Like many of today's dogs that have the benefit of dedicated breeders whose goal is the betterment of the breed, Old English Sheepdogs do not often suffer from a large number of inherited health problems. Despite this, though, there are some conditions that are occasionally seen in the breed and that can sometimes cause worry. Among these health issues there are a variety of conditions grouped under the category of autoimmune diseases.

The immune system is vital in protecting an animal's body from foreign invaders such as viruses and bacteria; it acts somewhat like an army, attacking any cells that enter the body which do not belong in the body. Its action depends on the fact that it can recognize what cells belong to the body of an animal and what cells don't. When an animal has an autoimmune disease, something malfunctions in the immune system's capability to distinguish what is "self" and what is "non-self"; the immune system views some part of the body of the animal as foreign and believes it is a threat, attacking it. An autoimmune disease can involve a single organ, a certain area of the body, or the entire body; the severity of the condition is dependent on how large an area and what vital organs are involved.

The Old English Sheepdog can present with any number of autoimmune diseases. One of the most prevalent is Autoimmune Hemolytic Anemia, or AIHA, in which the immune system attacks red blood cells and causes them to literally explode. Since red blood cells are the main transporters of oxygen throughout a animal's body, the explosion of red blood cells seriously curtails the blood's ability to transport oxygen. Another condition often seen in this breed is Immune-mediated thrombocytopenia, or ITP. This condition involves the destruction of platelets, important components of blood that help with clotting; if there is a low level of platelets in the blood, a dog can suffer from spontaneous bleeding that is difficult to stop. Nose bleeds are seen, as well as bleeding under the skin and mucous membranes.

Other common conditions are Autoimmune thyroiditis and Addison's Disease. The first involves immune-mediated destruction of thyroid hormone-producing cells and can lead to behavioral changes, allergies, resistance to infections, and sometimes seizures. The second, Addison's Disease, involves the adrenal glands, located above the kidneys, which are responsible for regulating sodium and potassium levels and organizing stress responses. The cells of the adrenal gland are destroyed in Addison's Disease, which can lead to heart failure, muscle weakness, weight loss, and anxiety. While Old English Sheepdogs seem to be genetically predisposed for developing autoimmune diseases, it seems as if there must be some kind of external factor which triggers the immune system's attack. Indeed, many researchers claim that most autoimmune diseases develop after the dog has experienced a serious, unrelated disease or has taken a certain drug. More research is needed to better understand the development of these diseases.

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