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Autoimmune Disease
Introductory article
Article Contents
Robert Volpé, University of Toronto, Toronto, Ontario, Canada
. Introduction
The term autoimmunity describes the inappropriate reaction of the immune system
against one or more of the organism’s own tissues. It does not necessarily imply any tissue
damage or dysfunction. When there is tissue infiltration, damage and/or dysfunction, the
condition is termed autoimmune disease.
Introduction
The term autoimmunity describes the inappropriate
reaction of the immune system against one or more of
the organism’s own tissues. It does not necessarily imply
any tissue damage or dysfunction. When there is tissue
infiltration, damage and/or dysfunction, the condition is
termed autoimmune disease.
The purpose of the body’s immune system is to fight off
infection, such as viruses or bacteria, and normally the
immune system can make a very fine distinction between
exogenous antigens (as, for example, manifested by those
microorganisms) and self antigens, against which it does
not normally react (self-tolerance). Autoimmunity has
traditionally been considered to represent a breakdown in
self-tolerance, although the mechanisms of this breakdown
may not be the same in each case and, in any event, are still
not fully understood. The mechanisms of tolerance are
considered in the next section.
Autoimmunity is characterized by the inappropriate or
excessive activity of immune effector cells directed to
tissue(s) in the body of the organism. Thus, B lymphocytes
may produce autoantibodies, and these may or may not
have functional effects on the target tissue; immune
complexes may be deposited in blood vessels; T lymphocytes may aggregate in tissues (or a tissue) with or without
resultant destruction; and the complement system may
activate phagocytic mononuclear cells. Generally speaking, in autoimmune disorders that are characterized by
tissue damage, the damage is mediated by T lymphocytes.
However, there are some conditions in which cellular
function may be disturbed primarily by antibodies (e.g.
Graves disease, myasthenia gravis). The development of
these diseases, including the disturbances in target cell
function, depends on a complex interplay between the
antigen(s) on the target cells, the antigen-presenting cells
(APCs), the helper or inducer T lymphocytes, T-effector
lymphocytes, regulatory or cytotoxic T lymphocytes, B
lymphocytes, antibodies and various cytokines (cytokines
are soluble factors with various functional properties that
are released by many cell types, including immune cells). In
turn, these elements stimulate the target cell to express
molecules of various types, such as intercellular adhesion
molecules, heat-shock proteins, class I and class II
. Self-tolerance
. Possible Aetiologies for Autoimmune Diseases
. Classification of Autoimmune Diseases
. Major Autoimmune Diseases
histocompatibility antigens, other autoantigens and so
forth, that will further modify the immune process.
Controversy abounds regarding the nature of the
autoimmune process, the role of antigen and of antigen
presentation, and the involvement of microorganisms in
these mechanisms. At times, the immune response may be
induced by a foreign antigen such as is carried by a virus,
while on many other occasions no such foreign antigen can
be identified (although there are many homologies between
antigens of microorganismic origin and autoantigens).
Where no exogenous antigen can be found, the abnormality may lie largely, if not entirely, in the regulation of the
immune system: a breakdown in tolerance has occurred.
The criteria involved in identifying human autoimmune
disease are depicted in Table 1.
Self-tolerance
Four major mechanisms are responsible for tolerance to
self: clonal deletion, clonal anergy, clonal ignorance and
active regulation.
Clonal deletion
Clonal deletion occurs when immature lymphocytes first
express their clonal receptors in primary lymphoid organs
(T lymphocytes in the thymus, B lymphocytes in the bone
marrow), and continues with lymphopoiesis throughout
life. Antigen-specific receptors interact with self antigens,
then delivering a signal that results in programmed cell
death, or apoptosis. Clonal deletion depends on the
presence of self antigens, which must be at tolerogenic
concentrations, and also on the functioning of the
apoptotic machinery within the lymphocyte. This process
is regulated so as to ensure the timely death of the
lymphocyte following encounters with self antigen. Selfreactive clones with high-affinity receptors are generally
more likely to be clonally deleted than those expressing low
affinity for self. While clonal deletion of autoreactive
lymphocytes is clearly important in self-tolerance, there are
many examples where autoreactive T and B lymphocytes
survive in the periphery.
