Download week 13.: autoimmunity i.

WEEK 13.: AUTOIMMUNITY I.
1. Definition of Autoimmunity
We have already seen how hypersensitivity to harmless environmental antigens leads to
acute or chronic diseases depending on the nature of the antigen and the frequency with which
is encountered (see week 12). This week we consider a related set of chronic diseases; i.e.
ones caused by adaptive immune responses that become misdirected at healthy cells and
tissues. The responses to autologous (self) antigens or antigens associated with the commensal
microbiota are called autoimmunity. A defining characteristic of autoimmune responses is the
presence of antibodies and T cells specific for antigens expressed by the targeted tissues.
These antigens are called autoantigens and they are a subset of the self-antigens. The
effectors of adaptive immunity that recognize them are known as autoantibodies and
autoimmune T or B cells. Therefore, the autoimmune responses are caused by the immune
system itself, which attacks cells and tissues of the body causing chronic impairment of tissue
and organ function. Chronic diseases of this kind are collectively known as autoimmune
diseases that are characterized by tissue damage. Autoimmune diseases very widely
distributed in the tissues they attack and the symptoms they cause. Although individual
autoimmune diseases are uncommon, collectively they affect approximately 5-10% of the
population. However, like IgE-mediated allergies, autoimmune diseases are more common in
the affluent, industrialized countries and their frequencies have increased like the allergies and
they, too, are attributed to recent and ongoing changes in human habits and lives.
Why is it important to study about autoimmune diseases?

These chronic diseases can be potentially fatal (for example autoimmune type 1
diabetes or pernicious anemia).

They cause serious, systemic, progressive inflammatory symptoms and induce tissue
damages.

They require life-long treatments and checkups. Upon early diagnosis, treatments
show better rates of lethality, regression of the disease, and longer life span of the
patients.
2. From tolerance to autoimmunity
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Nevertheless, the relative rarity of autoimmune diseases indicates that the immune
system has evolved multiple mechanisms to prevent damage to self-tissues. As discussed
earlier, tolerance to self-antigens is normally maintained by selection processes that prevent
the maturation of some self-antigen specific lymphocytes and by mechanisms that inactivate
or delete self-reactive lymphocytes that do mature. Central tolerance mechanisms eliminate
newly formed strongly autoreactive lymphocytes. This is an important mechanism of inducing
self-tolerance in lymphocytes developing in the thymus and bone marrow. On the other hand,
mature self-reactive lymphocytes that do not sense self strongly in the central lymphoid
organs, since their cognate self-antigens are not expressed there, may be for example killed or
inactivated in the periphery. The principal mechanisms of peripheral tolerance are anergy
(functional unresponsiveness), suppression by regulatory T cells, induction of regulatory T
cell development instead of effector T-cell development (functional deviation), and deletion
of lymphocytes from the repertoire due to activation-induced cell death. The exclusion of
lymphocytes from certain peripheral tissues such as brain, eye, testis (immune privileged sites
of the body) is also a mechanism that contribute to immunological self-tolerance. In addition,
in the absence of infection, signals that are crucial in enabling the activation of an adaptive
immune response to infection, are not generated. Generally, these signals, which include proinflammatory cytokines (for example IL-6 or IL-12) and co-stimulatory molecules (for
example the members of B 7.l protein family) are expressed only by activated antigenpresenting cells in response to infection.
Normally, these multiple tolerance mechanisms are able to prevent autoimmunity. Each
checkpoint is partly effective in preventing anti-self responses, and together they act
synergistically to provide efficient protection against autoimmunity without inhibiting the
ability of the immune system to mount effective responses to pathogens. The mechanisms of
central and peripheral tolerance were discussed in detail in week 10.
Loss of self-tolerance may develop if self-reactive lymphocytes are not deleted or
inactivated during or after their maturation; and if antigen-presenting cells are activated so
that self-antigens are presented to the immune system in an immunogenic manner.
Experimental models and limited studies in humans have shown that the following
mechanisms may contribute to the failure of self-tolerance:

Defects in deletion (negative selection) of T or B cells or receptor editing in B cells
during the maturation of these cells in the generative (primary) lymphoid organs.

Defective numbers and functions of regulatory T lymphocytes.

Defective apoptosis of mature self-reactive lymphocytes.
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
Inadequate function of inhibitory receptors.

Abnormal display of self-antigen: abnormalities may include increased expression and
persistence of self-antigens that are normally cleared, or structural changes in these
antigens resulting from enzymatic modifications, cellular stress or injury. If these
changes lead to the display of antigenic epitopes that are not present normally, the
immune system may not be tolerant to these epitopes, thus allowing anti-self responses
to develop.

