Download Autoimmune Disease

Dr. Yong-Sun Kim
Oct. 31, 2001
Autoimmune Diseases
The adult host usually exhibits tolerance to tissue antigens present during fetal life that are
recognized as “self”. However, in certain circumstances tolerance may be lost and immune
reactions may develop to host antigens, resulting in autoimmune diseases. Various bacteria,
viruses, and drugs are implicated as the source of cross-reacting antigens that trigger the activation
of autoreactive T cells or B cells. For example, Reiter’s syndrome is associated with outbreaks of
Shigella dysentery, and systemic lupus erythematosus is associated with the use of the drug
procainamide. The concept of “molecular mimicry” is used to explain these phenomena; ie, the
environmental trigger resembles (mimics) a component of the body sufficiently that an immune
attack is directed against the cross-reacting body component. One of the best-characterized
examples of molecular mimicry is the relationship between the M protein of Streptococcus pyogenes
and the myosin of cardiac muscle. Antibodies against certain M proteins cross-reactions can be
involved, but most are antibody-mediated. Many autoimmune diseases exhibit a marked familial
incidence, which suggests a genetic predisposition to these disorders. There is a strong association
of some diseases with certain human leukocyte antigen (HLA) specificities, especially the class II
genes. For example, rheumatoid arthritis occurs predominantly in individuals carrying the HLADR4 gene.
It should be noted, however, that whether a person develops an autoimmune disease or not is
clearly multifactorial, because people with HLA genes known to predispose to certain
autoimmune diseases nevertheless do not develop the rheumatoid arthritis. That is to say, HLA
genes appear to be necessary but not sufficient to cause autoimmune diseases. In general, class II
MHC-related diseases occur more commonly in women, eg, rheumatoid arthritis, Graves’s disease
(hyperthyroidism), and systemic lupus erythematosus, whereas class I MHC-related diseases
occur more commonly in men, eg, ankylosing spondylitis and Reither’s syndrome.
In summary, the current model is that autoimmune diseases occur in people (1) with a genetic
predisposition that is determined by their MHC genes and (2) who are exposed to an
environmental agent which triggers a cross-reacting immune response against some component of
normal tissue.
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Dr. Yong-Sun Kim
Oct. 31, 2001
Mechanisms
The following mechanisms for autoimmunity have been proposed.
A. Release of Sequestered Antigens :
Certain tissues, eg, sperm, central nervous system, and the lens and uveal tract of the eye, are
sequestered so that their antigens are not exposed to the immune system. When such antigens
enter the circulation accidentally, eg, after damage, they elicit both humoral and cellular reponses,
producing aspermatogenesis, encephalitis, or endophathalmitis, respectively. Sperm, in particular,
must be in a sequestered, immunologically privileged site, because they develop after
immunologic maturity has been reached.
B. Escape of Tolerance at the T Cell Level :
Unresponsiveness to a self antigen may be maintained by tolerance at the T cell level. Such
tolerance may be terminated by cross-reactions, ie, when the host responds to antigens that crossreact with tolerated self antigens. For example, in rheumatic fever, antibodies against streptococcal
antigens cross-react with heart tissue antigens.
C. Diminished Suppressor T cell Function:
In normal immune regulation, suppressor T cells may limit an immune response to self
antigens. If suppressor T cell functions decrease, antibodies to self antigens, eg, an antibody to
normal IgG, may be formed. Such antibody (IgM or IgG) occurs in rheumatoid arthritis, in which
antigen-antibody complexes form in joints.
Diseases
Some examples of diseases that involve autoimmune reactions are described below.
A. Allergic Encephalitis :
This is due to cell-mediated response to the basic protein of brain myelin. For example, when
animal brain substance mixed with adjuvant is injected into an animal of the same species, a
demyelinating encephalitis develops. It resembles postvaccinal encephalitis seen in persons
injected with older rabies vaccines made in rabbit brains. Rarely, it occurs following certain viral
infections, eg, measles or influenza, or following immunizations against these viral infections.
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Dr. Yong-Sun Kim
Oct. 31, 2001
B. Chronic Thyroiditis :
When animals are injected with thyroid gland material, they develop humoral and cellmediated immunity against thyroid antigens and a chronic thyroiditis. Humans with Hashimoto’s
chronic thyroiditis have antibodies to thyroglobulin, suggesting that these antibodies may provoke
an inflammatory process that leads to fibrosis of the gland.
C. Rheumatic Fever :
Group A streptococcal infections regularly precede the development of rheumatic fever.
Cross-reactions occur between cell membrane antigens of streptococci and human heart muscle
sarcolemma, which may play a causative role in disease.
D. Hemolytic Anemias, Thrombocytopenias, and Granulocytopenias :
Various forms of these disorders have been attributed to the attachment of autoantibodies to
cell surfaces and subsequent cell destruction. Pernicious anemia is caused by an autoimmune
reaction to intrinsic factor, a protein secreted by parietal cells of the stomach that facilitates the
absorption of vitamin B12. Idiopathic thrombocytopenic purpura is due to antibody directed
against platelets.
