T cells control the potencies of allergen-specific antibodies
Published: January 27, 2022
Acute anaphylaxis is the most severe and systemic clinical manifestations of food allergies including peanut allergy. Anaphylaxis is classically defined as an allergen-driven process that involves specific IgE and the activation of mast cells and basophils. However, non-IgE-mediated pathways can induce symptoms indistinguishable from those of IgE-mediated anaphylaxis. Furthermore, the subjects who have high titers of IgE antibodies to multiple food allergens, such as those with atopic dermatitis, do not necessarily experience anaphylaxis by ingesting foods. Major gaps in our knowledge remain; how one can explain the dissociation between IgE and food allergy in certain patients and what immunological mechanisms are involved in these heterogenous anaphylactic responses?
The newest subset of CD4+ T cells, T follicular helper (Tfh) cells, provides help to B cells to produce antibodies. Several recent studies suggested the critical roles for Tfh cells in promoting production of allergen-specific antibodies. Programmed cell death protein 1 (PD-1) is an inhibitory receptor expressed on T cells, and the blocking antibodies against PD-1 have been used to help cancer patients to enhance their immunity against cancer cells. Importantly, PD-1 is also highly expressed on Tfh cells; however, we know little about the roles of the molecule in Tfh cells. A recent study published by Lama et al. in The Journal of Allergy and Clinical Immunology (JACI) investigated whether and how PD-1 on Tfh cells regulates allergen-specific antibody production and anaphylaxis using a mouse model of peanut allergy. Mice were exposed to fine peanut particles to mimic environmental exposure in humans, and anti-PD-1 antibody, which is similar to those used for cancer patients, was administered to the animals. The authors then assessed the biological activities of peanut-specific IgE and IgG antibodies by challenging the mice by injecting peanut extract and by transferring the antibodies to naïve mice that have not been exposed previously to peanut.
Lama et al. found that the mice exposed to peanut fine particles become highly allergic to peanut and, when challenged, they developed acute systemic anaphylaxis identical to those observed in humans. Anti-PD-1 increased the number of Tfh cells and B cells and caused a marked increase in the plasma levels of peanut-specific IgG antibodies. However, when challenged, anti-PD1-treated mice were totally protected from anaphylaxis. Anti-PD1 also reduced the levels of peanut-specific IgE by 90%; however, the anaphylaxis in the model by Lama et al. was mediated by peanut-specific IgG, not by IgE. These observations raised the main question of the study; “why increased levels of peanut-specific IgG antibodies do not make the anaphylaxis worse in anti-PD-1-treated mice?” Importantly, when transferred to naïve mice, those IgG antibodies from anti-PD-1-treated mice did not provoke anaphylaxis and rather protected the animals that had received pathologic IgG antibodies known to cause anaphylaxis. Upon further immunological characterization, Lama et al found that anti-PD-1 treatment promotes production of IgG antibodies with altered functions, namely low-affinity antibodies, which can bind peanut allergens, but are unable to activate mast cells effectively or trigger anaphylaxis. These antibodies likely neutralized peanut allergens and protected the animals.
The results presented in this study have several implications to understand peanut allergy and anaphylaxis. First, if IgG antibodies have a strong affinity to allergens, they can cause anaphylaxis like IgE antibodies, and this may explain the anaphylaxis in certain patients who may not have detectable IgE antibodies. Second, binding of allergens to specific antibodies may not be sufficient to provoke anaphylaxis, and the strength of binding may greatly influence the outcomes. Third, in addition to their known functions to help antibody production, Tfh cells by engaging PD-1 and perhaps other receptors may regulate the functional properties, such as affinity, of antibodies and accordingly antibodies’ roles in the disease process. Finally, further research is needed to determine the potential risks and benefits of anti-PD1 treatment as a therapeutic option in patients with allergic diseases. In-depth biochemical and molecular characterization of allergen-specific IgE and IgG antibodies will also be needed to understand better how anaphylaxis develops.
The Journal of Allergy and Clinical Immunology (JACI) is an official scientific journal of the AAAAI, and is the most-cited journal in the field of allergy and clinical immunology.
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