Inflammation or an initial innate immune response: the innate immune response is a
strong stimulus for the subsequent activation of lymphocytes and the generation of
adaptive immune responses. Infections or cell injury may elicit local innate immune
reactions with inflammation. These may contribute to the development of autoimmune
disease, perhaps by activating antigen-presenting cells, which overcomes regulatory
mechanisms and results in excessive T cell activation.
3.
Development of autoimmunity: the genetic and environmental basis of
autoimmunity
Given the complex and varied mechanisms that exist to prevent autoimmunity, it is not
surprising that autoimmune diseases are the result of multiple factors, both genetic and
environmental. We first discuss the genetic basis of autoimmunity, attempting to understand
how genetic defects perturb the various tolerance mechanisms. Genetic defects alone are not,
however, always sufficient to cause autoimmune disease. Environmental factors such as
toxins, drugs, and infections also play a part; therefore, genetic and environmental factors
together can overcome tolerance mechanisms and result in autoimmune diseases.
3.1.
Genetic basis of autoimmunity
Most autoimmune diseases are complex polygenic traits in which affected individuals
inherit multiple genetic polymorphisms that contribute to disease susceptibility. Some of these
polymorphisms are associated with several autoimmune diseases, suggesting that the
causative genes influence general mechanisms of immune regulation and self-tolerance. It is
postulated that in individual patients, multiple such polymorphisms are coinherited and
together account for development of the disease. The best-characterized genes associated with
autoimmune diseases and our current understanding of how they may contribute to loss of
self-tolerance are described here:
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
Single gene defect in autoimmune regulator (AIRE) gene: The extraordinary array
of autoimmune disease symptoms presented by patients with immunodeficiency who lack the
transcription factor AIRE is compelling evidence for the connection between immunological
tolerance and autoimmunity. The function of AIRE is to induce the deletion of thymocytes
that recognize peptides cleaved from tissue-specific proteins expressed by one or a small
number of cells or tissues. AIRE ensures that these proteins are expressed in the thymus,
where their peptide antigens contribute to negative selection of the T cell repertoire. In this
case the normal array of tissue-specific proteins is not expressed in the thymus and hence
negative selection of the T cell repertoire is incomplete. In these patients’ circulation, there
are clones of naive T cells specific for peptides derived from tissue-specific proteins and
presented by self-MHC molecules. Starting in infancy, these self-reactive CD4+ and CD8+ T
cells respond to tissue-specific self-antigens. The effector CD8+ T cells kill cells expressing
the tissue-specific proteins, and the effector CD4+ T cells help B cells make high-affinity
antibodies against them. The B cell and T cell responses are directed against various tissues,
including most endocrine glands. These immunodeficient children exhibit a diversity of
symptoms, each typical of one or more autoimmune diseases. This syndrome of inherited
autoimmune polyglandular disease (APD), also called autoimmune polyendocrinopathy–
candidiasis–ectodermal dystrophy (APECED), strongly suggests that most autoimmune
diseases are due to a loss of T cell tolerance. The syndromes of APECED will be discussed in
detail on next week (week 14).

Single gene defect in FOXP3 gene: Another rare immunodeficiency disease reveals
the importance of regulatory T cells (Treg) in preventing autoimmune disease. Uniquely
defining Treg is their use of the transcriptional repressor protein FoxP3. All Treg, but no other
cells, express FoxP3. Mutation of the FOXP3 gene on the X chromosome causes an
immunodeficiency that principally affects boys and is called immune dysregulation,
polyendocrinopathy, enteropathy, and X-linked syndrome (IPEX). Although showing no
abnormalities at birth, children with IPEX rapidly develop enteritis with intractable diarrhea,
type 1 diabetes, and eczema within the first months of life. Over time, other organs become
subject to autoimmunity: the thyroids, for example. Because of their inflamed and disordered
intestines, the children do not thrive. They also suffer recurrent infections that exacerbate the
autoimmune symptoms. If infants with IPEX are not transplanted with hematopoietic stem
cells from an HLA-identical sibling, they die within the first year of life.

Single gene defect in CTLA-4 gene: CTLA-4 is an inhibitory receptor which is
constitutively expressed on Tregs and upregulated on effector T cells after activation. CTLA4
4 is homologous to the co-stimulatory protein of T cells, namely CD28, and both molecules
bind to CD80 and CD86, also called B 7-1 and B 7-2 respectively, on antigen-presenting
cells. However, CTLA-4 binds CD80 and CD86 with greater affinity and avidity than CD28
and transmits an inhibitory signal to T cells. The deficiency of CTLA-4 genes results in
abnormal T cell activation, lymphoproliferation, failures of anergy in CD4+ T cells, defective
function of regulatory T cells and disruption of multiple organs by infiltrating T cells. The
polymorphisms of CTLA-4 genes are associated with several autoimmune diseases including
type 1 diabetes, Graves' disease, Hashimoto's thyroiditis, Addison's disease, rheumatoid
arthritis and multiple sclerosis (see also later).

Single gene defect in CD25 gene: Polymorphisms affecting the expression or
function of CD25, the α chain of the IL-2 receptor on Tregs, are associated with multiple
sclerosis, type 1 diabetes, and other autoimmune diseases. These changes in CD25 likely
affect the generation or function of regulatory T cells, although there is no definitive evidence
for a causal link between the CD25 abnormality, regulatory T cell defects, and the
autoimmune disease.

Gene defect in FAS/FASL gene: An interesting case of a monogenic autoimmune
disease is the systemic autoimmune syndrome caused by mutations in the gene for Fas, which
is called autoimmune lymphoproliferative syndrome (ALPS) in humans. Fas is normally
present on the surface of activated T and B cells, and when ligated by Fas ligand it signals the
Fas-bearing cell to undergo apoptosis. In this way it functions to limit the extent of immune
responses. Mutations that eliminate or inactivate Fas lead to a massive accumulation of
lymphocytes (i.e. lymphoproliferation), especially T cells, and the production of large
quantities of pathogenic autoantibodies.

Gene defects in genes encoding complement proteins (C1q, C2, C4): Genetic
deficiencies of several complement proteins, including C1q, C2, and C4, are associated with
systemic lupus erythematosus (SLE)like autoimmune diseases. The postulated mechanism of
this association is that complement activation promotes the clearance of circulating immune
complexes and apoptotic cell bodies, and in the absence of complement proteins, these
complexes accumulate in the blood and are deposited in tissues and the antigens of dead cells
persist. If apoptotic cells and immune complexes are not cleared, the chance that their
antigens will activate low-affinity self-reactive lymphocytes in the periphery is increased.

