Menno C. van Zelm, PhD, professor of immunology at Monash University.

Menno C. van Zelm, PhD

house dust mite sublingual immunotherapy (SLIT)

 was associated with sustained symptom improvement and biphasic changes in allergen-specific type 2 memory B cells in patients with allergic rhinitis and asthma, according to a recent study.

Investigators longitudinally evaluated 38 patients with house dust mite allergy, including 21 treated with SLIT and 17 managed with standard pharmacotherapy alone. All patients had allergic rhinitis, and approximately 55% in each group had concomitant asthma.

Across 18 months, the SLIT group demonstrated significant reductions in visual analog scores, symptom diary scores, and medication scores, whereas the non-AIT group did not show comparable reductions in symptoms or medication use. Lung function remained stable throughout the study, with median FEV1 values above 90% predicted in both groups.

Immunologically, SLIT was associated with early increases in house dust mite–specific IgE, IgG2, and IgG4 levels. Median allergen-specific IgE levels peaked at 4 months before declining at 12 and 18 months, while IgG4 levels continued to rise over the treatment period. The team reported that increased IgG4 expression on Der p 1– and Der p 2–specific type 2 memory B cells correlated with lower symptom scores (Spearman rho, −0.5794; 

Investigators concluded that allergen immunotherapy may involve 2 immunologic phases: an early expansion and phenotypic shift of allergen-specific type 2 memory B cells, followed by later reduction of these populations as IgE production declines. They noted that additional studies are needed to determine whether these cellular changes predict long-term remission or treatment response.

In the accompanying Q&A, investigator Menno C. van Zelm, PhD, professor of immunology at Monash University in Australia, discussed the potential implications of these findings for understanding long-term immune remodeling during allergen immunotherapy.

 What is the key clinical takeaway from the biphasic response of allergen-specific type 2 memory B cells during HDM-SLIT?

: Sublingual allergen immunotherapy for house dust mite (HDM-SLIT) effectively ameliorates symptoms. However, at least 18 months and often 3 to 5 years of continuous treatment are needed for patients to have sustained effects, i.e., durable relief of symptoms after discontinuation of therapy. It is currently unknown why this takes so long and what immunological changes underlie sustained unresponsiveness.

Recently, a subset of immune cells was identified that carries the pathogenic immune memory to allergies. These are type 2 memory B cells. Those type 2 memory B cells that recognize the allergen are thought to respond upon allergen exposure and maintain the pathogenic IgE antibody levels.

In previous work, we demonstrated that early on treatment, allergen-specific type 2 memory B cells expanded, but changed their phenotype. Increased expression of IgG4 and CD29 seemed to keep these cells in check and reduce symptoms on treatment. We here studied what happened early (4 months) and later (12 and 18 months) on treatment and found that after expansion at 4 and 12 months, patients showed fewer allergen-specific Type 2 memory B cells at 18 months. This paralleled the decline in serum IgE, and it seems that this late change is needed for sustained treatment effects.

 What motivated you to focus on allergen-specific type 2 memory B cells as a target of allergen immunotherapy?

: Type 2 memory B cells were recently found to hold the pathogenic immune memory to allergies. Hence, we hypothesized that these cells should be diminished or their functionality changed to relieve allergy symptoms in patients.

 How do the early increases in allergen-specific type 2 B cells align with the rapid symptom improvement seen in patients?

: The early increase in allergen-specific type 2 B cells was initially a surprise to us in previous studies (PMID: 39268605), as these were thought to be pathogenic cells. However, we did show that these expanded cells showed a unique immunophenotype with increased expression of IgG4 and CD29, which likely inhibits their responses, thereby underlying the symptom relief.

 What mechanisms may explain the reduction in type 2 memory B cells by 18 months, and how does this relate to sustained tolerance?

: We are still unsure about the mechanism by which type memory B cells are diminished at 18 months. This might be a depletion due to cell death and/or a change in their phenotype towards conventional memory B cells, which are not prone to produce IgE upon stimulation/activation.

 How should clinicians interpret the observed increases in IgE early in treatment alongside clinical improvement?

: The early increases of serum IgE on treatment are well-described and commonly known. While still a paradigm, the concurrent increases in serum IgG2 and IgG4 are thought to inhibit the IgE responses on treatment.

 What role do IgG4 and CD29 expression on type 2 memory B cells play in modulating allergic responses?

: Both IgG4 and CD29 are thought to inhibit pathogenic IgE responses by type 2 memory B cells. IgG4-expressing B cells are the source of serum IgG4, which inhibits the effects of IgE. CD29 on the surface of memory B cells inhibits their activation and thus prevents further production of pathogenic IgE.

Hsin L, Reinwald S, von Borstel A, et al. Biphasic Effects on Allergen-Specific Type 2 Memory B Cells Over 18 Months Sublingual Immunotherapy for House Dust Mite Allergy. 

Articles

In 38 patients with house dust mite allergy, 18 months of SLIT was linked to early expansion and later reduction of allergen-specific type 2 memory B cells.