Primary Biliary Cirrhosis (cont.)
In this Article

What is the cause of PBC?
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?
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.
Next: What are antimitochondrial antibodies (AMA)? »
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