Type 2 Immune Response: Impact on Tissue Repair and Fibrosis

The immune system maintains tissue health by defending against infections and facilitating repair after injury. Type 2 immune responses play a key role in wound healing and regeneration but can also contribute to fibrosis, an excessive buildup of connective tissue that impairs organ function. Striking a balance between repair and fibrosis is crucial for preventing chronic disease. Understanding how type 2 immunity influences these processes offers insights into potential therapeutic strategies for conditions marked by abnormal tissue remodeling.

Hallmarks Of Type 2 Immune Response

The type 2 immune response is defined by specific cellular and molecular features that orchestrate defense against helminths, promote tissue repair, and regulate inflammation. A hallmark is the dominance of cytokines such as interleukin-4 (IL-4), interleukin-5 (IL-5), and interleukin-13 (IL-13), which activate immune cells tailored for barrier protection and wound healing. These cytokines also influence fibroblasts and epithelial cells, modulating tissue remodeling.

Key immune cells in type 2 responses include eosinophils, basophils, and mast cells, which release mediators such as histamine and leukotrienes that contribute to localized inflammation and tissue adaptation. Immunoglobulin E (IgE) amplifies these effects by sensitizing mast cells and basophils, triggering rapid responses upon antigen exposure. This mechanism is particularly relevant in allergic reactions, where exaggerated type 2 activity leads to heightened sensitivity to environmental triggers.

Beyond immune activation, type 2 responses impact tissue homeostasis. IL-13 stimulates mucus production by goblet cells, enhancing barrier function in mucosal tissues, while IL-4 and IL-13 promote alternative macrophage activation, driving extracellular matrix deposition and angiogenesis. While beneficial in controlled settings, persistent signaling can lead to excessive collagen deposition and fibrosis, highlighting the dual nature of type 2 immunity.

Key Players In Type 2 Immunity

A network of immune cells drives type 2 immunity, shaping outcomes that range from repair to fibrosis. These cells interact through cytokine signaling and direct cellular responses, influencing tissue remodeling.

Helper T Cells

CD4+ T helper 2 (Th2) cells are central to type 2 immunity, producing IL-4, IL-5, and IL-13, which regulate fibroblast activity, extracellular matrix deposition, and epithelial function. IL-4 and IL-13 promote fibroblast proliferation and collagen synthesis, contributing to both repair and fibrosis. Th2 cells also support alternative macrophage activation, enhancing extracellular matrix turnover and angiogenesis. Studies in Nature Reviews Immunology highlight how Th2-driven signaling pathways contribute to fibrotic diseases such as idiopathic pulmonary fibrosis and systemic sclerosis. Persistent Th2 activity in chronic conditions leads to pathological fibrosis rather than functional regeneration.

Innate Lymphoid Cells

Group 2 innate lymphoid cells (ILC2s) rapidly respond to tissue damage by releasing IL-5 and IL-13. Unlike Th2 cells, ILC2s do not require antigen presentation, allowing them to act as early responders in tissue repair. Their IL-13 production influences fibroblast activity, promoting extracellular matrix deposition and epithelial proliferation. Research in Science Immunology has shown that ILC2s contribute to lung fibrosis by sustaining IL-13-driven fibroblast activation, leading to excessive collagen accumulation. While beneficial in acute settings, persistent activation has been linked to fibrotic diseases such as liver cirrhosis and asthma-associated airway remodeling.

Eosinophils

Eosinophils store and release bioactive mediators, including major basic protein, eosinophil peroxidase, and transforming growth factor-beta (TGF-β), which influence fibroblast function and extracellular matrix composition. IL-5 promotes eosinophil survival and recruitment to damaged tissues, where they modulate local inflammation and tissue remodeling. A study in The Journal of Clinical Investigation demonstrated that eosinophils contribute to fibrotic lung diseases by releasing TGF-β, which enhances collagen deposition and fibroblast activation. In conditions such as eosinophilic esophagitis and hypereosinophilic syndromes, persistent eosinophil activity leads to structural tissue changes, impairing organ function.

