Clinical & Experimental Allergy | Exploring Siglecs: Immunomodulatory Roles in Food Allergy and Therapeutic Potential

This article systematically reviews the regulatory roles of Siglecs in immune cells involved in food allergy and their feasibility as potential therapeutic targets. It highlights that targeting Siglecs across multiple immune cell types may offer effective prevention or treatment strategies for food allergy while enhancing therapeutic efficacy and safety.

 

Literature Overview
The article titled 'Exploring Siglecs: Potential Modulators of Immune Cells in Food Allergy and Therapeutic Applications', published in the journal Clinical & Experimental Allergy, provides a comprehensive review of Siglecs' regulatory functions in food allergy and their potential as therapeutic targets. The study discusses Siglecs' expression in dendritic cells, T cells, B cells, mast cells, and basophils, along with their signal transduction mechanisms during sensitization and effector phases of food allergy.

Background Knowledge
Siglecs represent a family of immunoglobulin-like lectin receptors that recognize sialic acid on cell surfaces and recruit SHP-1/2 tyrosine phosphatases through ITIM domains to suppress downstream signaling. Food allergy (FA) involves multiple immune cell types including dendritic cells (DCs), T cells, B cells, mast cells, and basophils. Current FA management lacks curative treatments, relying primarily on allergen avoidance and emergency interventions, thus necessitating novel immunotherapeutic strategies. This article explores Siglecs' expression patterns across immune cells, their regulation of signaling pathways, and the feasibility of inducing immune tolerance through Siglec targeting. It identifies Siglec-2, Siglec-3, Siglec-6, Siglec-9 as promising targets for intervening at sensitization or effector stages of FA to enhance immunotherapy safety. However, most studies rely on murine models with limited validation in human cell systems, requiring future investigations in humanized models.

 

 

Research Methods and Experimental Design
This study employed a systematic literature review approach to analyze Siglecs' expression patterns and signaling regulatory mechanisms in food allergy-associated immune cells. Key research dimensions included: (1) Siglecs' regulation of immune responses during sensitization through dendritic cells, T cells, and B cells; (2) Siglecs' modulation of degranulation in mast cells and basophils during effector phases; (3) Development of synthetic liposomes or monoclonal antibodies targeting Siglecs to induce immune tolerance and suppress allergic reactions.

Key Conclusions and Perspectives

• Siglecs are broadly expressed across immune cells and inhibit FcεRI, TCR, and BCR signaling through ITIM-mediated recruitment of tyrosine phosphatases, thereby suppressing cell activation.
• Siglec-2 (CD22) targeting in B cells effectively reduces IgE production and allergic responses. Synthetic liposomes (STALs) containing Siglec-2 ligands and allergens can induce immune tolerance while lowering sIgE levels.
• Activation of Siglec-3, Siglec-6, Siglec-8, and Siglec-9 in mast cells and basophils inhibits FcεRI signaling, reducing allergic mediator release (e.g., histamine, cytokines).
• Multi-cell targeting (e.g., simultaneous B cell and mast cell modulation) could enhance therapeutic efficacy while improving specificity and safety of immunotherapeutic interventions.
• Current research remains limited to murine models with insufficient human cell validation. Future studies require clinical models to assess translational potential of Siglec-targeted therapies.

Research Significance and Prospects
This work establishes Siglecs as promising therapeutic targets for food allergy, particularly during immune sensitization. Targeting Siglecs may enable early intervention to suppress IgE production and mast cell activation. Future research should prioritize humanized models to validate clinical translatability and explore synergistic effects of multi-Siglec targeting strategies.

 

 

Conclusion
Food allergy represents a global health challenge with no curative treatments currently available. This study systematically summarizes Siglecs' immunoregulatory functions across multiple cell types, emphasizing their potential as immune checkpoint molecules for therapeutic development. Findings demonstrate that targeting Siglecs (including Siglec-2, Siglec-3, Siglec-6, Siglec-8, and Siglec-9) can effectively suppress activation of B cells, T cells, dendritic cells, mast cells, and basophils to mitigate allergic responses. While murine models support these conclusions, comprehensive human cell studies remain essential. Future developments in humanized anti-Siglec antibodies or synthetic ligands, combined with multi-targeting approaches, could provide novel immunotherapeutic strategies with enhanced efficacy and reduced side effects, establishing a foundation for precision immunotherapy.

 

J S H Schaapherder, K C M Verhoeckx, A M Ehlers, A C Knulst, and L A P M Meulenbroek. Exploring Siglecs: Potential Modulators of Immune Cells in Food Allergy and Therapeutic Applications. Clinical and Experimental Allergy.