Preprint Club
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Keywords

● Perinatal immunity

●  Asthma development

●  maternal antibody transmission

●  DC priming

Main Findings

Allergic asthma is a widespread respiratory disease that typically begins in early childhood. Development of asthma is driven by immune dysregulation, which can be triggered by various environmental factors, such as early-life respiratory infections. A key hypothesis underlying this association is that these infections disrupt the healthy barrier function in the lungs, thereby increasing sensitivity to allergens. Another well-known risk factor for asthma development is genetic predisposition, yet precise mechanisms underlying this link have remained largely uncharacterized.

In this manuscript, De Leeuw and colleagues investigate how maternal asthma and early-life respiratory infections jointly contribute to asthma development in children.

Leveraging a large patient cohort, the authors find that parental asthma and early-life respiratory syncytial virus (RSV) infection in humans are cumulative risk factors for development of childhood asthma. The authors further demonstrate in a mouse model, that neonatal infection with pneumonia virus of mice (PVM), an RSV relative, promotes asthma in offspring of allergic mothers, but not in progeny of non-allergic dams. Following the viral infection in the offspring, a subset of conventional dendritic cells (cDCs) acquires an inflammatory state, characterized by the overexpression of activating Fc gamma receptors. These receptors facilitate the uptake of antigen- IgG2 immune complexes transferred from an asthmatic mother through lactation, leading to activation of the cDCs. The authors show that these activated cDCs strongly polarize T helper 2 (Th2) cells, promoting asthma-associated inflammation.

The study further reveals that passive immunization of allergic mothers with a monoclonal anti-RSV antibody (MPE8) mitigates Th2 responses after PVM infection and reduces asthma severity in pups, suggesting its potential as a prophylactic intervention in humans.

Limitations

1.  Specificity to RSV/PVM to asthma development

•  The authors have analysed the large human dataset mainly in terms of RSV as a risk factor for development of asthma or allergic rhinitis. It would be very interesting to understand if other childhood infections can similarly impact asthma development, or if this is really RSV specific. In the subsequent mouse model experiments, it would be also very interesting to understand, whether the observed activation of cDCs and aggravated asthma development post PVM is specific to PVM, or if similar effects would occur with other respiratory or non-respiratory infections.

• Suggestion: The authors could check other childhood infections as risk factors for asthma development in their human dataset. Additional interesting risk factors to investigate would also be lifestyle factors (e.g. parental diet, smoking). In mice, other infection models, as Streptococcus pneumoniae, Haemophilus influenzae, or Influenza A virus (IAV), which are also particularly relevant infections in neonates, could be used in the same setup as PVM to assess the generalizability of the findings.

2.   Longterm effects

• The study mainly describes short-term asthma outcomes in the animal models, with the longest timepoint being 28 days after birth. Since asthma in humans is a chronic condition that can worsen with age or resolve during certain life stages, it would bring additional value to the study to understand if the aggravation of asthma in pups from HDM-primed mothers reduces or changes with time.

• Suggestion: In the animal experiments, assessments of asthma could be investigated at a longer timepoint after birth to understand whether offspring of asthmatic mothers and neonatal infections also experience worse long-term outcomes.

3.   Delay of PVM infection or HDM sensitization

• It is currently not addressed in the study if PVM induced aggravation of asthma is only happening when maternal antibodies or immunocomplexes are present in the pups, but not in weaned animals. In addition, the sensitization is administered to the pups while the PVM infection is probably still quite severe (judging from Fig 5A where adult animals have not recovered by day 14), and it would be interesting to see if a sensitization after recovery from PVM infection will not yield the same effect.

• Suggestion: The same experiment setup could be (PVM + HDM treatments) could be given to weaned pups from allergic vs. non-allergic dams or even longer after birth (e.g. 8 weeks). Should there be no effects, these experiments would also strengthen the point that the found effect is mainly due to the transferred maternal antibodies. In another experiment, the sensitization could be delayed until the pups have recovered from PVM infection, to understand if the DC priming is only happening in the context of acute disease.

4.   Other mechanisms of maternal antibody transfer

• While the authors address the transfer of antibodies from mothers to offspring via lactation, the possibility of transplacental transfer of antigens or antibodies is only mentioned in this study, but not explored.

• Suggestions:
  - It would be very interesting to assess the importance of different maternal antibody transfers with foster mother experiments: After birth, offspring of naïve dams are nursed by HDM-primed foster mothers, while offspring of HDM-primed dams are nursed by non-primed foster mothers and the PVM induced aggravation of asthma can be assessed.  
  - To distinguish between maternal antibody transfer and de novo antibody production in neonates, RAG2⁻/⁻dams could be mated with wild-type males to produce heterozygous offspring. This would ensure that maternal antibody transfer is the only source of antibodies in neonates.

5.  Lack of readability and clarity of experiments and methods

•  It is unfortunately sometimes difficult to follow the flow of the study because the experiment setups or choices for specific treatments are not completely well described. For example:  
  - It is not entirely clear from the text why the authors transfer 1-DER T cells to the pups.   
  - The description for the scRNAseq experiment in Figure 3 states that pups were sensitized with HDM or PBS (line 204-205), but Fig 3G only shows PVM infected or uninfected. Is the description incorrect, or do the authors not show their additional data? It would be extremely interesting to see how the DCs change upon HDM- sensitization and also would add a lot of information to the current study.
  - Generally, it would also increase the readability of the paper if the authors could explain their choices for the different treatment timepoints (PVM infection, time of sensitization) more extensively.  
  - In Fig 2B, the authors only show IgG levels in asthmatic dams, but not IgE levels, which are normally considered golden standard in asthma depiction and do not explain why.

4. Interesting role of paternal asthma

• The authors find paternal asthma to also be a risk factor for asthma development in children. It would be very fascinating to understand if this could be reproduced in mice, even though if the reason is a genetic component, this would be certainly very difficult to investigate in mouse models.

• Suggestion: It could be worth a test to try out the same mouse model with asthmatic fathers instead of mothers to determine whether paternal asthma could induce similar outcomes in offspring.

Significance/Novelty

The authors present compelling evidence of a causal relationship between neonatal infection and maternal asthma for the development of childhood asthma by transmission of maternal antigen-antibody immunocomplexes and Fc receptor mediated activation of inflammatory cDCs, which prime Th2 cell responses. This mechanistic insight not only deepens our understanding of the pathogenesis of asthma but opens avenues for targeted therapeutic interventions. Additionally, this study proposes a promising therapeutic strategy using passive immunization of lactating dams with monoclonal anti-RSV antibodies, which significantly reduces subsequent PVM disease severity and asthma development in pups, holding potential for clinical implementation.

Credit

Reviewed by Lisabeth Pimenov and Alina Fokina as part of a cross-institutional journal club between the Vanderbilt University Medical Center (VUMC), the Max-Delbrück Center Berlin, the Ragon Institute Boston (Mass General, MIT, Harvard), the Medical University of Vienna and other life science institutes in Vienna.

The author declares no conflict of interests in relation to their involvement in the review.