Genetic polymorphism of MHC gene: Among the genes that are associated with
autoimmunity, the strongest associations are with MHC genes. In fact, in many autoimmune
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diseases, such as type 1 diabetes, 20 or 30 disease-associated genes have been identified; in
most of these diseases, the HLA locus alone contributes half or more of the genetic
susceptibility. HLA typing of large groups of patients with various autoimmune diseases has
shown that some HLA alleles occur at higher frequency in these patients than in the general
population. Many more autoimmune diseases are associated with HLA class II than with HLA
class I indicating that CD4+T cells are inherently more likely to lose tolerance to a selfantigen than are CD8+T cells. The association of MHC genotype with disease is assessed
initially by comparing the frequency of different alleles in patients with their frequency in the
normal population. For type 1 diabetes, this approach originally demonstrated an association
with the HLA-DR3 and HLA-DR4 alleles identified by serotyping. Such studies also showed
that the MHC class II allele HLA-DR2 has a dominant protective effect: individuals carrying
HLA-DR2, even in association with one of the susceptibility alleles, rarely develop diabetes.
The mechanisms underlying the association of different HLA alleles with various
autoimmune diseases are still not clear. In diseases in which particular MHC alleles increase
the risk of disease, the disease-associated MHC molecule may present a self-peptide and
activate pathogenic T cells, and this has been established in a few cases. When a particular
allele is shown to be protective, it is hypothesized that this allele might induce negative
selection of some potentially pathogenic T cells, or it might promote the development of
regulatory T cells.
3.2. External or environmental basis of autoimmunity
 Role of infections in autoimmunity:
Chronic inflammation, epitope spreading: In general, autoimmune diseases are
characterized by an early activation phase with the involvement of only a few autoantigens,
followed by a chronic stage. The constant presence of autoantigen leads to chronic
inflammation. This in turn leads to the release of more autoantigens as a result of tissue
damage, and this breaks an important barrier to autoimmunity known as “sequestration”, by
which many self-antigens are normally kept apart from the immune system. It also leads to
the attraction of nonspecific effector cells such as macrophages and neutrophils that respond
to the release of cytokines and chemokines from injured tissues. Because of the longer
reaction, chronic inflammation is characterized by the appearance of adaptive immune cells
such as helper T lymphocytes too. The dominant cytokine production of helper T cells (IFNy, IL-17, IL-6) determine the direction of further reactions, generating Th1, Th2 and Th17
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responses. The processes of chronic inflammation can be found in detail in the material of
week 5.
The result is a continuing and evolving self-destructive process. The transition to the
chronic stage is usually accompanied by an extension of the autoimmune response to new
epitopes on the initiating autoantigen, and to new autoantigens. This phenomenon is known as
epitope spreading and is important in perpetuating and amplifying the disease.
Molecular mimicry: Infectious microbes may contain antigens that cross-react with selfantigens, so immune responses to the microbes may result in reactions against self-antigens.
This phenomenon is called molecular mimicry since the antigens of the microbe cross-react
with, or mimic self-antigens. One example of an immunologic cross-reaction between
microbial and self-antigens is rheumatic fever, which develops after streptococcal infections
and is caused by anti-streptococcal antibodies that cross-react with myocardial proteins. These
antibodies are deposited in the heart and cause myocarditis.
Focal infection: Focal infection was described as a localized or generalized infection caused
by bacteria or their toxins travelling through the blood stream from a distant focus of
infection. A focus of infection may be described as a circumscribed area of tissue infected
with pathogenic organisms. Foci may be primary or secondary. Primary foci usually are
located in tissues communicating with a mucous or cutaneous surface. Secondary foci are the
direct result of infections from other foci through contiguous tissues, or at a distance through
the blood stream or lymph channels. Primary foci of infection may be located anywhere in the
body.
The classically accepted mechanisms of focal infection:
1. Bacteria may be discharged from the focus into a free surface whence, conveyed by
mechanical means, they determine an extension of the disease by reinoculation.
2. Bacteria may be conveyed to distant parts of the body by way of the lymphatics or the
blood stream. They may be arrested in the nearest lymph nodes, leading to
lymphadenitis or even to abscess formation.
3. Products of bacterial metabolism may reach and damage remote parts of the body.
4. Bacteria at the focus may undergo dissolution. Dissolution’s products diffusing into
the blood or lymph may sensitize various tissues of the body in an allergic sense, and
later liberation of dissolution products may result in an allergic reaction.
Focal infection is very important to the Dentists due to two reasons: i) it is an
independent pathogenic influence within the body; and ii) it is a source of localized stress.
The pathogenesis of focal diseases has been classically attributed to dental pulp pathologies
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and periapical infections. Periodontal pathogens and their products, as well as inflammatory
mediators produced in periodontal tissues, might enter the bloodstream, causing systemic
effects and/or contributing to systemic diseases. On the basis of this mechanism, chronic
periodontitis has been suggested as a risk factor for cardiovascular or autoimmune diseases
such as diabetes mellitus or rheumatoid arthritis. For example, high levels of antibodies
against periodontal bacteria have been found in the synovial fluid of rheumatoid arthritis
patients, and a number of periodontal pathogens have been also identified in the synovial fluid
of patients with rheumatoid arthritis. Clinical studies have also indicated a plausible