ENCYCLOPEDIA OF LIFE SCIENCES © 2001, John Wiley & Sons, Ltd. www.els.net
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Autoimmune Disease
Table 1 Criteria for human autoimmune disease
1. Direct evidence
(A) Circulating autoantibodies producing dysfunction
(i) Damage to the target cell
(ii) Stimulation or inhibition of a receptor
(iii) Interaction with an enzyme or hormone
(B) Antibodies localized to the lesion
(i) Evidence of immunoglobulin and/or complement components at site of lesion
(ii) Antibodies can be eluted from lesions
(iii) Lesions may be represented by immunoglobulin eluates
(C) Immune complexes localized to site of lesion
(i) Elution of antigen–antibody complex
(ii) Antigen identification
(D) Passive transfer reproduction of disease
(i) Maternal–fetal passive transfer
(ii) Transfer to experimental animals
(iii) In vitro injury to target cell demonstrable
(E) T-cell mediated
(i) T lymphocytes proliferate in vitro in response to self antigen
(ii) Xenotransplantation of human target tissue plus sensitized T lymphocytes to immunodeficient mice.
(iii) Target tissues cocultured in vitro with sensitized T cells – in vitro cytotoxicity
2. Indirect evidence
(A) Reproduction by experimental immunization of autoimmune disease
(i) Need to identify and utilize initiating antigen
(ii) Immunization with appropriate susceptible syngeneic host with analogous antigen
(iii) Characteristic lesions should be demonstrable
(iv) Autoantibodies or T cells react with the same antigen or epitope
(B) Spontaneous models in animals
(i) Identification of disease in an animal species
(ii) Selection and breeding to increase frequency of disease
(iii) Production of self-reactive T lymphocytes and autoantibodies
(iv) Passive transfer and adoptive transfer of condition to syngeneic recipients
(C) Animal models produced by manipulation of immune system
(i) Neonatal thymectomy, with or without radiation
(ii) Homologous inbred animals deficient in cytokines
(iii) Transgenic animals with altered antigen expression, cytokine production or costimulatory factor expression
3. Circumstantial evidence
(A) Association with other autoimmune diseases
(B) Presence of autoantibodies
(C) Association with major histocompatibility complex haplotype
(D) Infiltration of lymphocytes in target organ
(i) Germinal centres in the lesions
(ii) Infiltrating lymphocytes show restricted V gene usage
(E) Favourable response to immunosuppression (specific, nonspecific)
Adapted with permission from Rose NR (1996) Foreword – the use of autoantibodies. In: Shoenfeld Y and Peter JB (eds) Autoantibodies, p.
xxiv. Amsterdam: Elsevier.
Clonal anergy
The second mechanism for maintaining tolerance is that of
clonal anergy, which refers to a state of specific functional
unresponsiveness. In contrast to clonal deletion, anergy
does not lead to apoptosis, but rather results in a
temporary dysfunction of reactivity to antigens. Anergy
in both B and T lymphocytes contributes to self-tolerance.
2
In the case of helper T lymphocytes, the induction of
anergy may be dependent on the signals they receive.
Professional APCs activate T lymphocytes by providing
two signals: (1) an antigen-specific signal through the
interaction of major histocompatibility complex (MHC)
class II molecule–peptide complexes and T-cell receptors
(TCRs), and (2) an activating costimulatory signal which is
also necessary for activation. Signalling through the TCR
Autoimmune Disease
alone induces a state of anergy, or unresponsiveness.
Professional APCs such as macrophages, dendritic cells, B
lymphocytes and Langerhans cells express costimulatory
molecules such as CD80–CD86 on their surface, and can
provide a costimulatory signal to T lymphocytes. In
contrast, most nonhaematopoietic cells in the tissues, such
as epithelial cells, do not express these molecules on their
surfaces even when they are stimulated by interferon g
(IFNg) to induce the expression of MHC class II
molecules. These cells are termed nonprofessional APCs
and cannot provide a costimulatory signal, thus inducing
anergy on T lymphocytes. This two-signal model for Tlymphocyte activation may explain the observation that T
lymphocytes are tolerant or unresponsive to self (or
foreign) antigen presented on peripheral tissue. Another
mechanism for inducing anergy in T lymphocytes is that of
a lack of proliferation signals provided by interleukin (IL)
2, IL-4 and IL-7 when T lymphocytes are stimulated with
both antigen-specific and costimulatory signals.
