Researchers have asked, is RAO initiated via the same mechanism that true allergies are—as allergen binds to IgE, promoting
mast cell release of various mediators of inflammation, such as cytokines and histamine? Or does it result from a nonspecific
inflammatory response to inhaled pro-inflammatory agents such as molds, endotoxins, particulates and noxious gases present
in the breathing zone of stabled horses.
In the case of the allergic response, once the pro-inflammatory mediators are released, a cascade of mucous secretion, vasodilation,
microvascular leakage and airway smooth muscle contraction may ensue. The result is narrowing of the airway lumen and obstruction.
Theoretically, a second phase response is T-cell mediation of an asthmatic response.
For horses with RAO, what's the immune mechanism? "We don't know that in horses," says Robinson. "We're pretty certain heaves
is not a typical IgE-mediated allergic immune response." It has all the characteristics of an allergic disease, he notes.
Horses exposed to certain environments get airway obstruction and airway inflammation. For example, if an RAO horse is purchased
in New York and is then moved to a stable in Kansas, it might not show heaves in that environment, Robinson says. "Heaves
seems to be related to something in the local environment that causes the problem."
In people, hayfever is mediated via mast cells. But that doesn't appear to be the case in equine heaves. "It does seem to
have the characteristics of an allergic disease, but the exact immune response is not understood," says Robinson. "Skin tests
don't predict the allergens that will cause heaves. The measurement of IgE doesn't predict the things that are going to initiate
the disease. So it's not a classical IgE immune-response hypersensitivity."
Another aspect that isn't typical of allergy—neutrophils are found in the airway of horses with heaves. Says Lavoie, "Usually
with allergy, it's more mast cells or eosinophils—granulocytes nonetheless—similar but different.
"When we started to work on the immunological component of the disease, we found the bronchial lavage from horses with heaves
express cytokines, which are similar to those we see with allergy, a Th2 profile," Lavoie continues. "We know that heaves
is not a true allergic response, in which within 30 or 45 minutes of exposure to the allergen, you'll start to see clinical
signs. When we take horses with heaves and bring them into the stables, some horses will become symptomatic within a day,
but others will take several days to show signs. With heaves, we don't see the initial stage of the disease—the immediate
allergic response. However, the rest of the response looks like an allergy because it's pretty much related to exposure to
antigen, primarily to hay. If we expose a horse with heaves to feeding on hay, it becomes symptomatic. If we remove the hay,
the clinical signs essentially disappear."
Initially, it was uncommon to see Th2-type, response-associated neutrophils, Lavoie says. At that time neutrophils were not
considered an important part of the asthmatic response in people. "But during the past 10 years that has changed, where today
there's a lot of interest regarding the role of neutrophils in asthma. Our grant work was to try to understand how Th2-type
cytokines could activate neutrophils."
His studies have shown that, using recombinant proteins, "if we make equine IL-4 and expose them to neutrophils, it activates
the neutrophils," says Lavoie. "Also, if you expose endothelial cells from the pulmonary artery of horses to IL-4, they'll
produce cytokines, mediators that are chemotactic factors to neutrophils. We and others have done a large body of studies
showing that Th2-type cytokines contribute to not only attracting neutrophils within the airways, but also activating them."
Robinson says RAO is different from human asthma, which tends to diminish as people age. "There is no 'childhood' heaves,
i.e., young foals getting heaves. It's a disease of older horses; 8 to 10 years old is the common age of onset."
Lavoie agrees, adding, "We do see young horses, even weanlings, coughing, but it's rare to see foals with RAO. The process
of airway remodeling, the changes in the lung architecture, including increases in smooth muscle surrounding the airways,
probably takes years to occur."