association between periodontitis or tooth loss and rheumatoid arthritis, hypothesizing the
possibility of a common genetic trait predisposing to both conditions that are associated to the
destruction of bone mediated by inflammatory cytokines. Therefore, periodontitis may be a
causal factor in the pathogenesis of rheumatoid arthritis and vice versa. The association
between diabetes and chronic periodontitis is also well known. Several studies indicated that
diabetes is associated with an increased prevalence, extent and severity of chronic
periodontitis. Moreover, chronic periodontitis may have a significant impact on the metabolic
state of diabetes. Systemic inflammation caused by chronic periodontitis increases insulin
resistance and makes it difficult for patients to control blood glucose levels. Periodontal
treatment, leading to a reduction of gingival tissue inflammation may help in obtaining
reduction of systemic inflammation, thereby improving glycaemic control.
The use of antibiotics (Amoxicillin, Clindamycin, Azithromycin) as prophylaxis for
focal infection is common practice, and has been widely accepted in the dental therapeutic
routines. The paradigm of this model of treatment is the prevention of bacterial endocarditis,
indicated in risk patients in the context of any invasive procedure within the oral cavity.
Antibiotic prescription is almost invariably associated with the prescription of nonsteroidal
anti-inflammatory drugs (NSAIDs). There are many potential interactions between these two
drug categories. The most common situation is an NSAID-mediated reduction of antibiotic
bioavailability and thus effect, but some combinations of drugs such as cephalosporins and
ibuprofen, or tetracyclines with naproxen or diclofenac, have been shown to exert the opposite
effect and can cause an increase in the bioavailability of the antibiotic.
 Role of microbiota in autoimmunity:
Oral microbiota: The oral microbial community is one of the most diverse in the human
body, including over 700 different species of bacteria and some species of fungi. Both
mutualistic and pathogenic microbes reside in the mouth. Pathogens often exist on pellicile,
coating the dental tissues (enamel, dentin, and cementum) and forming a complex matrix, or
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biofilm, more commonly known as dental plaque. These pathogens primarily affect the teeth,
causing dental caries, also known as tooth decay. In 1 mm3 of dental plaque weighing
approximately 1 mg, more than 108 bacteria are present. The modification of the
environmental conditions or the accumulation of dental plaque can cause periodontal diseases
such as gingivitis or periodontitis. Gingivitis is an inflammation of the gingiva around the
teeth which does not cause loss of periodontal attachment, while periodontitis is characterized
by the periodontal ligament detachment from the cement, with consequent formation of
periodontal pockets, alveolar bone resorption, gingival recession, tooth migration,
development of diastemas between the teeth, teeth mobility, abscesses and tooth loss.
Gingivitis is a reversible event and, when treated with proper oral hygiene, the prognosis is
good, otherwise it can progress in periodontitis. The progression from gingivitis to
periodontitis is characterized by periodontal pocket development, which favors further plaque
accumulation and a shift in its qualitative composition. Periodontitis is associated mostly with
various bacteria such as Porphyromonas gingivalis, Prevotella intermedia, Treponema
denticola or Tannerella forsythensis. These periodontal pathogens, as well as their toxins,
such as cytolitic enzymes and lypopolisaccharide (LPS) may invade the blood stream through
the compromised and/or ulcerated epithelium of the periodontal pocket. Moreover, within the
inflamed gingival tissue a number of inflammatory mediators, such as TNF-α, IL-1β,
prostaglandin E2, and IFN-γ are produced which can also enter the blood stream and
contribute to the global inflammatory burden. Porphyromonas gingivalis, most known for
causing periodontitis, or chronic inflammation of the gingiva, has also been shown to
exacerbate rheumatoid arthritis. Based on these evidences we can propose that the oral
mucosa, particularly the periodontal region, may be an initiating site of the autoimmune
responses.
Gut microbiota: During homeostasis, the gut microbiota has important roles in the
development of intestinal immunity. Beneficial subsets of commensal bacteria tend to have
anti-inflammatory activities. Pathobionts that are colitogenic are directly suppressed by
beneficial commensal bacteria partly through the induction of regulatory immune responses,
involving regulatory T cells and anti-inflammatory IL-10 cytokine. In inflammatory bowel
disease (IBD) a combination of genetic factors (for example, mutations in nucleotide-binding
oligomerization domain 2, or IL-23 receptor) and environmental factors (such as infection,
stress and diet) result in disruption of the microbial community structure, a process termed
dysbiosis. Dysbiosis results in a loss of protective bacteria and/or in the accumulation of
colitogenic pathobionts, which leads to chronic inflammation involving hyperactivation of
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Th1 and Th17 cells. Induced Th17 cells can promote autoimmune rheumatoid arthritis by
facilitating autoantibody production by B cells. When cytokines (IL-17, IL-22) derived from
Th17 cells are overproduced, they may spill into the systemic circulation. This may promote
inflammatory diseases in distal sites, such as the joints, perhaps through action upon jointresident lymphoid cell populations. Altered sensitivity to IL-23 may predispose people to
develop rheumatic diseases, such as ankylosing spondylitis.
 Drugs and toxins can cause autoimmune syndromes:
Perhaps some of the clearest evidence of external causative agents in human
autoimmunity comes from the effects of certain drugs, which elicit autoimmune reactions as
side effects in a small proportion of patients. Procainamide, a drug used to treat heart
arrhythmias, is particularly notable for inducing autoantibodies similar to those in SLE,
although these are rarely pathogenic. Several drugs are associated with the development of
autoimmune hemolytic anemia, in which autoantibodies against surface components of red
