The Role of Oxidative Stress in IMHA

Immune-mediated hemolytic anemia (IMHA) is a major cause of severe anemia in American dogs. IMHA occurs when the immune system attacks and destroys oxygen-carrying red blood cells (RBC), leading to symptoms including exhaustion, weakness, and panting. However, although scientists have known for years that the immune system destroys the RBCs in dogs with IMHA, they still have no idea what prompts it to attack. That’s why, with the help of the AKC Canine Health Foundation, researchers from the University of Guelph set out to compare the antibodies found on the RBCs of dogs with IMHA to those found on the RBCs of healthy dogs and dogs with other forms of anemia.

There are several mechanisms through which the immune system could target and destroy RBC. However, one critical element of any attack is recognition, and the immune system’s way of recognizing targets is through the production of antibodies. By analyzing what antibodies were bound to the blood cells of the three different groups of dogs, the scientists’ goal was to determine which targets were associated with premature cell destruction.

As it turns out, simply having antibodies bound to RBCs was not enough to cause IMHA. Every single dog that was tested had antibodies bound to a protein known as anion exchanger 1 (AE1). That’s not surprising, as AE1 is a protein expressed by older RBCs that are ready to be recycled by the body. It is a signal that the cells are ready to be destroyed. What the scientists needed to discover was whether dogs with IMHA also had antibodies targeting other proteins found in younger RBCs, cells that would normally have lived longer lives. They did. Dogs with IMHA also had antibodies bound to a number of other RBC proteins while healthy dogs, and dogs with other forms of anemia, did not. In addition, when their circulating antibodies were tested, the immune systems of dogs with IMHA targeted a larger number of RBC proteins than those of healthy dogs or dogs with other forms of anemia.

The telling piece of information was not that the immune systems of dogs with IMHA were on the attack. It was the specific proteins that the antibodies were latching on to. It turned out that dogs with IMHA were making antibodies against RBC proteins that are normally only “visible” in the blood during times of severe oxidative stress. That critical piece of data lent strong support to the idea that oxidative stress plays a role in the development of the disease, something that had been suggested by other studies.

It’s still too early to know whether oxidative stress leads to the development of IMHA or IMHA creates an environment where there is increased oxidative stress. However, this research is certain to prompt further investigation into such questions. It may even encourage scientists to look for other potential interactions between oxidative stress and the development of autoimmune disease, a relationship that, if found, could have a profound effect on our understanding of the nature of these increasingly common diseases.

This work was funded by AKC Canine Health Foundation grant 1013-A.

Publications:

Tan, E., D. Bienzle, et al. (2012). "Potentially antigenic RBC membrane proteins in dogs with primary immune-mediated hemolytic anemia." Vet Clin Pathol 41(1): 45-55.