404 MEDICINAL CHEMISTRY
with common and overlapping clinical, cellular, and molecular features. Some of the
disorders that are collectively referred to as collagen diseases include:
- Rheumatoid arthritis
- Systemic lupus erythmatosus
- Scleroderma
- Dermatomyositis
- Polyarteritis nodosa
Each of these major diseases exhibits prominent constitutional symptoms coupled with
varying patterns of organ involvement. The common cellular features of this group of
diseases include widespread immune-mediated inflammatory damage to connective
tissue and blood vessels. Connective tissues are composed of varying combinations of
collagen, elastin, proteoglycans, and other less well-characterized glycoproteins.
Although the precise molecular mechanisms underlying collagen diseases have yet
to be fully elucidated, they all appear to be autoimmune diseases.Autoimmunity occurs
when the body turns the immune system against itself, failing to distinguish “self” tis-
sues from “nonself” (foreign) tissues. When the body mounts an immune response
against itself, there is an activation of self-reactive T and B lymphocytes that generates
cell-mediated or humoral immune-mediated actions directed against self proteins.
Rheumatoid arthritis and systemic lupus erythmatosus are both well-characterized
examples of autoimmune diseases. In rheumatoid arthritis, self-directed antibodies
(rheumatoid factors) form immune complexes, leading to inflammation of the joints
and various other organs, including the kidneys. In systemic lupus erythmatosus,
autoantibodies are made against self-DNA, red blood cells, white blood cells, platelets,
mitochondria, ribosomes, histone proteins, and many other proteins.
Although abundant evidence supports the existence of such an autoimmune phe-
nomenon, the causative event that heralds this self-directed immune-mediated attack
remains uncertain. A number of mechanisms have been proposed to afford a molecular-
level explanation of autoimmunity. One such explanation is molecular mimicry.Molecular
mimicry occurs when a protein associated with a foreign substance bears structural sim-
ilarities to a protein found in the host. For example, if a person experiences an infection
from bacteria, there is a possibility that a protein in the bacterium shares certain simi-
lar geometrical and conformational features with a protein already existing in the
person. Thus, an immune response directed against the bacteria will cross-react with
organs in the host organism.
Because of this self-directed immune attack, the symptoms and signs of such diseases
are typically diffuse, arising from many different organ systems. Systemic lupus eryth-
matosus is a superb example of this. The clinical symptoms include weight loss, arthri-
tis, skin rashes (“butterfly rash” of the face), hair loss (alopecia), cold and blue finger tips
(Raynaud’s phenomenon), abdominal pain, lung inflammation, heart murmurs, enlarged
spleen, enlarged liver, psychosis, and epilepsy. Rheumatoid arthritis may also involve
several organs. Since rheumatoid arthritis can extend well beyond joint disease, some
clinicians regard this disorder as rheumatoid diseaserather than rheumatoid arthritis.
The treatment of collagen disease is based on immunosuppressive therapies.
Immunosuppressive agents, such as corticosteroids, are widely used. In addition, cytotoxic
agents (azathioprine, cyclophosphamide, and methotrexate) have also been administered.