Tissue Repair Processes

Restoring tissue integrity after injury involves a sequence of cellular and molecular events that regulate regeneration and structural remodeling. The process begins with hemostasis, where platelets form a fibrin clot, preventing blood loss and creating a matrix for cellular infiltration. This clot releases growth factors such as platelet-derived growth factor (PDGF) and TGF-β, which recruit fibroblasts and endothelial cells essential for tissue restoration.

During the proliferative phase, fibroblasts migrate into the wound, guided by fibronectin and collagen gradients, and synthesize structural proteins to rebuild the extracellular matrix. Endothelial cells rapidly proliferate to form new capillaries, ensuring oxygen and nutrient delivery. Vascular endothelial growth factor (VEGF) regulates this process, promoting endothelial cell survival and capillary sprouting. Studies in The Journal of Cell Biology demonstrate that VEGF-mediated angiogenesis is essential for effective wound healing, as impaired vascularization can lead to chronic wounds.

As new tissue matures, fibroblasts transition into myofibroblasts, contractile cells that facilitate wound closure by generating tensile forces within the extracellular matrix. Myofibroblasts secrete collagen and elastin, reinforcing structural integrity. However, prolonged myofibroblast activity can result in excessive matrix deposition, leading to fibrosis. Matrix metalloproteinases (MMPs) regulate collagen turnover, preventing excessive scarring. A review in Nature Communications highlighted how dysregulated MMP activity contributes to fibrotic conditions such as liver cirrhosis and pulmonary fibrosis.

Fibrosis Mechanisms

Fibrosis develops when extracellular matrix synthesis and degradation become imbalanced, leading to excessive collagen deposition and tissue stiffening. Persistent fibroblast activation promotes the transition into myofibroblasts, which continuously remodel the extracellular matrix, altering tissue architecture and impairing function.

A key feature of fibrosis is the dysregulation of MMPs and their inhibitors, tissue inhibitors of metalloproteinases (TIMPs). MMPs break down excess matrix components, while TIMPs prevent degradation. In fibrotic tissues, elevated TIMP levels lead to unchecked matrix accumulation. This imbalance is observed in conditions such as idiopathic pulmonary fibrosis and systemic sclerosis, where biopsies reveal increased TIMP expression correlating with disease severity. Additionally, stiffened extracellular matrices further activate myofibroblasts through mechanotransduction pathways, perpetuating fibrosis.

Conditions With Heightened Type 2 Activity

Certain diseases are marked by an exaggerated type 2 immune response, leading to persistent inflammation, tissue remodeling, and fibrosis. These conditions often involve chronic allergen exposure, persistent infections, or dysregulated immune signaling that sustains type 2 cytokine production.

Asthma is one of the most well-characterized conditions associated with heightened type 2 activity. In allergic asthma, airborne allergens trigger IL-4 and IL-13 release, driving airway hyperresponsiveness, mucus overproduction, and eosinophilic inflammation. Chronic asthma leads to airway remodeling, smooth muscle thickening, and collagen deposition, reducing lung elasticity and contributing to irreversible airflow obstruction. Research in The Journal of Allergy and Clinical Immunology identifies IL-13 as a major driver of these fibrotic changes, prompting the development of biologic therapies targeting this cytokine.

Beyond asthma, atopic dermatitis and eosinophilic esophagitis also exhibit sustained type 2 immune activation. In atopic dermatitis, chronic allergen exposure disrupts the epidermal barrier, increasing keratinocyte-derived cytokine release and inflammation. IL-13-driven fibroblast activation contributes to skin thickening and lichenification. Similarly, eosinophilic esophagitis involves IL-5-driven eosinophil infiltration into the esophageal mucosa, leading to tissue remodeling and fibrosis. Studies show that patients with eosinophilic esophagitis exhibit increased expression of pro-fibrotic genes, highlighting the link between sustained type 2 signaling and structural tissue changes.