How Does the Immune System Cause Allergies?

The Th2 Immune Axis: Why Some Immune Responses Become Allergic

The immune system's T helper (Th) cell population differentiates into distinct functional subtypes depending on cytokine signals in the environment. Th1 cells mediate responses to intracellular pathogens (bacteria, viruses). Th2 cells evolved to defend against parasites — they orchestrate IgE production and eosinophil recruitment. In allergic disease, Th2 responses are inappropriately activated against innocuous environmental substances.

Key Th2 cytokines driving allergy include IL-4 (promotes IgE class switching in B cells), IL-13 (airway remodeling, mucus production), IL-5 (eosinophil production and survival), and IL-33/TSLP/IL-25 (alarmin cytokines from epithelial cells that initiate the Th2 cascade after barrier disruption by allergens, pollution, or detergents).

Regulatory T cells (Tregs), which normally suppress both Th1 and Th2 responses, are reduced in allergic individuals. This loss of immune tolerance — mediated by the cytokine IL-10 and TGF-beta — is a key reason why some people develop allergy while others with similar exposures do not. Allergen immunotherapy works partly by expanding Tregs and restoring immune regulation.

Dendritic Cells: The Immune Sentinels That Start the Cascade

Dendritic cells (DCs) at epithelial surfaces — in the skin, gut, and airways — are the first immune cells to encounter allergens. They capture allergen proteins, process them into peptide fragments, and migrate to local lymph nodes where they present these fragments on MHC class II molecules to naive T cells. Whether the resulting T cell response becomes Th1 or Th2 depends critically on the DC's cytokine environment at the time of antigen presentation.

Plasmacytoid DCs and conventional DCs respond differently to different danger signals. Allergens lack the strong 'danger signals' (PAMPs) that pathogens carry, leading DCs to present them in a tolerogenic or Th2-skewing context rather than an activating Th1 context. This innate immune 'misread' of allergens as parasite-like rather than pathogen-like is a central step in allergy pathogenesis.

Mast Cells: The Effector Cells of the Allergic Reaction

Mast cells are tissue-resident immune cells located at all external interfaces — skin, gut, lungs, nasal mucosa, and connective tissue. They express high-affinity IgE receptors (FcεRI) on their surface. After systemic IgE production during sensitization, allergen-specific IgE coats these mast cells throughout the body, effectively 'arming' them against future allergen encounters.

When an allergen crosslinks two or more IgE molecules on adjacent FcεRI receptors, it initiates a calcium-dependent signaling cascade that causes preformed mediator granules to fuse with the cell membrane. Within seconds, stored histamine, tryptase, and other mediators are released (immediate phase). Over the next hours, newly synthesized leukotrienes and prostaglandins are released, and cytokines initiate the late-phase response.

Eosinophils and the Late-Phase Inflammatory Response

Eosinophils are granulocytes produced in the bone marrow under the influence of IL-5 and recruited to allergic tissues by eotaxin. They arrive 4–8 hours after the mast cell early phase and release toxic granule proteins (major basic protein, eosinophil cationic protein) that damage airway epithelium in asthma and amplify inflammation in atopic dermatitis.

The chronic recruitment of eosinophils is responsible for the tissue remodeling seen in long-standing asthma (airway wall thickening, smooth muscle hypertrophy), nasal polyp formation, and lichenification in chronic eczema. Biologic medications targeting eosinophil biology (anti-IL-5: mepolizumab, benralizumab; anti-IL-4Rα: dupilumab) have transformed treatment of severe eosinophilic disease.