blood cells attack and destroy these cells. Toxins in the environment can also cause
autoimmunity. When heavy metals, such as gold or mercury, are administered to genetically
susceptible strains of mice, a predictable autoimmune syndrome, including the production of
autoantibodies, ensues. The extent to which heavy metals promote autoimmunity in humans is
debatable, but the animal models clearly show that environmental factors such as toxins could
have key roles in certain syndromes. The mechanisms by which drugs and toxins cause
autoimmunity are that they react chemically with self-proteins and form derivatives that the
immune system recognizes as foreign. The immune response to these haptenated self-proteins
can lead to inflammation, complement deposition, destruction of tissue, and finally immune
responses to the original underivatized self-proteins.
 Smoking can trigger the symptoms of autoimmune diseases:
The habit of smoking tobacco is a non-genetic factor that damages the mucosa of the
airways and exacerbates many diseases. All patients with Goodpasture’s syndrome develop
glomerulonephritis, but only those who habitually smoke cigarettes develop additional
pulmonary hemorrhage. In nonsmokers, the basement membranes of lung alveoli are
inaccessible to antibodies, and hence neither deposition of antibody nor disruption of the
tissue occurs. Alveoli in the lungs of smokers are chronically damaged from their daily
exposure to cigarette smoke. This lack of integrity gives circulating antibodies access to the
basement membranes, where deposition of immune complexes activates complement, causing
blood vessels to burst and hemorrhage.
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Smoking is the major environmental factor associated with rheumatoid arthritis. This
effect, however, is only seen for the subset of patients who have antibodies against
citrullinated self-proteins. Thus smoking, HLA-DR4, and an immune response to citrullinated
proteins are all tied together in the same disease-causing mechanism. A working model is that
the damage caused by smoking induces the expression of peptidyl-arginine deiminases (PAD)
enzyme in the respiratory tract, and that this stimulates an autoimmune response to
citrullinated self-proteins. This immune response is not immediately destined to attack the
joints, consistent with observations that antibodies against citrullinated self-proteins appear
years before the symptoms of arthritis. The joints are attacked later, when some independent
trauma such as a wound or an infection induces a state of inflammation in the joint and the
activation of PAD. In these circumstances, effector and memory lymphocytes specific for
citrullinated self-proteins enter the inflamed joint tissue and respond to their specific antigens.
The actions of effector T cells and the deposition of immune complexes exacerbate the
inflammation and lead to the symptoms of rheumatoid arthritis.
 Role of hormones in autoimmunity:
Many autoimmune diseases have a higher incidence in women than in men. For
instance, SLE affects women about 10 times more frequently than men. Conservative
estimates indicate that nearly 80% of individuals with autoimmune diseases are women. This
female predominance results from the influence of sex hormones or other gender related
factors. Sex hormones circulate throughout the body and alter the immune response by
influencing gene expression. In general, estrogen can trigger autoimmunity and testosterone
can protect against it. In addition women produce a higher titer of antibodies, have higher
number of CD4+ T cells and higher level of serum IgM, and display a more vigorous and
more Th1-dominated immune responses than men which factors can promote autoimmune
responses.
4.
Effector mechanisms of autoimmune responses
Various effector mechanisms are responsible for tissue injury in different autoimmune
diseases. Like hypersensitivity reactions described in week 12, autoimmune diseases can be
classified according to the effector mechanism causing the disease. It is important to note that
there is no autoimmune disease which is mediated by IgE, the cause of type I hypersensitivity
reactions. So based on this observation three kinds of autoimmune diseases are distinguished,
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and their effector mechanisms correspond to the effector mechanisms of type II, type III, and
type IV hypersensitivities:
 autoimmune diseases corresponding to type II hypersensitivity are mediated by antibodies
directed against components of cell surfaces or the extracellular matrix:
-in Autoimmune hemolytic anemia, autoantibodies bind to components of the erythrocyte
surface, where they activate the complement system via the classical pathway. This leads
to assembly of the membrane-attack complex and hemolysis.
-in Myasthenia gravis, autoantibodies bind to acetylcholine receptors and inhibit
acetylcholine binding so downregulate the normal receptor functions. This leads to
impaired neuromuscular junction function and hence muscle weakness.
-in Graves’ disease, autoantibodies bind to TSH receptors and stimulate the receptor
functions and activate thyroid hormone production. This leads to hyperthyroidism,
 autoimmune diseases corresponding to type III hypersensitivity are mediated by soluble
immune complexes deposited in tissues:
-in SLE, autoantibodies bind to DNA, histones and other nuclear proteins and form
immune
complexes
deposited
in
kidney,
blood
vessels,
or
joints
causing
glomerulonephritis, vasculitis or arthritis.
 autoimmune diseases corresponding to type IV hypersensitivity are mediated by effector T
cells:
-in Insulin-dependent diabetes mellitus, cytotoxic T cells destroy insulin-producing βcells in pancreas and cause tissue destruction and insulin deficiency
Since the effector mechanisms of autoimmune responses resemble those causing certain
hypersensitivity reactions, we do not detail these here; instead, these mechanisms were
discussed in the material of week 12.
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WEEK 14.: AUTOIMMUNITY II.
1. Classification of Autoimmune diseases
We have already discussed that autoimmune diseases can be classified according to the
effector mechanism causing the disease. Therefore, autoimmune diseases are classified as
type II, III and IV since their tissue-damaging effects are similar to those of hypersensitivity
reactions types II, III and IV respectively. The effector mechanisms of type II are mediated by