E. Diabetes, Myasthenia Gravis, and Hyperthyroidism (Graves’ Disease) :
In these diseases, antibodies to receptors play a pathogenic role. In extreme insulin resistance
in diabetes, antibodies to insulin receptors have been demonstrated that interfere with insulin
binding. In myasthemia gravis (a nervous system disease), antibodies to acetylcholine receptors of
neuromuscular junctions are found in the serum. Some patients with Graves’ disease have
circulation antibodies to thyrotropic receptors, which, when they bind to the receptor, resemble
thyrotropin in activity and stimulate the thyroid to produce more thyroxine.
F. Systemic Lupus Erythematosus (SLE), Rheumatoid Arthritis, and Other Collage
Vascular Disease :
These disorders feature vasculitis and collagen degeneration plus a variety of focal
inflammatory lesions and the presence of autoantibodies against many different self antigens. For
example, antibodies to DNA are found in SLE and antibodies to IgG (rheumatoid factor) occur in
rheumatoid arthritis. Complement levels are low, and the nephritis associated with these disorders
is an immune-complex disease. Although the causes of these disorders are unknown, typical cases
have followed sensitization by drugs, foreign proteins, and other immune stimuli.
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Dr. Yong-Sun Kim
Oct. 31, 2001
Other diseases in this category include ankylosing spondylitis, which is very common in
people carrying the HLA-B27 gene; polymyositis-dermatomyositis; Sjögren’s syndrome; and
Reiter’s syndrome.
G. Reiter’s Syndrome :
This syndrome is characterized by the triad of arthritis, conjunctivitis, and urethritis. Cultures
of the affected areas do not reveal a causative agent. Infection by one of the intestinal pathogens,
eg, Shigella, Salmonella, Yershinia, and Campylobacter, as well as other organisms such as
Chlamydia, predisposes to the disease. Most patients are men who are HLA-B27-positive. The
pathogenesis of the disease is unclear, but immune complexes may play a role.
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Dr. Yong-Sun Kim
Oct. 31, 2001
Table 1. Inducers of Autoimmune Diseases
Inducer
Mechanism
Viral infection
Virus integrates into host genome;
Causes expression of altered cell-surface markers,
polyclonal activation of B lymphocytes, etc.
Drugs
Binding of drug alters Ags and elicits immune
response
Antigen crossreaction
Abs directed against infective agent (e.g., Treponema
pallidum [in syphilis]), also react with normally
expressed Ags on healthy cells (e.g., erythrocytes,
causing their unintended autoimmune destruction)
Expression of novel
Antigenic determinants
Newly exposed determinants in Fc region of Abs
(IgG) can evoke immunological attack (e.g., attack by
rheumatoid factor [IgM and IgG] against portions of
certain IgGs)
Table 2. Means Through Which the Immune Network Might Break Down in
Autoimmune Diseases
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Dr. Yong-Sun Kim
Oct. 31, 2001
Production defects
Modified expression
Somatic mutation or alteration
progenitor cells
Thymus and bone marrow defects
of
lymphoid
Contrasuppression of T cell function
Enhanced TH activity
Polyclonal B cell activation
Breakdown in idiotype network
Defects in macrophage function
Breakdown in lymphokine release
Abnormal gene expression
Table 3. Mechanisms of Tissue Damage in Autoimmune Diseases
Mechanism
How Damage is induced
Complement-fixing Abs
Binding of complement to Ab attached to cell-surface
Ag; causes cytolysis
Ab binding to cell receptor*
Binding of Ab to cell-surface receptor impairs normal
function by blocking access of normal ligand to its
receptor
Immune-complex formation
Formation of immune complexes between self-Ags
and self-Abs trigger inflammatory reaction, which
can damage local tissues
TC cells
Activation of TC cells against normal surface Ags leads
to their destruction
*This is considered a form of hypersensitivity (Type V) by some; see chapter 14 for further discussion.
Table 4. Autoimmune Diseases Associated with Histocompatibility Antigens
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Dr. Yong-Sun Kim
Oct. 31, 2001
Antigen
Disease
Disease Risk*
DR2
Goodpasture’s syndrome
Multiple sclerosis
5
5
DR3
Juvenile-onset diabetes
Graves’ disease
Myasthenia gravis
SLE
5
5
10
5
DR4
RA
10
DR5
Hashimoto’s thyroiditis
5
*Disease risk defines likehood of disease occurring when particular histocompatibility
Ag is expressed, as compared with the general population at large, whose risk factor is
assigned a value of 1.
Table 5. Tests Used to Diagnose Autoimmune Diseases
Test
Autoantibody Detected
Autoimmune Disease
Coombs test
Immunoprecipitation
IF
Antierythrocyte Ab
Abs to Ach receptors
Abs to islet cells
Abs to myelin
Abs to TSH receptors
Anti-basal lamina Abs
Abs to thyroglobulin
Anti--globulin Ab
Antinuclear Ab
Autoimmune hemolytic anemia
Myasthenia gravis
Diabetes mellitus (juvenile)
Multiple sclerosis
Graves’ disease
Goodpasture’s syndrome
Hashimoto’s thyroiditis
RA
SLE
RIA
IF and RIA
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