Immunoglobulin E (IgE) is directed against allergens and drives allergen-induced upper airway inflammation and allergic rhinitis. In cases of allergen re-exposure, IgE can cross-link, leading to immune cell activation and inflammatory responses, and eventually to symptoms of allergic diseases, including allergic rhinitis.
However, the mechanisms underlying pathologic IgE synthesis in allergic rhinitis are not understood well, even though a combination of genetic predisposition and allergen exposure have been implicated. Genome-wide association studies (GWAS) have found a significant association of single nucleotide polymorphisms (SNPs) in the D-2-hydroxyglutarate dehydrogenase (D2HGDH) gene with allergic rhinitis and other IgE-mediated diseases.
Notably, the D2HGDH gene encodes an enzyme regulating the conversion of D-2-hydroxyglutarate (D2HG) to a-ketoglutarate. a-Ketoglutarate is an important substrate for a-ketoglutarate-dependent enzymes, whereas D2HG inhibits 2-oxoglutarate-dependent enzymes.
At the 2024 American Rhinologic Society (ARS) meeting at the COSM that took place on May 15–16, 2024 in Chicago, Anuj Tharakan, PhD presented a study from Virginia Commonwealth University elucidating the roles of D2HGDH and D2HG in allergic rhinitis.
The authors hypothesized that D2HGDH may play a mechanistic role in regulating IgE synthesis and used the Encyclopedia of DNA Elements (ENCODE) database to analyze its regulatory landscape. They found that the sentinel SNP in the D2HGDH locus associated with allergic diseases, rs34290285, is located in a distal enhancer-like region, suggesting it may be involved in gene regulation. Moreover, rs34290285 has been associated with reduced D2HGDH expression and a protective effect against IgE-mediated diseases like allergic rhinitis.
To gain insight into the role of a-ketoglutarate and D2HG in allergic responses, the researchers in this study measured the a-ketoglutarate/D2HG ratio in bone marrow-derived dendritic cells from mice that were unexposed, exposed to the bacterial component LPS, or exposed to the typical fungal allergen Alternaria. They found that, in cells exposed to Alternaria, the ratio of a-ketoglutarate/D2HG was significantly increased, suggesting that a-ketoglutarate may play a mechanistic role in initiating allergic responses via dendritic cells.
Next, the investigators set out to determine the in vivo effects of D2HG. Mice were treated with a cell-permeable form of D2HG or a vehicle prior to intranasal administration of the allergen Alternaria, and IgE synthesis and T cell polarization were analyzed in draining lymph nodes. D2HG administration prior to Alternaria exposure suppressed the synthesis of IgE. It also inhibited the polarization of T follicular helper 2 cells and T follicular helper 13 cells, which play an important role in initiating and propagating IgE responses. Contrarily, D2HG administration increased the number of T follicular regulatory cells that largely suppress antibody production. In addition, D2HG reduced the number of IgE-positive B cells in regional lymph nodes. Thus, an initial exposure to D2HG altered the T cell profile and reversed IgE production.
Subsequently, the effect of cell-permeable D2HG was tested in a treatment paradigm in a murine model of allergic rhinitis. Mice were treated with intranasal Alternaria on days 0, 10, 20, and 27–30. On days 20 and 27, they also received D2HG or a vehicle control. Nasal lavage cellularity and local IgE production were determined to assess nasal inflammation. Notably, D2HG administration led to a reduction of the overall cellularity, eosinophils, and antigen-specific IgE in nasal lavage.
In summary, an analysis of the regulatory landscape surrounding the rs34290285 SNP demonstrated that SNPs in these enhancer regions are protective against allergic disease, and D2HGDH downregulation ameliorates the risk of allergic rhinitis. Moreover, D2HGDH downregulation led to D2HG accumulation. In vivo, D2HG administration reduced T follicular helper cell polarization and promoted T follicular regulatory cell proliferation in response to allergens. Moreover, D2HG impaired IgE production in mice and ameliorated an established murine model of allergic rhinitis. These findings suggest that molecules downstream of D2HG, including a-ketoglutarate-dependent enzymes, may be promising therapeutic targets for allergic diseases, such as allergic rhinitis.