 39 , and mCD33 −/− 15 mice were obtained from The Jackson Laboratory. Transgenic mice expressing hCD33M in the Rosa26 locus ( R26-hCD33M ) were described previously 38 . All animals used were maintained in an access-controlled barrier facility under specific-pathogen-free conditions.…”

Section: Methodsmentioning

confidence: 99%

Repression of phagocytosis by human CD33 is not conserved with mouse CD33

et al. 2019

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“…Recently, the soluble form of the high‐affinity IgE receptor (FcεRI has been described as an endogenous inhibitor of mast cell activation, as a potential biomarker for IgE‐mediated disease, and also as a potential confounder to affect IgE measurement . Other inhibitory mechanisms dependent on SLAP, STAT3, C‐terminal Src kinase, the ubiquitin ligase Nedd4‐2, the adaptor Nedd4 family interacting protein 1, and CD33 when co‐ligated with the FcεRI have also been discovered and may help to develop novel therapeutic approaches.…”

Section: Introductionmentioning

confidence: 99%

Recent developments and highlights in food allergy

Eiwegger

Hung

Diego

et al. 2019

Allergy

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The achievement of long-lasting, safe treatments for food allergy is dependent on the understanding of the immunological basis of food allergy. Accurate diagnosis is essential for management. In recent years, data from oral food challenges have revealed that routine allergy testing is poor at predicting clinical allergy for tree nuts, almonds in particular. More advanced antigen-based tests including component-resolved diagnostics and epitope reactivity may lead to more accurate diagnosis and selection of therapeutic intervention. Additional diagnostic accuracy may come from cellular tests such as the basophil activation test or mast cell approaches. In the context of clinical trials, cellular tests have revealed specific T-cell and B-cell populations that are more abundant in food-allergic individuals with distinct mechanistic features.Awareness of clinical markers, such as the ability to eat baked forms of milk and egg, continues to inform the understanding of natural tolerance development.Mouse models have allowed for investigation into multiple mechanisms of food allergy including modification of epithelial metabolism, and the induction of regulatory cell subsets and the microbiome. Increasing numbers of children who underwent food immunotherapy enlarged the body of evidence on mechanisms and predictors of treatment success. Experimental immunological markers in conjunction with clinical determinants such as lower age and lower initial specific IgE appear to be of benefit.More research on the optimal dose, preparation, and route of application integrating a high-level safety and efficacy is demanded. Alternatively, biologics blocking TSLP, IL-33, IL-4 and IL-13, or IgE may help to achieve that. K E Y W O R D Sallergy treatment, biologics, food allergy, immune tolerance, immunotherapy | 2357 EIWEGGER Et al.

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“…showed that dual targeting of CD33 and specific IgE on mast cells with liposomes expressing CD33L and a synthetic antigen (TNP) could prevent IgE-mediated anaphylaxis (63). These liposomes prevented TNP-induced degranulation in human mast cells and prevented clinical response during PSA in transgenic mice expressing human CD33.…”

Section: Siglec-3/cd33mentioning

confidence: 99%

Targeting the FcεRI Pathway as a Potential Strategy to Prevent Food-Induced Anaphylaxis

2020

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Despite attempts to halt it, the prevalence of food allergy is increasing, and there is an unmet need for strategies to prevent morbidity and mortality from food-induced allergic reactions. There are no known medications that can prevent anaphylaxis, but several novel therapies show promise for the prevention of food-induced anaphylaxis through targeting of the high-affinity IgE receptor (FcϵRI) pathway. This pathway includes multiple candidate targets, including tyrosine kinases and the receptor itself. Small molecule inhibitors of essential kinases have rapid onset of action and transient efficacy, which may be beneficial for short-term use for immunotherapy buildup or desensitizations. Short courses of FDA-approved inhibitors of Bruton’s tyrosine kinase can eliminate IgE-mediated basophil activation and reduce food skin test size in allergic adults, and prevent IgE-mediated anaphylaxis in humanized mice. In contrast, biologics may provide longer-lasting protection, albeit with slower onset. Omalizumab is an anti-IgE antibody that sequesters IgE, thereby reducing FcϵRI expression on mast cells and basophils. As a monotherapy, it can increase the clinical threshold dose of food allergen, and when used as an adjunct for food immunotherapy, it decreases severe reactions during buildup phase. Finally, lirentelimab, an anti-Siglec-8 antibody currently in clinical trials, can prevent IgE-mediated anaphylaxis in mice through mast cell inhibition. This review discusses these and other emerging therapies as potential strategies for preventing food-induced anaphylaxis. In contrast to other food allergy treatments which largely focus on individual allergens, blockade of the FcϵRI pathway has the advantage of preventing clinical reactivity from any food.

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CD33 recruitment inhibits IgE-mediated anaphylaxis and desensitizes mast cells to allergen

Cited by 82 publications

References 65 publications

Repression of phagocytosis by human CD33 is not conserved with mouse CD33

Repression of phagocytosis by human CD33 is not conserved with mouse CD33

Recent developments and highlights in food allergy

Targeting the FcεRI Pathway as a Potential Strategy to Prevent Food-Induced Anaphylaxis

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