Dietary Epitopes Drive Oral Tolerance, With Jamie Blum, PhD

New translational research is beginning to clarify a long-standing gap in immunology: which specific food-derived antigens drive oral tolerance. A study identified discrete dietary epitopes from common seed storage proteins that are recognized by intestinal regulatory T (Treg) cells, offering mechanistic insight into how the immune system classifies foods as “safe.”

, Jamie Blum, PhD, of the Salk Institute, emphasized that advancing understanding of tolerance is critical to addressing

“While we understand more and more about food allergies, we actually know comparably little about oral tolerance,” Blum said. “What is it? How does it develop? So, I think my study is starting to identify what are the protein antigens that are recognized, and if we understand how those antigens are normally seen through the tolerance response, we might be able to apply those same principles to allergy cases to help better prevent food allergies.”

Using murine models fed standard chow, investigators isolated intestinal Treg cells and identified their cognate antigens through T cell receptor (TCR) mapping. The analysis revealed 3 key epitopes derived from seed storage proteins in corn, wheat, and soybean.

 One of the most robust responses was directed against a maize protein, α-zein, a digestion-resistant storage protein.

“When we started the study, I had expected we might find dozens of different epitopes, and it was unexpected and striking that we saw the strong convergence on just 1 protein, which may suggest that a few key proteins in diet are… are garnering most of the immune response,” Blum said. “If you can tune how the immune response sees those proteins, you can set the overall tone for interpretation of the food.”

These proteins are highly abundant and resistant to digestion, allowing prolonged exposure in the gut for immune sampling. As Blum noted, they “resist proteases,” enabling their role in tolerance induction. Clinically, this convergence suggests a small number of dietary antigens may disproportionately shape immune tolerance.

The study also provides insight into the ontogeny of tolerance. Blum and colleagues observed that antigen-specific Treg populations emerge around the time of weaning, coinciding with initial exposure to solid foods.¹ Blum noted that this developmental window aligns with clinical data supporting early allergen introduction for immune tolerance. This paradigm is supported by the Learning Early About Peanut Allergy (LEAP) trial, which demonstrated that early peanut exposure significantly reduces the risk of peanut allergy and informed current guideline recommendations to introduce allergens between 4 and 6 months of age.

Mechanistically, the identified Treg cells exhibited canonical immunosuppressive functions, including secretion of anti-inflammatory cytokines and inhibition of effector T cell proliferation.

 These cells help maintain immune homeostasis.

An additional finding is the potential for cross-tolerance. The study demonstrated that TCRs recognizing a soybean-derived epitope also responded to structurally similar proteins in other foods, including sesame and quinoa.

 This suggests that exposure to 1 food antigen could confer tolerance to related proteins, even in the absence of direct exposure.

“What this could suggest, and my lab is working on this a bit now, is perhaps if we could map cross reactivity for things like a peanut, you could become tolerant to peanut by eating something that has those shared proteins without actually having the peanut exposure,” Blum said.

Blum JE, Kong R, Schulman EA, et al. Identification and characterization of dietary antigens in oral tolerance. 

. 2026;11(117):eab4684. doi:10.1126/sciimmunol.aeb4684. 

https://www.science.org/doi/10.1126/sciimmunol.aeb4684

Du Toit G, Roberts G, Sayre PH, et al. Randomized trial of peanut consumption in infants at risk for peanut allergy. 

. 2015;372(9):803-813. doi:10.1056/NEJMoa1414850. 

https://www.nejm.org/doi/full/10.1056/NEJMoa1414850

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New research identifies dietary epitopes driving oral tolerance, offering insight into Treg responses, early exposure, and future food allergy therapies.

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Experts discuss therapeutic switching in patients already on biologic therapy and adherence challenges specific to oral agents.