Clonal ignorance
The third mechanism, clonal ignorance, refers to the state
in which certain autoantigens appear to be undetected by
the immune system under normal circumstances. Neither
clonal deletion nor anergy, nor stimulation of the
lymphocytes, occurs in this situation. The explanation
may be that the antigens are sparse, or normally
sequestered from the immune system, or not presented
with appropriate costimulation. Clonal ignorance may be
overcome if these factors change.
Active regulation
The fourth mechanism, active regulation, represents a
concept that has been revived and clarified. One recently
developed theory approaches the problem of the control of
self-reactivity from the angle of a balance between two
mutually antagonistic T-helper (TH) subsets characterized
by the cytokines they secrete (TH1 cells secrete IL-2 and
IFNg, whereas TH2 cells secrete IL-4, IL-5 and IL-10).
According to this theory, failure of a target organ should be
viewed as caused predominantly by TH1-mediated pathways in which the target cells are destroyed by IFNgactivated scavenger macrophages; the macrophages are
very important in this concept. The TH1–TH2 balance
theory emphasizes the reciprocal relation between the TH1
and TH2 pathways, and suggests that if the TH1 pathway is
diverted into the TH2 pathway the autoimmune reactivity
is dampened. That is, tolerance to self is not restored, but
the harmful reaction to self is diverted to a less harmful or
benign one. However, this model may be too simplistic,
since regulatory T-lymphocyte populations other than TH2
cells exist, including TH3 cells which secrete the inhibitory
cytokine transforming growth factor b. Controversy
surrounds the question as to whether antigen-specific
suppressor T lymphocytes exist as a distinct subpopulation.
Possible Aetiologies for Autoimmune
Diseases
It is now clear that autoimmune diseases result from the
interaction of multiple factors which either determine
susceptibility to disease or trigger autoimmune responses.
Immunogenetics of Autoimmune Diseases
There appears to be a genetic contribution in most, if not
all, of the autoimmune diseases. The prevalence of a given
autoimmune disease may vary widely between different
ethnic groups (e.g. insulin-dependent diabetes mellitus
(IDDM) is much more rare in Japanese people than in
Caucasians), suggesting different genetic contributions. A
family history of the disease in question may indicate a
genetic element, but a common environmental factor could
also be involved. If a given condition provides a family
history suggestive of mendelian inheritance, a genome
search might confirm a genetic contribution. Studies of
identical (monozygotic) twins have demonstrated that
many autoimmune diseases (e.g. IDDM, Graves disease)
are present in both twins more often than the expected
disease prevalence. Such studies are particularly useful
when the twins have been separated, as environmental
factors can thus be ruled out. Since the concordance rate in
twins for an autoimmune disease does not approach 100%
(usually about 50%), this indicates that the penetrance and
expressivity of the gene will vary widely, assuming that
there is no genetic heterogeneity.
At a more fundamental level, human leucocyte antigen
(HLA) haplotypes show clear associations with many of
the autoimmune diseases. The genes that code for the
restriction elements of the immune system are located in a
cluster on the short arm of chromosome 6, designated the
MHC; this encompasses the HLA system in humans.
Distinction should be made between the three major
classes of MHC factors: class I antigens are membranebound surface molecules present on most cells of the body;
class II antigens are biochemically different cell surface
molecules found only on certain cell types; and class III
factors comprise some of the components of the complement cascade. MHC expression is essential for antigen
presentation and immune responses. Both class I and II
molecules bind processed antigenic peptides and present
them to T lymphocytes. Class II factors have had the
closest correlation with many of the autoimmune disorders
(see Table 2). Persons possessing certain class II HLA
haplotypes have an increased risk of developing certain
autoimmune diseases, probably via abnormal antigen
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Autoimmune Disease
Table 2
Associations between human leucocyte antigen (HLA) haplotypes and some autoimmune disorders
Frequency (%)
Condition
Autoimmune Addison disease
Graves disease
Insulin-dependent diabetes
Myasthenia gravis
Sjögren syndrome
Atrophic thyroiditis
Goitrous thyroiditis
Pernicious anaemia
Ankylosing spondylitis
Reiter syndrome
Disseminated lupus erythematosus
Rheumatoid arthritis
*
HLA
D/DR3
D/DR3
D/DR3
D/DR4
D/DR2
D/DR3
D/DR3
DR3
DR5
Dw5
B27
B27
DR3
Dw4
Patients
69
56
56
75
10
50
78
64
53
25
79–100
65–100
56
38–65
Controls
26.3
26.3
28.2
32.2
30.5
28.2
26.3
23.8
26.3
5.8
4–13
4–14
28.2
18–31
Relative risk*
6.3
3.7
3.3
6.4
0.2
2.5
9.7
5.7
3.1
5.4
90
36
3.7
4.4
Indicates how many times more frequently the disease develops in individuals carrying the HLA antigen, compared with the frequency of the
disease in individuals lacking the antigen. The data refer exclusively to Caucasians. Adapted with permission from Svegaard et al. (1996). In:
Volpé R (ed.) Autoimmunity in Endocrine Disease, p.93. New York: Marcel Dekker.
