| A.
Loss of Self Tolerance A defect in the central mechanism
underlying self-recognition (auto-tolerance, self-tolerance)
can result in autoimmune responses, that is, immune
responses of an individual to antigens present in the
host’s own tissue which can be mediated by humoral (circulating
antibodies, immune complexes) or cellular (delayed
hypersensitivity) mechanisms. Autoimmune diseases have
been divided into two clinical types:
Organ-specific (e.g.,
thyroiditis, pernicious anemia)
Systemic (non
organ-specific; e.g., systemic lupus erythematosus, SLE,
rheumatoids arthritis.
B.
Theories for the origen of Autoimmunity:
Several theories
have been proposed to explain autoimmune responses, or
the termination of self-tolerance:
a. An excess of self-reactive
helper T (Th)-cell activity induced, for example, by
altered forms of self-antigen or with antigen that
cross-reacts with self-antigen, which might be
produced by a coupling of chemicals or drugs (e.g.,
hydralazine) or viruses to self-antigen: the modified
chemical (drug)-host or viral-host antigens would
then trigger a self-reactive Th-effect and elicit
autoantibody production.
b. A bypass of the lack of
requisite self-reactive Th-cell activity or bypass of
the need for such Th-cell activity via polyclonal B-cell
activation with materials such as bacterial
lipopolysaccharide, Epstein-Barr virus, or purified
protein derivative (PPD) of tuberculin.
c. A deficiency of
suppressor T (Ts) cells designed to down-regulate the
immune response to self-antigen.
d. Release of sequestered
antigen (e.g., from lens of the eye, sperm) not
ordinarily available for recognition by the immune
system: release might occur via such means as trauma
or infection.
e. There is clearly a role
for genetic factors in autoimmune disease. Most
autoimmune diseases appear to be HLA associated with
DR2, DR3, DR4, and DR5.
f. Autoimmune diseases
tend to occur at a higher frequency in females than
in males. The incidence of SLE in women is six to
nine times more common in females.
B.
Representative Autoimmune Diseases
Acute disseminated
encephalomyelitis may occur following vaccination (e.g.,
rabies immunization) or viral infection (e.g., measles,
influenza).
1. Pathologic examination
reveals perivascular accumulation of macrophages,
lymphocytes, and some neutrophils throughout the gray
or white matter of the brain with variable
demyelination.
2. Immunologic findings
suggested that the disease represents a cell-mediated
allergic response to basic protein of myelin similar
to that seen in experimental allergic
encephalomyelitis
Experimental
allergic encephalomyelitis is the experimental model
for postvaccinal and postinfectious encephalomyelitis
that can be induced in animals (e.g., guinea pig) by
the injection of either homologous or heterologous
brain or spinal cord extracts emulsified in complete
Freund’s adjuvant.
Chronic
thyroiditis
(Hashimoto’s thyroiditis) is a disease of the
thyroid that mainly affects women in the age group
between 30 and 50 years.
1. Various antibodies to
thyroid-specific antigens can be demonstrated.
2. Experimental animals
injected with homologous or autologous thyroid
extract incorporated in complete Freund’s
adjuvant develop lesions and other features similar
to those seen in human disease.
Multiple sclerosis is a relapsing disease
with exacerbations between periods of remission.
Epidemiologic studies have revealed high-risk and low-risk
areas of the world and a possible role for a
transmissible agent. Evidence that susceptibility close
association with HLA-DR2.
1. Inflammatory lesions (sclerotic
plaques) are confined to the myelin in the central
nervous system and consist of mononuclear cell
infiltrates and demyelination.
2. The cause of multiple
sclerosis remains unknown, but the clustering
character of cases suggests an infectious agent. Of
interest in this regard is the finding that patients
tend to have elevated levels of antibodies to measles
virus in their serum and spinal fluid; however, the
exact role of measles virus is unknown. There is, in
fact, evidence that other viral agents may also be
involved.
Graves’
disease
(thyrotoxicosis, hyperthyroidism) results from the
overproduction of thyroid hormone (thyroxine).
1. Current evidence
suggests that patients produce antibodies to
thyrotropin receptors, which are referred to as
thyroid-stimulating antibodies since they compete
with thyroid stimulating hormone (thyrotropin, which
is made in the pituitary) for receptor sites on the
thyroid cell membrane and mimic the action of
thyrotropin. The end result is overproduction of
thyroid hormone and hyperthyroidism.
Guillain-Barré
syndrome (acute
idiopathic polyneuritis) commonly occurs after an
infectious disease (e.g., measles, hepatitis) or after
vaccination (e.g., influenza) and affects all age groups.
1. Examination of
peripheral nerve tissue reveals a perivascular
mononuclear cell infiltrate and demyelination.
2. A similar disease can
be produced in experimental animals by injection of
peripheral nerve extracts, or peptides derived
therefrom, incorporated in complete Freund’s
adjuvant. The experimental disease appears to be cell-mediated
as evidenced by sensitivity of lymphocytes to nerve
extracts. Anti-nerve antibodies can be detected but
seem to play no role in pathogenesis.
