New Targets Discovered for Allergy Drug Development
Key findings
- How the innate immune system detects allergens has been unclear
- Massachusetts General Hospital researchers have found that sensory neurons are the missing link between skin exposure to allergens and migration of dendritic cells (DCs)
- Specifically, they showed in an animal model that papain activates a subset of sensory neurons, leading to the release of substance P, a neuropeptide
- Substance P acts on DCs in the skin to promote their migration to the draining lymph node, where they activate T cells that trigger an allergic response
- The critical role of TRPV1+ sensory neurons and substance P in immune responses to cutaneous allergens suggests this pathway is a target for new drugs to prevent and treat allergic diseases
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The innate immune system relies on a large family of pattern recognition receptors on immature dendritic cells (DCs). Once DCs detect a pathogen, they mature and ultimately migrate to the draining lymph node, where they present antigen and stimulate T cells. Thus, DCs link innate immune sensing with adaptive immune responses.
During the immune response to pathogens, maturation of DCs is marked by upregulation of CCR7, a chemokine receptor, which acts as a "molecular switch" that prompts the DC to migrate. However, no CCR7 upregulation occurs during the immune response to allergens. It's been unclear what signals DCs to migrate out of the skin after exposure to an allergen.
Massachusetts General Hospital researchers have found the missing link: sensory neurons. This discovery, which has implications for novel therapeutics, is explained by Caroline Perner, MD, PhD, research fellow in the Department of Medicine, Caroline L. Sokol, MD, PhD, assistant physician in the Division of Rheumatology, Allergy and Immunology at Mass General and researcher in the Center for Immunology and Inflammatory Diseases, and colleagues in Immunity.
Activation of Sensory Neurons
The sensory nervous system, which is highly concentrated in the skin, has been shown in vitro to react to many allergens, such as bee venom, house dust mites and papain.
When injected papain into mice, papain activated specialized sensory neurons that express TRPV1 channels, which previously have been associated with pain and inflammation. Indeed, the mice did exhibit signs of itching and pain. In addition, neurons exposed to papain released substance P, a neuropeptide.
Activation of DCs
DCs in the skin that respond to allergens are called CD301b+ DCs. The researchers observed that MRGPRA1, a mouse receptor for substance P, was present in dermal CD301b+ DCs. Substance P acted on these DCs to promote their migration to the draining lymph node, where they activated T cells that triggered an allergic response.
Breaking the Cycle
The critical role of TRPV1+ sensory neurons and substance P in immune responses to cutaneous allergens suggests this pathway is a target for new drugs to prevent and treat allergic diseases. For example, drugs that target MRGPRX2, the human equivalent of MRGPRA1, may be relevant.
On the other hand, many common drugs are MRGPRX2 agonists, and it will be worthwhile to investigate their effect on DC migration and allergic sensitization.
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