presentation. However, in most instances these genes
confer only weak susceptibility, making it evident that
other genes must be involved.
The two approaches used to study susceptibility genes of
complex diseases are association and linkage analyses.
Association studies are performed most simply by comparing the frequency of the specific phenotype of the marker
studied (e.g. HLA DR3) in patients having the disease in
question, with the frequency of that marker in an ethnically
similar disease-free population. However, linkage studies
are more effective in analysing disease-related genes
because they are capable of detecting genes that are
required (but not necessarily sufficient) for the development of the disease. Linkage analysis relates to the
observation that, if two genes are close together on a
chromosome, they will tend to segregate together. Thus, if
a marker is near to a disease-related gene, it will
cosegregate with the disease in families. The value of
linkage analysis is that it identifies genes that are necessary
for disease expression. Linkage analysis is expressed as a
lod score (i.e. the measure of the probability of linkage
between a disease and a genetic marker).
Still another approach comes from the Human Genome
Program, which has been extremely useful for identifying
genes for diseases that have a simple mendelian genetic
basis. Individuals in suitable families are ‘typed’ using a
‘genome screen’ of genetic markers (microsatellites) covering the entire genome, and it is then determined which
markers segregate with the disease. However, autoimmune
diseases do not follow simple mendelian rules, and
represent more complex inherited conditions; only recently
have microsatellites proved also to be useful in studying
such disorders as these. Practically, microsatellites are
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regions in the genome that are composed of repetitive
sequences. Microsatellites are abundant and uniformly
distributed throughout the genome at distances of less than
one million base pairs. Thus, microsatellites can act as
markers in linkage studies in the search for unknown
disease susceptibility genes. The suspected gene region can
then be further defined and refined by means of denser
markers and cloning techniques, with the ultimate
objective of identifying the appropriate gene.
Using these techniques, it has been demonstrated that
the HLA-related gene region provides an important
contribution to the genetic susceptibility of many but not
all of the autoimmune diseases, but this varies from disease
to disease; in some conditions, the contribution is minimal,
and these genes may confer only a modulating effect on
disease development in such cases. Non-HLA genes may
also be important, exemplified by the association between
inherited defects in complement proteins and particular
autoimmune diseases. Other candidate genes for the
various autoimmune diseases are currently being sought,
primarily through whole genome screening using microsatellites. Data from such studies suggest that the genetic
susceptibility to many of the autoimmune diseases is
probably influenced by shared alleles at several unlinked
loci across the genome. The identification of the responsible genes at these foci remains to be accomplished.
Other predisposing factors
The increased prevalence of many autoimmune diseases
often observed in women suggests that female hormones
predispose to autoimmunity, and this view is supported by
Autoimmune Disease
experimental evidence in animal models that oestrogens
can exacerbate disease, while testosterone is protective.
The question of whether immune dysregulation is the
primary abnormality in autoimmune disease remains
unanswered. Ageing in humans and in animals is often
associated with autoimmune phenomena such as increased
autoantibody levels, and some autoimmune diseases show
increased clinical expression with ageing (e.g. Hashimoto
thyroiditis); in other instances, the presence of autoantibodies alone may not reflect clinical disease. A number of
autoimmune diseases are also associated with concurrent
neoplastic conditions, but it is unclear whether neoplasia
may cause immune dysregulation and so predispose to
autoimmunity, or whether both diseases may have a
common aetiology.