3. The human disease has
several of the same immunologic features as the
experimental animal model (e.g., lymphocytes
sensitive to peripheral nerve extracts, lymphokine
production, and anti-nerve antibodies).
Myasthenia gravis is a chronic disease
resulting from faulty neuromuscular transmission.
1. Muscle weakness and
neuromuscular dysfunction result from depletion of
acetylcholine receptors at the myoneural junction.
2. Injection of experimental
animals with purified acetylcholine receptor incorporated
in complete Freund’s adjuvant induces experimental
myasthenia gravis that closely mimics human disease.
Systemic lupus
erythematosus is
a chronic, multiorgan disorder that predominantly affects
young women of childbearing age. Multiply tissues that
are involved include the skin, mucosa, blood vessels,
kidney, brain, and blood.
1. The butterfly rash, an
erythematosus rash that occurs over the nose and
cheeks.
2. Diffuse proliferative
glomerulonephritis and membranous glomerulonephritis
are common manifestations.
3. Central nervous system
(CNS) manifestations appear to 50% of patients and
include depression, psychoses, seizures, and
sensorimotor neuropathies.
4. Three primary types of
antibodies to DNA (either IgG or IgM) can be detected:
a. Antibodies to
single-stranded DNA (ss-DNA)
b. Antibodies to
double-stranded DNA (ds-DNA).
c. Antibodies that
react with both ss-DNA and ds-DNA, in addition to
anti-DNA antibodies, antibodies are formed
against RNA, erythrocytes, platelets,
mitochondria, ribosomes, lysosomes,
thromboplastin, and thrombin. Some patients
demonstrate a positive test for rheumatoid factor.
Rheumatoid
arthritis is
a chronic inflammatory joint disease, with possible
systemic involvement as well.
1. The disease affects
primarily females and is associated with HLA-DR4,
which may impart genetic susceptibility.
2. An unknown etiologic
agent initiates a nonspecific immune response. An
inflammatory joint lesion that begins in the synovial
membrane can become proliferative, destroying
adjacent cartilage and bone and resulting in joint
deformity.
3. Rheumatoid factor. A
hallmark of rheumatoid arthritis is the presence of
rheumatoid factor, an immunoglobulin (mainly IgM but
also IgG and IgA) produced by the B cells and plasma
cells in the synovial membrane with antibody
specificity for the Fc fragment of IgG.
4. The joint synovial
fluid contains immune complexes consisting of
rheumatoid factor IgG-complement.
Sjogren’s
syndrome, also
called sicca syndrome, is a chronic inflammatory disease
that affects multiple systems of the body, although the
primary target appears to be secretory arthritis or SLE.
1. Salivary and lacrimal
glands are infiltrated with plasma cells, B cells,
and T cells. Some patients show a quantitative and
qualitative T-cell suppression in peripheral blood.
All of these features suggest an immunologic etiology.
Hemolytic diseases
that
have been characterized as having an autoimmune basis
include warm antibody hemolytic anemia, cold antibody
hemolytic anemia, and paroxysmal cold hemoglobinuria.
Idiopathic
thrombocytopenic purpura, which may be either acute or chronic,
results from antibody-mediated platelet destruction. In
children, it is sometimes preceded by a viral infection.
Goodpasture’s
syndrome is
a rare, progressive disease of the lungs and kidneys. The
disease occurs in all age groups, affecting mainly young
men. The prognosis is poor. IgG appears to represent an
antibody specific for an antigen shared by kidney and
lung basement membranes.
Pernicious anemia results from defective red
blood cell maturation due to faulty absorption of vitamin
B12.
Normally, dietary B12
is transported across the small intestine into the body
as a complex with intrinsic factor synthesized by
parietal cells in gastric mucosa. In patients with
pernicious anemia, the process is blocked.
1. The hallmark of the
disease is the progressive destruction of stomach
glands associated with loss of parietal cells which
secrete intrinsic factor. This leads to failure of B12
absorption.
2. The gastric mucosa is
infiltrated with mononuclear leukocytes and
neutrophils.
Bullous (vesicular)
diseases are
chronic dermatologic problems that result when
destruction of intercellular bridges (desmosomes)
interferes with cohesion of the epidermis, leading to the
formation of blisters.
1. Pemphigus
vulgaris skin lesions, when
examined by immunofluorescence, show deposition of
antibody (mainly IgG) and complement components in
squamous intercellular spaces.
2. Bullous
pemphigoid lesions, by
immunofluorescence examination, demonstrate
deposition of antibody and complement along skin
basement membrane. Circulating antibasement membrane
antibodies can also be detected.
Polymyositis-dermatomyositis
is an
acute or chronic inflammatory disease of the muscle and
skin.
1. Deposition of
immunoglobulin and complement in the vessel walls of
the skin and muscle.
2. Cellular immunity may
also play a role in pathogenesis as judged from
studies of cellular passive transfer and lymphokine
release from lymphocytes.
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