Key Highlights :
1. The researchers used human transcriptomic data from the Mechanisms of the Development of Allergy (MeDALL) study to differentiate the molecular mechanisms associated with two phenotypes of allergic rhinitis: rhinitis alone (R) and rhinitis in multimorbidity with asthma (R+A). Rhinitis alone affects nearly 70–80% of patients with allergic rhinitis (R). However, it clusters with asthma (A) in multimorbidity to affect 20–30% of patients. Conversely, the majority of patients with asthma had or still have rhinitis. There are genetic, clinical, and immunological differences between monosensitization (one allergen) and polysensitization (multiple allergens). This raises the possibility of distinct molecular pathways in R + A and R.
2. Previous efforts to comprehend the connections between R and R+A have included using the atopic march sequence and characterizing the molecular mechanisms governing these diseases and the interactions between them. Interactomics, a branch of systems biology, applies biostatistical methodologies and data mining to provide a molecular context to the cell behavior and functions under different physiological conditions, including pathological ones, and facilitate an understanding of the complexity of many phenotypes.
3. In the present study, researchers used whole blood samples from three birth cohorts from Sweden, Spain and Germany from the MeDALL study. Next, they applied an interactomics approach to characterize the molecular pathways associated with R and R+A, including obtaining data on differentially expressed genes (DEGs). The team used the IntAct database to independently generate the interactomes of the DEGs for R and R+A that comprised >106 protein–protein interactions in human cells. Similarly, they used the DAVID web-based tool to annotate these interactomes functionally. They considered molecular pathways in levels 3 and 4 (intermediate) of the Reactome database hierarchy.
4. Intriguingly, 25 genes were common to both interactomes, implying a degree of interconnectedness larger than random expectation. Functional annotation revealed that several pathways were specific to R, including but not limited to toll-like receptor (TLR) signaling cascades and WNT5A-dependent signaling. Signal-transduction-related processes were more represented in pathways specific to R + A. Interleukin (IL)-33-mediated signaling stood out as a pathway specific to R + A. IL-33 is an alarmin cytokine with a critical role in inflammation, allergy, and type 2 immunity.
5. The study analysis showed high connectivity within the interactomes of R and R+A, but a lack of common DEGs. Despite having some core common mechanisms, the two R phenotypes were significantly different. Differences were seen in the molecular pathways specific to R (SUMO pathways, MyD88 and TLR signaling cascades) and
Allergic rhinitis (AR) is a common chronic inflammatory disorder of the nasal mucosa that affects up to 20-30% of the global population. It is usually caused by an allergic reaction to airborne allergens such as pollen or dust mites. AR is often accompanied by asthma, which is a chronic inflammatory disorder of the airways that affects over 300 million people worldwide. The combination of AR and asthma is referred to as multimorbidity and affects a significant number of patients.
In a recent study published in Scientific Reports, researchers used human transcriptomic data from the Mechanisms of the Development of Allergy (MeDALL) study to differentiate the molecular mechanisms associated with two phenotypes of allergic rhinitis: rhinitis alone (R) and rhinitis in multimorbidity with asthma (R+A). The team used whole blood samples from three birth cohorts from Sweden, Spain and Germany to obtain data on differentially expressed genes (DEGs). They applied an interactomics approach to characterize the molecular pathways associated with R and R + A, including the IntAct database and the DAVID web-based tool to annotate the interactomes functionally.
The analysis revealed that the R interactome had 464 genes connected by 466 edges, while the R+A interactome had 130 genes connected by 149 edges. Random distributions testing the degree of interconnectedness of the interactomes showed that the interactomes of R and R+A were denser than random expectation. Functional annotation revealed that several pathways were specific to R, including but not limited to toll-like receptor (TLR) signaling cascades and WNT5A-dependent signaling. Signal-transduction-related processes were more represented in pathways specific to R + A. Interleukin (IL)-33-mediated signaling stood out as a pathway specific to R + A.
The study showed that despite having some core common mechanisms, the two R phenotypes were significantly different. Differences were seen in the molecular pathways specific to R (SUMO pathways, MyD88 and TLR signaling cascades) and R + A (FGFR-mediated signaling, IL-33-mediated signaling). Together these findings indicate that rhinitis alone and rhinitis in comorbidity with asthma are mechanistically different diseases with varying underlying molecular pathways. This data could help refine the MeDALL hypothesis on allergic diseases and provide insight into the development of novel treatments for AR and asthma.