Factors that induce autoimmune disease
It is clear that, even in individuals with the appropriate
predisposition to autoimmunity, environmental factors
are necessary to trigger disease. The importance of such
factors is demonstrated by the finding that the concordance rate for autoimmune conditions in human monozygotic twins, although high, does not approach 100%. A
variety of hypotheses have been put forward to explain the
onset of autoimmune disease, but most of the proposed
mechanisms are dependent on the activation of autoreactive T and/or B lymphocytes that have escaped deletion
and are normally clonally ignorant or anergic. Infectious
agents are commonly implicated. The possible mechanisms
by which infectious agents may provoke autoimmunity are
diverse and include antigenic cross-reactivity between the
microorganisms and the host tissues, the production of
microbial superantigens that stimulate T lymphocytes
expressing particular receptor genes, direct infection of
immune cells, deviation of the balance between T-helper
subsets towards TH1, exposure of autoreactive lymphocytes to costimulatory signals or inflammatory cytokines,
and presentation of previously hidden autoantigenic
epitopes. Particular drugs are also associated with autoimmune disease. Other environmental factors include
stress, trauma, smoking and nutritional factors which tend
to downregulate the immune system.
antibodies or specifically sensitized T lymphocytes are
directed against components of different organs of a given
host. Examples of this type of autoimmune disease would
be disseminated lupus erythematosus (DLE) and rheumatoid arthritis. In such cases, it is unclear whether the
immune system is responding to several antigens or
whether the immune response is more restricted, responding to common antigenic determinants present in the
different organs. The autoimmune polyglandular endocrine failure group of diseases should be considered, not as
examples of nonorgan-specific autoimmune disease, but
rather as examples of multiple organ-specific disease, as it is
clear that the target-cell antigens involved are quite
different from one another, hence the antibodies are
likewise separate.
Major Autoimmune Diseases
Organ-specific autoimmune diseases
A brief description will follow for a few of the main
examples of this group, categorized by organ or system.
Endocrine system
The autoimmune diseases of the endocrine system include
Graves disease (autoimmune hyperthyroidism), Hashimoto (autoimmune) thyroiditis, IDDM, autoimmune Addison disease (adrenocortical failure), hypoparathyroidism,
autoimmune hypophysitis and autoimmune gonadal failure. These entities may occur singly, or more than one
condition may appear in one individual or one family. This
appears to be due to genetic overlap, as it cannot be
accounted for by antigenic overlap in most instances;
indeed the antigens in the different glands are not
homologous. These disorders may also be associated with
organ-specific autoimmune diseases outside the endocrine
system, such as myasthenia gravis, pernicious anaemia,
vitiligo, alopecia areata, autoimmune hepatitis, primary
biliary cirrhosis, idiopathic thrombocytopenic purpura
and others.
Some of the major autoimmune endocrinopathies will be
more fully described below.
Graves disease
Classification of Autoimmune Diseases
Autoimmune diseases may arise spontaneously in animals
and humans, and several experimental models have been
induced in animals. This account focuses on spontaneous
disorders in humans, which may be divided into organspecific and nonorgan-specific autoimmune diseases. In the
former, antibodies or specifically sensitized T lymphocytes
are directed against a component or components of one
organ of a given host. In nonorgan-specific conditions,
Graves disease is the commonest form of hyperthyroidism
(overactive thyroid). It is mediated by an antibody directed
against the thyroid-stimulating hormone (TSH) receptor
on the thyroid cells, which acts as an agonist for TSH, thus
stimulating the thyroid cells to hyperactivity. Mild to
moderate lymphocytic infiltration is seen in the hyperplastic thyroid gland. The eyes are frequently involved with an
autoimmune inflammatory reaction as well (Graves
ophthalmopathy), the nature of which is still not understood. Patients are very nervous, lose weight, have a rapid
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Autoimmune Disease
heart beat, sweating, weakness and tremor. Graves disease
can be treated with medication that suppresses the thyroid,
or with thyroid ablation with radioactive iodine or surgery.
Hashimoto (autoimmune) thyroiditis
This condition is characterized by marked lymphocytic
infiltration of the thyroid gland, often with lymphoid
follicles and variable fibrosis. Thyroid enlargement (goitre)
is common. Thyroid cell damage is largely due to the action
of T lymphocytes (possibly directed against thyroperoxidase and thyroglobulin), and is the commonest form of
spontaneous hypothyroidism. Antibodies to thyroperoxidase and thyroglobulin are usually found in the circulation, and correlate with, but do not cause, the thyroid cell
damage. Antibodies to the TSH receptor which interfere
with TSH binding and action may be associated with
hypothyroidism in some cases of atrophic thyroiditis.
