Allergen-Specific B Cell Responses Following Desensitisation and Natural Tolerance to Cow's Milk Allergy

Abstract

Food allergy (FA) is a major public health concern, estimated to affect up to 10% of the global population [1]. Cow's milk allergy (CMA) is the most common FA in younger children, with around 50% outgrowing the condition by the age of 5 (“natural tolerance”) [2]. However, those who develop persisting CMA often have multiple allergic comorbidities and present with a more severe phenotype. As a result, in some countries, cow's milk is now the most common cause of fatal anaphylaxis in children and young people [3]. In these patients, historical management has been the complete elimination of milk and milk-containing products from the diet. More recently, oral immunotherapy (OIT) has been used to induce desensitisation and remission to the sensitising allergen [4].

OIT involves a gradual introduction of small amounts of the allergenic food (i.e., milk, peanut and egg) into the affected person's diet over time, leading to a state of desensitisation, and ideally longer-term remission (previously named ‘sustained unresponsiveness’) allowing the patient to consume the food ad libitum. This ultimately results in improved dietary flexibility and health-related quality of life. However, OIT is associated with significant challenges, including high rates of treatment-related adverse events including anaphylaxis, adherence issues as well as psychological and logistical implications and burden from the treatment. OIT for CMA appears to be a particular issue in terms of safety [5]. In addition, outcomes from OIT vary considerably among individuals, with some achieving significant benefits whereas others showing limited or no improvement [6]. Understanding the key immunological factors driving the response to OIT and identifying biomarkers that identify responders and non-responders and the induction of remission remains a key unmet need.

The recent article entitled “Allergen-specific B cell responses in oral immunotherapy-induced desensitisation, remission, and natural outgrowth in cow's milk allergy” by Satitsuksanoa et al. [7] interrogated the trajectory profile of allergen-specific B cells during OIT (those who go on to reach desensitised or remission state) uniquely comparing these findings against the development of natural tolerance to the allergy. The study utilised time-course samples from children with CMA who received OIT, children who naturally outgrew CMA and healthy controls. In this seminal article, the authors revealed that albeit in small proportions, Bos 9-specific B cells are found in all patient groups investigated ruling out the common perception that allergen-specific cells are often confined to allergic individuals. Bos 9-specific B cells from healthy controls differ in that they are proficient in producing sIgG1 and sIgG4 but lack the ability to produce sIgE.

Using a single cell transcriptomic approach to fully elucidate the molecular profile of Bos 9-specific B cells at these different stages of therapy, the authors demonstrated a clear difference in gene signatures between desensitised and remission groups, classifying them as distinct states post-OIT, with desensitisation being an earlier stage of remission. Specifically, the authors highlighted that IL10RA and TGFB3 were exclusively upregulated in desensitised OIT patients, whereas genes associated with B cell activation (i.e., RIF1, FOXP1, JAK3), BCR signalling (PIK3CA, PIK3CD, PRKCB) and B cell migration (CCR6) and differentiation (i.e., BCL11A, CARD11, DOCK11, MALT1) were downregulated in both desensitised and natural tolerance patient groups. Interestingly, the authors also highlighted TLR4, IGHG1, IGHA2 and IGHA2 as genes significantly upregulated in those who are in remission. Although OIT resulted in significant changes in gene signatures in those who reached remission state, the changes did not fully overlap with those seen in patients achieving natural tolerance. Finally, the authors employed proximity extension assay technology to reveal that allergen-specific B cells from those receiving OIT or those who developed natural tolerance had a higher capacity to produce IL-10 and TGF-b compared to healthy controls.

Findings from this study offers new insight into the trajectory pathway of antigen-specific B cells over the course of OIT and the important role these cells play in those who develop a state of non-responsiveness. Furthermore, evidence from this study demonstrated that OIT is effective in modulating gene signatures beyond a desensitised state to somewhat mimic gene profiles seen in those who develop natural tolerance. As there is uncertainty as to the duration for which tolerance is maintained in remission post-OIT, this finding is of particular interest towards our understanding of natural tolerance and our ability to induce this ideal long-term state of tolerance that we all seek as a resolution for FA.

These data support the assertion that the mechanisms of food allergen tolerance following OIT are similar—but not identical—to that resulting from natural tolerance. This leads to two important considerations: First, identifying genes that are in fact not rectified post-OIT compared to natural tolerance will ultimately provide us with a good grasp of how we could improve future therapies. Second, as clinicians, are we potentially interfering with natural tolerance and inducing a suboptimal state when we perform OIT in children who have a high probability of outgrowing their allergy naturally? For some foods, where dietary inclusion is very common (such as dairy), this may be less of a concern—in contrast to foods such as peanut where daily consumption is less common. Ultimately, this question can only be answered through further research to understand the mechanism of tolerance induction following OIT, and the validation of biomarkers more able to predict the likelihood of natural tolerance in food-allergic children.

M.H.S. and J.A.L. drafted the initial manuscript. E.H.K., M.V.-O., and P.J.T. critically read and contributed to the writing of the manuscript.

M.H.S. reports research grants from Immune Tolerance Network, Medical Research council, Allergy Therapeutics, LETI Laboratorios, Revolo Biotherapeutics, and lecture fees from Allergy Therapeutics and Leti Laboratorios. E.H.K. reports consulting fees from ALK-Abello, Allakos, Cellergy Pharma, DBV Technologies, Genentech, Hanimune Therapeutics, Novartis, Phylaxis BioScience, Revolo Biotherapeutics, and Ukko Inc., and research grants to his institution from NIH-NIAID and Food Allergy Research and Education (FARE). M.V.-O. receives research grants from Food Allergy Research and Education (FARE). P.J.T. declares grants from the UK Medical Research Council, the UK Food Standards Agency, The Jon Moulton Charity Trust, and the NIHR/Imperial Biomedical Research Centre, outside the submitted work, as well as personal fees from the UK Food Standards Agency, UpToDate, Elsevier, ALK, and Allergenis. J.A.L. reports grants from Biomedical Research Funding (Imperial College BRC). All declaration are outside the submitted work.