Hypothesis of Head and Lateral Line Erosion in Fish

Part - 2

What Really Causes HLLE?

By: Terry D. Bartelme

Hypothesis

I believe Head and Lateral Line Erosion is a disease complex and symptomatic of an immune system that is not functioning properly. HLLE may be an autoimmune disease in fish. This could be why HLLE is only seen in captive fish. All of the other so-called causes for HLLE contribute to the stress that causes the immune system to function improperly in the first place, or they are merely secondary infections. If true, this would enlighten us as to why so many different explanations have been given for what causes HLLE. In an immuno-compromised state opportunistic bacterium, virus, etc., can easily become pathogenic.

In human autoimmune disease (we will refer to autoimmune disease as AD), it is common for people to suffer from more that one related disease at a time. It is also possible for multiple aspects of the immune system to be malfunctioning simultaneously. If HLLE is actually caused by an improperly functioning immune system wouldn't the symptoms be more likely to be systemic rather than localized? HLLE lesions are often symmetrical and they usually appear simultaneously on both sides of the fish. The fact that these lesions also are not limited to the lateral line itself indicates a systemic rather than localized infection or condition. This further implicates improper immune response as the cause.

Chemicals treatments for fish disease such as kanamycin, malachite green, tetracycline, formaldehyde and heavy metals inhibit proper immune function. Copper certainly has been established as immunosuppressive. Should it be any surprise that some of the more copper-sensitive species of fish are also some of the most susceptible to HLLE? Is it a coincidence that tangs which are reported to produce less mucus (less protection from pathogens) than other families of fish are also frequently the victims of Head and Lateral Line Erosion?

Could Head and Lateral Line Erosion actually be an autoimmune disease brought about by chronic stress? We have not been able to identify a pathogen that systematically kills the cells in the lateral line system. In autoimmune disease, the body's immune system destroys cells that it should be protecting. Could the fish's own immune system be killing the cells in the lateral line system? I believe that anything that creates undue stress contributes to HLLE.

How Autoimmune Disease Works

There are several ways in which the immune system may function incorrectly causing damage to self-tissues. T cells are immune system cells that coordinate the immune response and help to destroy infected cells. T cells have what is called a T-cell receptor. This receptor combines with major histocompatibility complex (MHC) molecules that help the T cells recognize invading foreign materials (antigens). When T cells and MHC interact they can secrete cytokines and chemokines. Chemokines are cytokine molecules that attract destructive immune system cells such as macrophages, neutrophils and T cells. The overproduction of chemokines in the joints of humans causes rheumatoid arthritis. Is it possible that an overproduction of a protein such as this could cause autoimmune disease in fish?

Macrophages are white blood cells that play a vital role in the body's immune function. When macrophages (means big eater) and neutrophils locate foreign antigens (invaders) they surround or consume these organisms (this process is called phagocytes). These immune system cells then produce toxic molecules such as reactive oxygen intermediate molecules (ROIM) that destroy invading antigens. If ROIM are overproduced they will destroy body tissues surrounding the macrophages and neutrophils along with foreign antigens.

Another agent of the immune system is B cells. In some types of autoimmune disease B cells produce antibodies against self-tissue. These antibodies or auto-antibodies destroy body tissue and interfere with normal cell function. One condition that this causes in humans is a skin disease called pemphigus vulgaristhat produces skin blisters. Could something similar to this occur in fish that causes the loss of the epidermis (skin) in the lateral line region?

When antibodies accumulate in the bloodstream they form a network called an immune complex. A large immune complex can block the blood flow in a small blood vessel that would otherwise nourish tissues. This can cause tissue loss. Another possible explanation for the loss of skin, scale and tissue in HLLE could be Ischemia. Ischemia is a condition that causes localized tissue anemia due to the obstruction of the influx of arterial blood. This leads to hypoxia of body tissue and the death of cells.

We already know that stress in fish can lead to "Frayed Fin Syndrome." This is a loss of tissue between fin rays and is associated with stress and dietary deficiency. One such stressor that is already known to cause anemia in fish is the presence of heavy metals in the water such as copper. Could this same syndrome and consequent tissue loss play a part in HLLE?

How is AD Diagnosed?

Autoimmune disease is difficult to diagnose in humans, especially early in the course of the disease. Diagnosis is based on a physical examination, results of laboratory tests and an individual's symptoms. Laboratory tests are often inadequate or non-conclusive. Needless to say confirming autoimmune disease in fish is something beyond the capabilities of the average aquarist. We cannot ask how the fish feels or what other symptoms that is has, but we can observe them for signs of lethargy, lack of appetite, behavioral changes, etc. In the case of HLLE most fish continue to behave and act normally, at least until the condition has become quite advanced. Even at that point, any changes observed may be the result of secondary infections rather than caused directly by HLLE. That leaves us with just a physical examination or observation of the fish for the obvious signs of HLLE such as eroded tissue and loss of pigmentation along the lateral line sensory system. At this point, we must speculate, use deductive reasoning and hypothesize as to the cause of HLLE.