Insulin-dependent diabetes mellitus
IDDM is secondary to lymphocytic infiltration of pancreatic islets, with T lymphocyte-mediated damage directed specifically to b cells (which produce insulin). Several
candidate antigens are present within the b cells, with
glutamic acid decarboxylase (GAD) most strongly suspected. Destruction of over 80% of the b cells (which may
take years) is necessary before the production of insulin
becomes inadequate, blood glucose rises, and diabetes is
initiated. Antibodies to GAD and other islet cell antigens
act as markers for IDDM.
Autoimmune adrenocortical failure (Addison disease)
Autoimmune destruction of the adrenal cortices is
mediated by T lymphocytes, probably directed against
17-a and 21-hydroxylase. Antibodies against these enzymes act as markers for this condition, which is frequently
associated with other autoimmune diseases in the syndrome of autoimmune polyendocrine failure. When
damage is severe, inadequate cortisol and aldosterone
concentrations are produced, with dire consequences of
sodium loss, hypotension, hypoglycaemia and weight loss.
Haematopoietic disorders
Autoimmune haemolytic anaemia, idiopathic thrombocytopenic purpura and autoimmune neutropenia are caused
by autoantibody binding to erythrocytes, platelets and
neutrophils, respectively. The target cells are destroyed by
phagocytic macrophages and/or by complement-mediated
lysis.
Gastrointestinal disorders
Pernicious anaemia is due to an immune reaction directed
against gastric parietal cells, resulting in reduced absorption of vitamin B12, in turn leading to macrocytic anaemia
and a neurological condition (i.e. subacute combined
degeneration of the spinal cord). Antibodies to the parietal
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cells act as a marker for the disease. Other probable
autoimmune conditions of the gastrointestinal tract (e.g.
autoimmune sprue, Crohn disease, ulcerative colitis,
autoimmune hepatitis and primary biliary cirrhosis) are
not discussed further here.
Neuromuscular diseases
Myasthenia gravis is an uncommon neuromuscular
disease, characterized by progressive muscular weakness
with muscular activity. This is another antibody-mediated
disease, in which the antibody is directed against acetylcholine receptors at the neuromuscular junction, blocking the
reception of impulses normally initiated at the acetylcholine receptor by acetylcholine. Several patients with this
disorder also have thymic hyperplasia or even thymomas.
Neurological disease
Multiple sclerosis involves demyelinization of central
nervous tissue, leading to a relapsing–remitting or a
chronic progressive paralytic course. While the pathogenesis is incompletely understood, available evidence indicates that it is a T-cell disease, with an association with
HLA-DR2.
Eye
Diseases specific to the eye which are considered to be of
autoimmune origin include various forms of uveitis,
sympathetic ophthalmia and Sjögren syndrome (keratoconjunctivitis sicca). The eye may also be involved in
systemic (nonorgan-specific) autoimmune disease, such as
rheumatoid arthritis, DLE, ankylosing spondylitis and
Reiter syndrome. Sjögren syndrome is most common with
rheumatoid arthritis. Involvement of the lachrymal and
salivary glands leads to dryness of the eyes and mouth.
Heart
Rheumatic heart disease, with valvular damage, can be
considered an autoimmune disease, although the inciting
antigen clearly appears to be of bacterial origin, namely
Streptococcus haemolyticus. Cross-reactivity with multiple
cardiac antigens appears to explain the involvement of the
heart. Other conditions with a probable autoimmune basis
include idiopathic cardiomyopathy and endomyocardial
fibrosis. The heart can also be affected in nonorgan-specific
systemic autoimmune diseases, such as DLE and rheumatoid arthritis.
Skin
Bullous pemphigus and dermatitis herpetiformis are
serious skin eruptions, the former with bullae and the
latter with vesicular rashes, both due to autoimmune
processes. The skin, like the heart, can also be involved in
systemic autoimmune disorders, such as DLE, rheumatoid
arthritis, polyarteritis nodosa and scleroderma. Vitiligo, an
autoimmune disorder of the skin in which the melanocytes
Autoimmune Disease
are the immune target, causes patches of skin depigmentation and is associated with autoimmune thyroid disease in
20% of cases.
