Primary Biliary Cirrhosis (cont.)

The cause of PBC remains unclear. Current information suggests the cause may involve autoimmunity, infection, or genetic (hereditary) predisposition, acting either alone or in some combination. A complete understanding of the cause of PBC will require two types of information. One, referred to as the etiology, is identification of the initiating (triggering) events. The other, referred to as the pathogenesis, is a discovery of the ways (mechanisms) by which the triggering events lead to the inflammatory destruction of bile ducts and hepatocytes. Unfortunately, neither the etiology nor the pathogenesis of PBC has yet been defined.

The following topics relate to the cause of PBC:

• What is the role of autoimmunity?
• What are antimitochondrial antibodies (AMA)?
• Do the AMA react with the bile ducts?
• What causes destruction of the bile ducts in PBC?
• What is the role of infection?
• What is the role of genetics?

What is the role of autoimmunity?

PBC is presumed by most experts to be an autoimmune disease, which is an illness that occurs when the body's tissues are attacked by its own immune (defense) system. (Auto means self.) Childhood diabetes is one example of an autoimmune disease in which some type of transient infection (one that later goes away) triggers an immune reaction in a susceptible (genetically predisposed) person. This particular immune reaction in diabetes selectively destroys the cells in the pancreas that produce insulin.

Despite strong evidence to support the concept that PBC likewise is an autoimmune disease, some features of PBC are uncharacteristic of autoimmunity. For example, all other autoimmune diseases occur in both children and adults, while, as already mentioned, PBC has never been diagnosed in childhood. PBC and other autoimmune diseases, however, are associated with antibodies (small proteins found in the blood and bodily secretions) that react with the body's own proteins, which are referred to as autoantigens.

Table 1 shows a comparison between primary biliary cirrhosis and classic autoimmune diseases.

Feature	Primary Biliary Cirrhosis	Classic Autoimmunity
Predominantly females	Yes	Yes
Age at diagnosis	Adults only	Children and adults
Autoantibodies	Yes	Yes
Antigens recognized by autoantibodies	Restricted (few)	Diverse (many)
HLA (Human Lymphocyte Antigen) associations	Weak	Strong
Association with other autoimmune diseases	Yes	Yes
Response to drugs that suppress the immune system	Poor	Good

Specific types of white blood cells called B-lymphocytes make antibodies. Antibodies recognize specific protein targets called antigens (substances that are capable of causing the production of antibodies.) To facilitate our discussion of autoimmunity, let us first look at what happens in the more common type of immunity. It takes new or foreign antigens to produce this usual type of immunity. Vaccines, infectious organisms (like viruses or bacteria), or surgically transplanted tissues contain such foreign antigens. So, for instance, when a person is first vaccinated to prevent tetanus, that person is newly exposed to tetanus proteins, which are foreign antigens. What happens then?

First, specialized cells within tissues of the body take up and digest the tetanus proteins. Then the protein fragments are attached to special molecules called HLA molecules that are produced by the HLA complex. (HLA is an abbreviation for Human Leukocyte Antigen). The HLA complex is a group of inherited genes located on chromosome 6. The HLA molecules control a person's immune response. Next, the protein (antigen) fragments bound to the HLA molecules set into action (activate or stimulate) specialized white blood cells called T-lymphocytes. The T-lymphocytes then begin to multiply (reproduce) and secrete chemical signals into their environment.

Another type of white blood cell, called B-lymphocytes, also enters the picture. B-lymphocytes have molecules on their surface, called immunoglobulins (Ig) that can bind directly to undigested tetanus antigens. An essential part of the body's immune system, immunoglobulins are antibodies that attach to foreign substances, such as bacteria, and assist in destroying them. This binding activates the B-lymphocytes, that is, gets them ready for action. Meanwhile, the above-mentioned secreted chemicals of the activated T-lymphocytes provide a helper signal for the B-lymphocytes. This signal tells the B-lymphocytes to begin secreting the immunoglobulins (specific antibodies) that precisely recognize the stimulating tetanus antigen.

The bottom line here is that antibodies that specifically bind and inactivate tetanus proteins prevent an immunized person from developing tetanus. What is more, both the T- and B-lymphocytes reside in the body as memory cells. This means that they can remember to generate increased amounts of antibodies against tetanus antigens whenever a person has a booster shot of the vaccine. So, that's what happens in the common type of immunity.

By contrast, in autoimmunity, autoantibodies, produced by B-lymphocytes react against self or auto antigens rather than against foreign antigens. In this reaction, the activated B-lymphocytes still require help from chemicals secreted by activated T-lymphocytes. Although the human immune system is capable of recognizing a nearly infinite number of antigens, normally it does not recognize or respond to autoantigens. The expected absence of immune responses against self is called tolerance.

Thus, in all autoimmune diseases, including PBC, tolerance (absence of an immune response) becomes defective (is lost) for autoantigens recognized by both T- and B-lymphocytes. In other words, an immune response to autoantigens does occur. What's more, in autoimmune diseases, B-lymphocytes initially produce autoantibodies that recognize a single autoantigen. With time, however, B-lymphocytes produce new autoantibodies that recognize additional autoantigens that are distinct from the initial autoantigen. PBC, however, is the only allegedly autoimmune disease in which this sequence does not occur. In other words, in PBC, the autoantibodies recognize only the initial autoantigen.