Treatments

Studies investigating autoimmune diseases in humans are focusing on: 1) the immune system during the progression of an autoimmune disease; 2) the role of infectious agents in autoimmune diseases; 3) studies of animal models of autoimmune diseases; 4) The influence of genetics on autoimmune disease progression and expression; and 5) the effects of therapeutic intervention on the immune system in an autoimmune disease.

The treatment of Head and Lateral Line Erosion is purely empirical. We must rely on eliminating any possible causes. There are medications or therapies that that are used to slow or suppress the immune system response in humans. These immunosuppressive medications include: cyclosporin, methotrexte, cyclophosphamide, azathioprine and corticosteroids. Corticosteroids are released by the body's own immune system in response to stress. These drugs or therapies also suppress the ability of the immune system to fight infection and have other potentially serious side effects making them difficult to use at best. In practical terms, we must rely on eliminating any or all of the purported causes for HLLE. In the process we will enhance the diet, reduce stress and improve the environment of the animal, thereby supporting healthy immune function.

Stress-Nutrition-Immune Function

What can we do to treat HLLE if it is the result of autoimmune disease or suppressed immune function? Treating autoimmune disease in humans is challenging and this is probably true to a greater degree for fish. The link between stress, nutrition and immune function in humans and other animals is well established. The most practical therapies for treating such diseases in fish include reducing stress, improving nutrition and perhaps stimulating or enhancing the animal's immune system. The goal of this effort is to support the animal's own ability to heal itself.

Stress

As stated in the first article in this series, "HLLE, Stress and Immune Function", stress suppresses immune function and can cause it to malfunction in other ways. Phagocytosis is the action of white blood cells (macrophages) when they consume foreign materials in the body. Once the macrophage has surrounded the antigen or invader lysosomes fuse with the foreign antigen and release digestive enzymes. Cortisol hormone that is released as part of the stress response interferes with this process. Cortisol also chemically changes the membrane of lysosomal preventing them from attaching to foreign antigens. Some evidence suggests that vitamin C can prevent this chemical change allowing the lysosomes to fuse with foreign antigens normally. The enzymes can then digest the bacteria or other invading pathogen. Stress also greatly inhibits mucus production limiting the protection that it would normally provide.

Stress Reduction

Before we can reduce or eliminate stress in fish we must first identify any potential sources. Stressors can be loosely placed into four categories. These four categories are: extreme changes in the physical environment, animal interactions, water pollution and human interference. An example of the first category would be large, sudden changes in temperature, or salinity. Animal interactions include predation and competition for space or food. Water pollution includes organic chemicals, heavy metals, nitrogenous waste and low pH. Human interference would include handling, crowding, transport and netting.

Understanding and identifying any sources of stress that your fish may be exposed to will go a long way in helping you prevent problematic circumstances. Stability in the environment is especially imperative to reef fish. Even those changes that improve the water quality should be made slowly.

It is of vital importance that only fish that are compatible be housed in the same aquarium. Study and make yourself familiar with the animal's natural environment, diet and compatibility with tank-mates prior to purchase.

Fish are more intimate and dependant on their environment than terrestrial animals. This makes water quality of paramount importance to their health and well-being. Keep a batch of well-aged and aerated water ready at all times for an emergency water change. Water that has not been aged and aerated prior to use is not chemically stable and it will irritate delicate gill tissues. Test your water parameters regularly to insure that they stay within the optimum range for your animals. A parameter that is tolerated but not optimal places stress upon the animals.

We are responsible for a large portion of the stress imposed upon our aquatic friends in the form of human interference. Many fish (especially wild-caught) suffer from intense, acute stress in the form of handling, transport and netting before they ever reach a retail outlet. Then the abuse (albeit unintentional) can continue at the local fish store and even after arriving into your care. Overcrowding is more than common in home aquariums and netting is a standard practice. Unfortunately overcrowding is detrimental to the health of all the animals that share the aquarium and netting causes more injuries than any other practice.

Knowledge is our best defense against all of these potential stressors. This can help prevent, or reduce the frequency and severity of episodes that cause stress in fish. Read several good books and magazines that can be used later as references.

The third and final installment in this series will continue in the next issue of this magazine. It will include sections on the relationship between nutrition and the immune system, how we can enhance immune function, the treatment of diseases secondary to HLLE and the prognosis for recovery.