Kidney
Goodpasture disease is caused by autoantibodies specific
for type IV collagen in the kidney glomerular basement
membrane.
Nonorgan-specific autoimmune disease
Examples of nonorgan-specific autoimmune diseases
include DLE, rheumatoid arthritis, polyarteritis nodosa,
ankylosing spondylitis and, possibly, scleroderma. Only
the first two are discussed here.
Disseminated lupus erythematosus
DLE attacks many organs of the body, causing a butterfly
rash across the bridge of the nose, with fever, joint pains,
central nervous system damage, heart damage, thrombocytopenia and kidney damage. The latter can be the most
serious complication of this disease. In this condition,
antibodies are produced against several nuclear components of cells, most notably against native double-stranded
deoxyribonucleic acid (DNA). Occasionally, antibodies
are also produced against denatured, single-stranded
DNA, and against nucleohistones. These various antibodies are believed to form circulating soluble complexes
with DNA derived from the breakdown of normal tissue
such as skin. These soluble complexes are filtered from the
blood by the kidneys, and thus become trapped against the
basement membrane of the glomeruli where they may form
characteristic irregular deposits, leading to inflammation
(glomerulonephritis) and loss of protein from the kidneys
(proteinuria). Similar deposits may also be seen in
arteriolar walls and synovial spaces of the joints. Many
other tissues can be affected in this condition, as noted
above, and may lead to very serious complications and
death. Several possible inciting factors have been suspected, including bacteria and drugs. The disease may run
a course of remissions and exacerbations over years.
Rheumatoid arthritis
This is a chronic systemic disease in which joint manifestations are most dominant, although the condition may also
involve the eyes, skin, heart and intestinal tract. The joint
synovium is inflamed and densely infiltrated with lymphocytes, plasma cells, dendritic cells and macrophages.
Lymphoid follicles may also be seen. Various immune
elements participate in this disorder, including T lymphocytes, complement, antigen–antibody complexes, cytokines, enzymes and mediators, leading to the destruction of
joint cartilage, with further exposure of the cartilagenous
cells to the immune system, leading to perpetuation of the
disease. The inflammation is characterized by rheumatoid
factor, an abnormally produced IgM antibody, which is
directed against a determinant on the Fc portion of the
patient IgG molecules. Rheumatoid factor–IgG complexes may deposit in the joint synovia, contributing to
the activation of the complement cascade, which releases
chemotactic factors, in turn attracting inflammatory
neutrophils. It is also thought that autoreactive T
lymphocytes may have an important role in driving the
inflammation. The joints may ultimately be destroyed by
this process. Generally, other tissues are not as seriously
involved.
Further Reading
Gill RG and Haskins K (1993) Molecular mechanisms underlying
diabetes and other autoimmune diseases. Immunology Today 14(2):
49–51.
Iwatani Y, Amino N and Miyai K (1989) Peripheral self-tolerance and
autoimmunity: the protective role of expression of class II histocompatibility antigens on non-lymphoid cells. Biomedicine Pharmacotherapy 43: 593–605.
Nepom GT and Erlich H (1991) MHC class II molecules and
autoimmunity. Annual Review of Immunology 9: 493–525.
Ott J (1996) Analysis of Human Genetic Linkage. Baltimore: Johns
Hopkins University Press.
Shoenfeld Y and Peters JB (1996) Autoantibodies. Amsterdam: Elsevier.
Theofilopoulos AN (1995) The basis of autoimmunity. Immunology
Today 16: 90–98 (Part I), 150–159 (Part II).
Tomer Y, Barbesino G, Greenberg D and Davies TF (1997) The
immunogenetics of autoimmune diabetes and autoimmune thyroid
disease. Trends in Endocrinology and Metabolism 8: 63–70.
Volpé R (1999) Autoimmune Endocrinopathies. Contemporary Endocrinology Series. New Jersey: Totowa, Humana Press.
Weber JL (1990) Human DNA polymorphisms based on length
variations in single sequence tandem repeats. Genome Analysis 1:
159–181.
Zouali M, Kalsi J and Isenberg D (1993) Autoimmune diseases – at the
molecular level. Immunology Today 14(10): 473–476.
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