autoantibodies against cell-surface or matrix autoantigens whereas type III mediated by
immune-complexes and type IV regulated by T cells. However, from a clinical perspective it
is often useful to distinguish between the following two major patterns of autoimmune
disease: the diseases in which the expression of autoimmunity is restricted to specific organs
of the body, known as organ-specific autoimmune diseases; and those in which many tissues
of the body are affected, the systemic autoimmune diseases. In both types of autoimmunity,
the disease has a tendency to become chronic since, with a few notable exceptions (for
example type 1 diabetes or Hashimoto's thyroiditis), the autoantigens are never cleared from
the body. In organ-specific diseases, autoantigens from one or a few organs only are targeted.
Examples of organ-specific autoimmune diseases are Hashimoto's thyroiditis affecting the
thyroid gland, and type 1 diabetes, which is caused by immune attack on insulin-producing
pancreatic β-cells. Examples of systemic autoimmune disease are SLE and primary Sjögren's
syndrome, in which tissues as diverse as the skin, kidneys, and brain may all be affected.
In the following table a selection of autoimmune diseases were collected indicating the
autoantigens associated with the immune responses, the symptoms, and the classification’s
systems of the diseases. Autoimmune diseases can be grouped in the same way as
hypersensitivity reactions, according to the predominant type of immune response. But in
many autoimmune diseases, several immunopathogenic mechanisms operate in parallel. This
is illustrated here in a separate category, namely „Complex mechanisms” for autoimmune
diseases displaying multiple immunopathogenic mechanisms.
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Autoimmune
disease
Autoantigen
Organ(s)
affected
Consequences
Antibody against cell-surface or matrix antigen type (II)
Autoimmune hemolytic
anemia
Rh blood group antigens, I
antigen
Systemic
Destruction of red blood
cells by complement and
phagocytes, anemia
Autoimmune
thrombocytopenic
purpura (ITP)
Platelet integrin gpIIb:IIIa
Systemic
Abnormal bleeding
Goodpasture’s
syndrome
Non-collagenous domain
of basement membrane
collagen type IV
Kidney, Lung
Glomerulonephritis,
pulmonary hemorrhage
Pemphigus vulgaris
Desmoglein
Skin
Blistering of skin
Pemphigus foliaceus
Desmoglein
Skin
Mild blistering of skin
Streptococcal cell wall
antigens
Antibodies cross react with
cardiac muscle
Heart, joints
Arthritis, myocarditis, late
scarring of heart valves
Thyroid-stimulating
hormone (TSH) receptor
(agonistic autoantibody)
Thyroid gland
Hyperthyroidism
Myastenia gravis
Acetylcholine receptor
(antagonistic autoantibody)
Neuromuscular
junction
Progressive weakness
Type 2 diabetes
(insulin-resistant
diabetes)
Insulin receptor
(antagonistic autoantibody)
Systemic
Hyperglycemia, ketoacidosis
Hypoglycemia
Insulin receptor (agonistic
autoantibody)
Systemic
Hypoglycemia
Acute rheumatic fever
Graves’ disease
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Autoimmune
disease
Autoantigen
Organ(s)
affected
Consequences
Immun- complex diseases (type III)
Subacute bacterial
endocarditis
Bacterial antigen
Kidney
Glomerulonephritis
Mixed essential
cryoglobulinemia
Rheumatoid factor
IgG complexes
(with or without
hepatitis C antigens)
Blood vessels
Systemic vasculitis
DNA, histones,
ribosomes, snRNP,
ScRNP
Systemic
Glomerulonephritis, vasculitis,
arthritis, rash
Systemic lupus
erythematosus
T-cell mediated disease (type IV)
Type1 diabetes (insulindependent diabetes
mellitus)
Pancreatic β- cell
antigen
Pancreas
Insulin deficiency
Celiac disease
Tissue
transglutaminase,
gluten-derived
peptides
Small intestines
Reduced absorption of nutrients,
diarrhea, stomach pain
Multiple sclerosis
Myelin basic protein,
proteolipid protein
Brain, Spinal
cord
Brain degeneration, muscle
weakness, paralysis, other
symptoms
Sjögren’s syndrome
Salivary protein-1, Ro
(SSA), La (SSB)
Systemic
Dry mouth, dry eyes, swelling of
salivary glands
Complex mechanisms
APECED
Numerous
Mucocutanous candidiasis,
Mostly endocrine
Gastrointestinal manifestations,
tissues
Dental enamel dysplasia
Behçet's disease
Alpha-enolase,
Kinectin,
Tropomyosin
Multi-organ,
blood vessels
Recurrent oral aphthous
ulcers, genital ulcer, uveitis
Hashimoto’s thyroiditis
Thyroid tissue
Thyroid gland
Hypothyroidism
Unknown synovial
antigen
Systemic
Joint inflammation and
destruction
Rheumatoid arthritis
15
2. Examples for Autoimmune diseases displaying oral symptoms
Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APACED)
Etiopathogensis: The AIRE gene is defective in patients with a rare inherited form of
autoimmunity, namely APECED that leads to the destruction of multiple endocrine tissues,
including insulin-producing pancreatic islets. Defective alleles of the AIRE gene are
infrequent worldwide, they are sufficiently common in some populations—Finns, Sardinians,
and Iranian Jews—for some children to inherit two defective alleles. For these infants, the
normal array of tissue-specific proteins is not expressed in the thymus and hence negative
selection of the T cell repertoire is incomplete causing autoimmune reactions in various
tissues.
Symptoms: When B and T cell responses are directed against endocrine glands this
cause mostly hypoparathyroidism and adrenal or ovarian failures. Usually the first sign of the
syndrome
is
chronic
Candida
albicans
infection,
followed
by
autoimmune
hypoparathyroidism and Addison's disease. Hypoparathyroidism, appearing within the first
decade of life, is the most frequent, and sometimes the only, endocrine disease seen in
APECED patients. Hypoparathyroidism is often followed by adrenocortical insufficiency,
with an age at onset of about 4–12 years but in several cases it may appear at 20 years of age.
Premature ovarian failure in females is far more common than primary testicular failure in
males. Ectodermal skin diseases, alopecia, as patchy loss of hair, and vitiligo, as pigment-free
skin areas, have been reported in approximately 40% and 25% of patients.
The ectodermal dystrophy also manifests itself as abnormalities of teeth, hair, and
fingernails. In these patients linear or reticular brown areas or spots and pitted, irregular
tooth enamel can be observed indicating the symptoms of dental enamel hypoplasia. Despite
the range and severity of their symptoms, patients with APECED have substantial life-spans;