Managing Established Patients: Switching, Adherence, Spontaneous Remission, and Treatment Duration 

For patients currently well-controlled on omalizumab or dupilumab, routine therapeutic switching is not indicated and may introduce unnecessary disruption to a successful regimen. The clinical rationale for switching or adding remibrutinib is strongest in patients experiencing breakthrough disease where BTK inhibition offers a mechanistically distinct intervention. The availability of 3 step-up agents also creates a practical bridging opportunity: remibrutinib's rapid onset makes it well-suited for patients experiencing a flare while pursuing prior authorization for a long-term biologic. For new patients, presenting all 3 options with a clear explanation of their respective profiles supports genuine shared decision-making without defaulting to a prescribing hierarchy that the evidence does not support.

Adherence to a twice-daily oral regimen presents a real-world challenge distinct from the adherence profile of injectable biologics. Patients managed with injections typically have adherence supported by clinic-based or pharmacy-based administration schedules; oral agents depend entirely on patient behavior. This is compounded by a disease-specific dynamic: patients who achieve rapid symptom control on remibrutinib may question the need for continued therapy precisely because the treatment has worked. Clinicians should proactively address this at initiation, counseling patients that symptom improvement does not signal that therapy is no longer necessary and that premature discontinuation will likely result in recurrence. A structured re-evaluation at 6 to 12 months of complete control is a reasonable framework for discussing a monitored discontinuation attempt in appropriate patients.

In this video segment, Nicole Chase, MD, and Jason Hawkes, MD, examine spontaneous remission as the key variable underlying discontinuation decisions. Without a validated biomarker to predict its onset, the only practical way to determine whether a patient has remitted is to attempt discontinuation after a defined period of disease control. Chase suggests a minimum of 6 months of sustained control, and ideally 1 year, before considering this step in patients with severe disease, framing the continued treatment period as suppression of the underlying pro-inflammatory state rather than simply symptom management. Both experts agree that patients who discontinue and experience recurrence typically return to therapy quickly, because the memory of symptomatic disease reasserts itself rapidly once hives return — a self-correcting dynamic that reduces the clinical stakes of a monitored discontinuation attempt while reinforcing the importance of patient education about the likely outcome.

Managing Established Patients: Switching, Adherence, Spontaneous Remission, and Treatment Duration

Experts address how quickly clinicians should escalate from antihistamines to step-up therapy and examine remibrutinib's clinical trial data on speed of response.

Antihistamine Escalation, Time to Step-Up, and Remibrutinib's Rapid Onset of Action

The guidelines support prompt escalation from antihistamines to step-up therapy in patients who demonstrate inadequate response. Evidence for adding leukotriene receptor antagonists or other antihistamine-adjacent agents to improve CSU control is weak, and prolonged sequential antihistamine trials delay access to effective targeted therapy without meaningful clinical benefit. The guidelines make clear that combining multiple antihistamine mechanisms does not improve outcomes in patients already inadequately controlled on a core regimen. A practical and time-efficient approach is to establish fourfold high-dose antihistamine therapy, assess response within 2 to 4 weeks, and proceed to step-up therapy if control is inadequate. Importantly, the majority of patients presenting to specialist practices have already tried antihistamines, often at above-labeled doses, well before their appointment, making the escalation question largely moot; the clinical record itself documents the non-response.

Remibrutinib's onset of action profile is clinically distinctive. Approximately 50% reductions in UAS7 scores within the first 1 to 2 weeks of treatment represent a faster response trajectory than has been observed with dupilumab, which typically requires approximately 1 month to produce comparable early-phase improvements. Some clinical trial participants experienced measurable relief within hours to days of initiation. The 12-week timepoint marks a practical efficacy plateau for remibrutinib; patients who have not responded substantially by this point are unlikely to achieve further benefit without a change in management strategy. This is analogous to the 12-week assessment used for omalizumab and should be incorporated into patient communication at the time of prescribing. For remibrutinib specifically, the fast onset may also be leveraged as a bridge strategy in patients who require quick relief while awaiting insurance authorization for a longer-term biologic therapy.

In this video segment, Nicole Chase, MD, notes that she approaches remibrutinib's onset data conservatively, advising patients to expect meaningful improvement within a month while acknowledging that some may see relief considerably sooner. Hawkes frames this as a case where the clinical data genuinely support optimism: roughly a 50% reduction in disease activity within the first 1 to 2 weeks is a response profile that few therapies in any specialty can match. Setting appropriate patient expectations at the initiation of step-up therapy is a clinically undervalued element of CSU management. Patients who have been inadequately controlled have often experienced prolonged suffering, and providing a realistic but optimistic framing — meaningful improvement likely within weeks, with full assessment at 12 weeks — supports adherence and reduces premature discontinuation driven by impatience or unrealistic short-term benchmarks.

