The effector functions of most antibody isotypes are well understood, but the role of secreted IgD has remained an enigma. Now, reporting in Immunity, Andrea Cerutti and colleagues show that IgD recognizes soluble antigens such as food allergens and can dampen their immunogenicity by promoting protective humoral responses and constraining IgE-mediated mast cell and basophil degranulation.
IgD is best known for its role as a B cell antigen receptor. However, some tissues, such as nasal-associated lymphoid tissue, also harbour IgD-secreting plasma cells.
The authors observed that IgD-deficient mice have fewer peripheral basophils than controls and these express less of the T helper 2 (TH2)-type cytokine IL-4. To investigate the role of secreted IgD, NP (4-hydroxy-3-nitrophenylacetyl)-specific IgD was injected into mice deficient in both B cells and T cells. It was found to bind to basophils and its crosslinking with NP-haptenated ovalbumin (NP–OVA) or anti-IgD antibody increased the frequency of peripheral basophils and boosted their IL-4 production.
Immunization experiments using NP–OVA showed that NP-specific IgD has similar adjuvant properties to papain, a TH2 cell-inducing protease known to activate basophils. Immunization with NP–OVA and papain induced antigen-specific IgD responses in wild-type mice. These mice also had higher levels of antigen-specific IgG1 and IgE and higher serum levels of the TH2-type cytokines IL-4, IL-13 and IL-21 compared with IgD-deficient mice. Responses in IgD-deficient mice were completely restored by co-administering exogenous NP-specific IgD. Using mice deficient for T cells or for enzymes involved in class-switch recombination, it was shown that IgD augments TH2-type humoral responses by inducing TH2 cell polarization in germinal centres.
An analysis of IgD-secreting plasma cells from human tonsillar crypts revealed serum IgD antibodies specific for common small soluble antigens including food proteins. Using immunoprecipitation experiments and several knockout mouse models, the authors demonstrated that IgD binds to basophils via the degranulation inhibitor galectin-9, which, in turn, binds to the surface receptor CD44 on basophils.
Further analyses showed that crosslinking of IgD on human basophils upregulates gene sets implicated in TH2 cell-mediated immunity, chemotaxis, inflammation and signalling while inhibiting cytoskeleton remodelling and IgE-induced degranulation.
“IgD on human basophils upregulates gene sets implicated in TH2 cell-mediated immunity, chemotaxis, inflammation and signalling”
The relationship between IgD and IgE was further explored in a mouse model of lung inflammation, where IgD inhibited IgE-mediated basophil degranulation and thereby alleviated inflammation. In humans, a positive correlation between IgD levels and tolerance to bee venom and food allergens was observed. In vitro experiments with human basophils showed that IgD mitigates IgE-induced basophil and mast cell degranulation by inhibiting IgE-mediated cytoskeleton remodelling and degranulation.
The authors propose that strategies to boost the activity of IgD, such as galectin-9 administration, might serve to alleviate acute IgE-dependent allergic reactions to food antigens.
Shan, M. et al. Secreted IgD amplifies humoral T helper 2 cell responses by binding basophils via galectin-9 and CD44. Immunity https://doi.org/10.1016/j.immuni.2018.08.013 (2018)
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Flemming, A. Uncovering the mystery of secreted IgD. Nat Rev Immunol 18, 668–669 (2018). https://doi.org/10.1038/s41577-018-0080-9