The Th2 Pathway: Fighting Parasites and Fueling Allergies

The immune system uses many cells to defend the body, and T helper cells are the primary coordinators. Also known as CD4+ cells, they assess threats and dictate the strategy for defense. When a T helper cell is activated, it can develop along several pathways, each tailored to combat a specific type of invader.

One of these strategies is the T helper 2, or Th2, pathway. The Th2 response involves producing specific signaling molecules and recruiting certain cell types. This pathway provides a targeted defense against threats that exist outside of the body’s cells, such as parasites and toxins.

Th2 Pathway Activation and Cytokine Release

A Th2 response begins when a naive T helper cell encounters an antigen-presenting cell (APC). An APC, such as a dendritic cell, captures a piece of a foreign invader and displays it on its surface. The T helper cell uses its T-cell receptor to recognize this fragment, receiving an activation signal. This interaction, along with other co-stimulatory signals, activates the naive cell.

Once activated, the cell multiplies, creating a population of cells ready for further instructions. The instructions depend on the chemical signals, or cytokines, present in the environment. If the cytokine Interleukin-4 (IL-4) is present, it guides the developing T helper cells to differentiate into the Th2 lineage. This process is driven by the genetic regulator GATA3, which is switched on by IL-4 and locks the cell into its Th2 identity.

As a differentiated Th2 cell, its job is to release its own set of cytokines. One of its main products is more IL-4, which creates a positive feedback loop, encouraging more T helper cells to become Th2 cells and stimulating B cells. It also releases Interleukin-5 (IL-5), a signal that calls eosinophils to the site of infection. A third cytokine, Interleukin-13 (IL-13), increases mucus production and smooth muscle contraction to physically trap and expel invaders.

The Protective Role Against Parasites

The Th2 pathway is well-suited for fighting large, extracellular parasites like helminths (parasitic worms). These invaders are too large to be engulfed by immune cells, requiring a different strategy. The Th2 response orchestrates this defense.

When a helminth infection is detected, the release of IL-5 from Th2 cells recruits eosinophils to the infected tissue. These eosinophils are loaded with toxic granules. Upon arrival, they attach to the surface of the worm and release these contents, damaging the parasite’s outer layer.

Simultaneously, IL-4 and IL-13 affect the surrounding tissues. IL-13 stimulates goblet cells in the lining of the intestines and airways to increase mucus production. This increased mucus helps trap the parasites, while IL-13 also promotes smooth muscle contractions to help dislodge and expel the worms from the body.

The Link to Allergies and Asthma

The same mechanisms the Th2 pathway uses to expel parasites can be mistakenly directed against harmless environmental substances. This response is the basis of allergies and asthma. In some individuals, the immune system identifies substances like pollen or pet dander as threats, triggering a Th2 response.

In an allergic reaction, Th2 cells release IL-4, which instructs B cells to produce the antibody Immunoglobulin E (IgE). This IgE circulates and attaches to the surface of mast cells, which are immune cells in tissues like the skin and airways. These mast cells then become primed for the next encounter with the allergen.

Upon subsequent exposure, the allergen binds to the IgE on the mast cells, causing them to degranulate and release inflammatory chemicals, including histamine. This release causes the immediate symptoms of an allergic reaction, such as:

• Sneezing
• Itching
• Watery eyes
• Constriction of the airways

In chronic conditions like asthma, the persistent Th2 response leads to ongoing inflammation and airway hyper-responsiveness due to the presence of eosinophils and excessive mucus.

Maintaining the Th1/Th2 Immune Balance

The activation of the Th2 pathway is part of a regulated system. The primary counterpart to the Th2 response is the T helper 1 (Th1) pathway. The Th1 pathway specializes in fighting intracellular pathogens like viruses and bacteria by enhancing the ability of cells to kill invaders hiding within them.

The immune system works to maintain a balance between the Th1 and Th2 responses, which are mutually inhibitory. Cytokines produced by Th1 cells can suppress Th2 cell development, and Th2 cytokines like IL-4 and IL-10 can inhibit the Th1 pathway. This cross-regulation ensures the immune system mounts the most appropriate response for a specific threat.

The “hygiene hypothesis” connects this balance to modern health. This theory suggests that a lack of exposure to microbes during early childhood may lead to an underdeveloped Th1 system. With a less active Th1 system, the balance can tilt towards a more dominant and easily triggered Th2 system. This may explain the increasing prevalence of allergic and autoimmune diseases in developed countries, as the Th2 arm targets harmless environmental antigens.