Antihistamine Escalation, Time to Step-Up, and Remibrutinib's Rapid Onset of Action 

Updated ACC/AHA Dyslipidemia Guidelines Incorporate LDL-C Goals, Lp(a) Focus, With Deepak Bhatt, MD, MPH

On March 13, 2026, the American College of Cardiology (ACC) and American Heart Association (AHA) released an updated clinical guideline for the management of 

, replacing the 2018 Guideline on the Management of Blood Cholesterol.

Among some of the most significant changes, the new guidelines encourage clinicians to enhance their focus on lipoprotein(a), or Lp(a). This updated version suggests clinicians measure Lp(a) ≥1 time in all adults when addressing 

atherosclerotic cardiovascular disease (ASCVD) 

risk. This suggestion is now a Class of Recommendation (COR) 1 suggestion.

“I’ve been a believer in measuring Lp(a) for a long time, way before it was in vogue. I used to test it in patients who came in with premature MI,” Deepak Bhatt, MD, MPH, director of Mount Sinai Fuster Heart Hospital and the Dr. Valentin Fuster Professor of Cardiovascular Medicine at the Icahn School of Medicine at Mount Sinai, told 

 in an exclusive interview. “I think one can debate the exact level of evidence – we’re all eagerly awaiting, probably later this year, the first randomized clinical trials looking at Lp(a) drugs. If those trials are positive, that validates that specific therapeutics lowering Lp(a) as clinically useful.”

Additionally, the 2026 guidelines have shifted from percent reduction of LDL-C back to specific, targeted goals. The previous 2018 version introduced the use of percent LDL-C reductions as a method of monitoring lipid levels and guiding lipid-lowering therapy (LLT). This method was widely considered vague, as these percentages were inherently subjective between patients. Goals, however, establish concrete targets. Although percentage risk reduction in LDL-C was retained as a priority for individuals, LDL-C and non-HDL-C treatment goals are reclaiming their spot as the backbone of LLT guidance.

Specific goals are determined by PREVENT risk tier, with those at borderline risk – between 3 and <5% - having a goal LDL-C of <100 mg/dL and a goal non-HDL-C of <130 mg/dL. Those at intermediate risk – 5 to <10% - have a goal LDL-C of <100 mg/dL, while those at high risk - ≥10% - have a goal LDL-C of <70 mg/dL and a non-HDL-C goal of <100 mg/dL.

Secondary prevention also incorporates LDL-C goals based on these new guidelines; those with high risk, defined as ≥2 major ASCVD events or 1 event and ≥2 high-risk features have a goal LDL-C of <55 mg/dL and non-HDL-C <85 mg/dL. These patients should also receive ezetimibe in addition to maximum tolerated statin. However, those not at very high risk have an LDL-C goal of <70 mg/dL and non-HDL-C of <100 mg/dL.

“I do like the fact that targets are clearly back in the guidelines,” Bhatt said. “That was a real backward step some years ago when the guidelines eliminated targets for LDL. It’s a good illustration of the fact that the guidelines are not always sacrosanct. If you look at different times and places, guidelines have made mistakes. They don’t replace good clinical judgment or individualized patient care.”

Editors’ Note: Bhatt reports disclosures with GSK, Merck, Cereno Scientific, Angiowave, Boehringer Ingelheim, Novo Nordisk, and others.

Blumenthal RS, Morris PB, Gaudino M, et al. 2026 ACC/AHA/AACVPR/ABC/ACPM/ADA/AGS/APHA/ASPC/NLA/PCNA guideline on the management of Dyslipidemia: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation. Published online March 13, 2026. 

Livingston R. AHA/ACC Dyslipidemia Guidelines Reinstate LDL-C Goals, With Viet Le, DMSc, PA-C. 