the most life-threatening complications are squamous-cell carcinoma and fulminant
autoimmune hepatitis. Persistent Candida infection is the only symptom of disease that is
common to all APECED patients. Candida infection usually starts already within the first two
years of life and appears in more chronic cases as oral thrush. Several cases of oral carcinoma
have been reported, suggesting that oral candidiasis might be (at least pre-) carcinogenic.
Type 1 diabetes, hypophyseal failure, and autoimmune thyroid disease deserve to be
mentioned as less common disease components of the syndrome.
16
Therapy: Hormone replacement is used to treat endocrine disorders. A long course of
oral systemic antifungal treatment is effective to treat candidiasis, although some patients
remain resistant. Immunosuppressive treatment is recommended for cases with autoimmune
hepatitis or with severe squamous-cell carcinoma.
Pemphigus vulgaris
Etiopathogensis: Pemphigus vulgaris and the milder variant pemphigus foliaceus are
autoimmune conditions characterized by blistering of the skin. “Pemphigus” is derived from
the Latin word for blister, and “vulgaris” means common or ordinary. Patients with this
disease have IgG autoantibodies against different type of desmoglein (desmoglein-1, Dsg-1 or
desmoglein-3, Dsg-3), which is a protein component of the desmosome one of the
intercellular junctions that link skin cells and other epithelial cells tightly to each other. The
autoantibodies impair this binding and with it the integrity of the skin. Desmogleins are
members of the cadherin family of cell adhesion molecules, proteins that effect intercellular
adhesion in a calcium-dependent manner. Disruption of desmoglein causes blisters to form in
the skin and on the mucous membranes; extensive sloughing of the skin may ensue. The
extracellular (EC) part of desmoglein comprises four structurally similar domains, EC1–EC4,
and a structurally divergent fifth domain, EC5. People first make IgG against epitopes of EC5,
the domain closest to the cell membrane, and these antibodies are not associated with disease.
The onset of pemphigus coincides with the presence of antibodies against the EC1 and EC2
domains. These IgGs bind to cell-surface desmoglein, and cause skin blistering disease when
injected into mice.
Symptoms: Thus the major symptom of pemphigus vulgaris is the development of clear,
soft, and painful (sometimes tender) blisters of various sizes. In addition, the top layer of skin
may detach from the lower layers in response to slight pinching or rubbing, causing it to peel
off in sheets and to leave painful areas of open skin (erosions). Pemphigus vulgaris usually
starts with lesions in the oral and genital mucosa; only later does the skin become involved.
The blisters often first appear in the mouth and soon rupture, forming painful sores (ulcers).
More blisters and ulcers may follow until the entire lining of the mouth is affected, causing
difficulty swallowing, eating, drinking, and brushing teeth. Blisters form in the throat as well.
The voice can become hoarse if they spread to the larynx. In the mucosal stage, only
autoantibodies against certain epitopes on desmoglein-3, Dsg-3 are found, and these
antibodies seem unable to cause skin blistering. Progression to the skin disease is associated
both with epitope spreading within Dsg-3, which gives rise to autoantibodies that can cause
17
deep skin blistering, and to another desmoglein-1, Dsg-1, which is more abundant in the
epidermis. The skin blisters are fragile and can easily burst open, leaving areas of raw
unhealed skin that are very painful and can put you at risk of infections. Dsg-1 is also the
autoantigen in a less severe variant of the disease, pemphigus foliaceus. In that disease, the
autoantibodies first produced against Dsg-1 cause no damage; disease appears only after
autoantibodies are made against epitopes on parts of the protein involved in the adhesion of
epidermal cells.
Therapy:
Treatment
usually
involves
high
doses
of
corticosteroids
or
immunosuppressive drugs which helps stop new blisters forming and allows existing ones to
heal.
Sjögren syndrome
Etiopathogensis: Sjögren's disease is a systemic autoimmune disease in which loss of
salivary gland and lachrymal gland function is associated with hypergammaglobulinemia,
autoantibody production, mild kidney and lung disease and eventually lymphoma. Sjögren's
syndrome involves dry eyes and dry mouth without systemic features that may be either
primary or secondary to another autoimmune disease, such as SLE. While antibodies to Ro
and La ribonucleoproteins are used as diagnostic criteria for Sjögren’s syndrome, this is a
complex heterogeneous disease characterized by a broad spectrum of clinical and serological
manifestations.
Symptoms: The most common symptoms of the disease are dry eyes or a dry mouth
(sometimes both together), and feeling very tired and aching. In addition, Sjögren's syndrome
may cause skin, nose, and vaginal dryness, and may affect other organs of the body, including
the kidneys, blood vessels, lungs, liver, pancreas, peripheral nervous system (distal axonal
sensory motor neuropathy) and brain. Diminished tear production due to lacrimal gland
involvement leads to the destruction of both corneal and bulbar conjunctival epithelium and a
constellation of clinical findings termed keratoconjunctivitis sicca. Patients usually complain
of a burning, sandy, or scratchy sensation under the lids, itchiness, redness, and mild
photophobia. Physical signs include dilation of the bulbar conjunctival vessels, pericorneal
injection, irregularity of the corneal image, and lacrimal gland enlargement. Xerostomia, or
dry mouth, is the result of the decreased production of saliva by the salivary glands. Patients
report difficulty swallowing dry food, inability to speak continuously, changes in sense of
taste, a burning sensation in the mouth, an increase in dental caries, and problems in wearing
complete dentures. Physical examination may show a dry erythematous sticky oral mucosa,
18
poor dentition, scant and cloudy saliva from the major salivary glands, and atrophy of the
filiform papillae on the dorsal tongue. Parotid or major salivary gland enlargement occurs in
60% of primary Sjögren’s syndrome patients. The parotid gland enlargement may be episodic
or chronic, unilateral or bilateral. Dryness of the upper respiratory tract or the oropharynx