. March 17, 2026. Accessed March 25, 2026. 

https://www.hcplive.com/view/aha-acc-dyslipidemia-guidelines-reinstate-ldl-c-goals-with-viet-le-dmsc-pa-c

Bhatt shares his thoughts on the recently released dyslipidemia guidelines, highlighting the return of goal-based LDL-C therapy and Lp(a) receiving a COR 1 suggestion.

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Allergist-immunologist at Yale New Haven Hospital

The Case for Delabeling NNAALs in Obstetric Care, With Chang Su, MD

Non-narcotic analgesics allergy labels (NNAAL) significantly elevated rates of eclampsia (aRR, 1.5; 95% CI, 1.06–2.12), preterm birth (aRR, 1.21; 95% CI, 1.14–1.28), NICU admission (aRR, 1.17; 95% CI, 1.10–1.25), and neonatal withdrawal syndrome (aRR, 1.51; 95% CI, 1.24–1.84) among labeled mothers across 2,244,210 California singleton livebirths — point toward a clear intervention target: the family planning stage, before pregnancy makes formal drug challenge testing contraindicated.

American Academy of Allergy, Asthma & Immunology (AAAAI)

 2026 Annual Meeting held in Philadelphia, Pennsylvania, from February 27 to March 2, Chang Su, MD, allergist-immunologist at Yale New Haven Hospital outlined why timing matters enormously for NNAAL de-labeling efforts. Evaluating a prior ibuprofen reaction, for example, ideally requires a provocation challenge — which is contraindicated during pregnancy. Waiting until a patient is already pregnant to initiate drug allergy evaluation therefore forecloses the most definitive diagnostic pathway. Su's preferred model is pre-conception referral, integrated into routine family planning screening by OB-GYN and cardiology colleagues, so that allergy status is clarified before it becomes clinically urgent. She described active efforts to work NSAID allergy screening into standard documentation templates and electronic health record workflows used by APPs and physicians in OB practices at her institution — a structural intervention designed to normalize proactive referral rather than relying on reactive, crisis-driven evaluation.

Su also used the final portion of the conversation to reframe how the field should think about drug allergy labels more broadly. NNAALs affect approximately 2% of the population — rarer than beta-lactam labels, which appear in roughly 10% of charts, and therefore harder to study at scale. The study does not overturn existing paradigms around allergy labeling, Su acknowledged, but it extends the known harms of inappropriate labels from beta-lactams into the NSAID class, and makes it easier to extrapolate that other inaccurate allergy labels likely carry similar outcome consequences. Her broader call to action was cultural as much as clinical: rather than entering a blank medication allergy into the chart, clinicians should document the specific reaction type, severity, and any confirmed tolerability thresholds — information that allows downstream providers to make nuanced decisions rather than defaulting to broad avoidance. As Su put it, allergy labels are not a single entity, and the field is increasingly recognizing that indiscriminate labeling carries real repercussions, particularly when it walls patients off from first-line therapies tied to the best outcomes.

Su has no relevant disclosures to report.

1. Su C, Baer R, Otani I, Schatz M, Chambers C. The relationship between maternal non-narcotic analgesics allergy labels and maternal and fetal outcomes: results from a large, administrative cohort. Presented at: AAAAI 2026 Annual Meeting, February 27-March 2, Philadelphia, Pennsylvania. Abstract #L24

2. Non-Narcotic Analgesics Allergy Labels Linked to Adverse Maternal and Fetal Outcomes. News release. AAAAI. February 26, 2026. 

https://www.aaaai.org/about/news/news/2026/narcotic

Su emphasized how care should be shifted to reflect known impacts of NNAALs on obstetric care.

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Why De-Labeling NNAALs Should Be Routine Obstetrics Care, With Chang Su, MD

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Dietary Epitopes Drive Oral Tolerance, With Jamie Blum, PhD

Managing Established Patients: Switching, Adherence, Spontaneous Remission, and Treatment Duration

Antihistamine Escalation, Time to Step-Up, and Remibrutinib's Rapid Onset of Action

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The Case for Delabeling NNAALs in Obstetric Care, With Chang Su, MD