causes hoarseness, recurrent bronchitis, and pneumonitis. Loss of exocrine function may also
lead to loss of pancreatic function and hypochlorhydria. Patients may also experience dermal
dryness and loss of vaginal secretions.
Therapy: Current treatments focus on managing the symptoms. Moisture replacement
therapies help relieve dryness and non-steroidal anti-inflammatory drugs (NSAIDs) to control
inflammation. People with severe Sjögren’s syndrome may receive corticosteroids or diseasemodifying anti-rheumatic drugs (DMARDs), which suppress the body’s immune response.
Behcet’s disease
Etiopathogensis: Behcet’s disease, also known as the Silk Road Disease, is a rare
systemic vasculitis disorder of unknown etiology. Behcet’s disease exhibits a diversity of
clinical manifestations, indicating the co-existence of a large number of autoantigens. In fact,
efforts by some research groups have led to the successful identification of some
autoantigens, including some retinal antigens. However, vascular syndromes, which widely
occur during Behcet’s disease progression, made researchers regard vascular endothelial cell
target antigens as important factors in the pathogenesis of Behcet’s disease. Anti-endothelial
cell antibodies (AECAs) have been detected in Behcet’s disease patients and have been
proven to be associated with vasculitis symptoms.
Symptoms: Recurrent attacks of acute inflammation characterize Behcet’s disease.
Frequent oral aphthous ulcers, genital ulcers, skin lesions and ocular lesions are the most
common manifestations. The disease occasionally generates severe manifestations involving
the cardiovascular system, the central nervous system, and the gastrointestinal tract. Behcet’s
disease is classified as a systemic vasculitis associated with significant morbidity and
mortality, particularly in males with early age onset. Children exhibit more frequent perianal
aphthosis and arthralgia, less frequent genital ulcers and vascular involvement and a more
severe course of uveitis. Prognosis for the disease is usually reserved, especially when ocular,
cardiovascular, neurological, and gastrointestinal manifestations appear. Recurrent oral ulcers
represent the earliest disease manifestation in 47–86 % of patients. It may take years for the
other symptoms to appear afterwards, and oral ulcers are observed in all patients during
their clinical course. Lesions have disciform appearance with round and sharp erythematous
19
border, covered with a grayish-white pseudomembrane or a central yellowish fibrinous base
and grow rapidly from a flat ulcer to a deep sore.
Genital ulcers develop in 57–93 % of patients. They are painful and morphologically
resemble oral ulcers, but are larger, deeper, have more irregular margins and heal with white
or pigmented scars. Ocular disease, involving the retina and the uvea, occurs in 30–70 % of
Behcet’s disease patients and is associated with high morbidity. Ocular manifestations also
include iridocyclitis, keratitis, episcleritis, scleritis, vitritis, vitreous hemorrhage, retinal
vasculitis, retinal vein occlusion, retinal neovascularization and optic neuritis. Skin
involvement affects 38–99 % of Behcet’s disease patients. Cutaneous manifestations
commonly include papulopustular (28–96 %) and acne-like lesions. Wounds exhibit a wide
distribution affecting the face, limbs, trunk, and buttocks.
Therapy: The treatment approach depends on the individual patient, severity of disease,
and major organ involvement. The goal of treatment is to reduce discomfort and prevent
serious complications. Topical medication or creams are applied directly to the ulcers and
skin lesions in order to relieve pain and discomfort. Anti-TNF drugs, systemic glucocorticoids
and immunosuppressive drugs are also used as therapy of the disease.
3. Possible treatments for autoimmune diseases
Traditional therapies for autoimmune disease have relied on anti-inflammatory and
immunosuppressive medications that globally dampen immune responses. These agents are
highly effective for many patients; however; long-term treatments with high doses are often
needed to maintain disease control, leaving the patient susceptible to life-threatening
opportunistic infections and long-term risk of malignancy. In addition, the benefits of many of
these drugs are counterbalanced by toxicity and serious side effect profiles. Thus, there has
been an ungent needfor the development of more specific strategies that lower the risk of
systemic immune suppression and improve tolerability.
Current treatments for autoimmune diseases include for examples: non-steroidal antiinflammatory drugs (NSAIDs), corticosteroids, disease-modifying anti-inflammatory or antirheumatic drugs (DMARDs), plasmapheresis, intravenous immunoglobulin therapy (IVIG),
anti-cytokine therapies, inhibition of intracellular-signaling pathways or co-stimulation,
biological inhibitors of T cell or B cell function, induction of regulatory T cells or
hematopoietic stem cell transplantation. New biologic drugs that target specific cells or
20
cytokines involved in the early inflammatory response, have improved efficacy and limited
toxicity.
3.1.Therapies aimed at reducing symptoms by providing non-specific “gross”
suppression of the immune system:
•
Anti-inflammatory drugs: Traditional NSAIDS including aspirin, ibuprofen,
indomethacin, ketoprofen, tolmetin, naproxen and others, are among the most
commonly prescribed pharmaceuticals in the world and are generally used in
scleroderma, arthritis, autoimmune and rheumatic diseases. Non-Steroidal AntiInflammatory Drugs are medications which, as well as having pain-relieving
(analgesic) effects, have the effect of reducing inflammation when used over a period
of time. A newer addition to the NSAID group is celecoxib (Celebrex) which is a
selective COX-2 inhibitor that directly targets COX-2, an enzyme responsible for
inflammation and pain. This selective action provides the benefits of reducing
inflammation without irritating the stomach.
•
Immunosuppressive drugs:
•
Methotrexate is
considered a disease-modifying anti-rheumatic drug
(DMARD). Methotrexate interferes with the production and maintenance of
DNA. This is the most common DMARD used to treat rheumatoid arthritis. It
is not known exactly how methotrexate works in rheumatoid arthritis, but it
can reduce inflammation and slow the progression of the disease.
•
Corticosteroids
(hydrocortisone,
ethamethasoneb,
triamcinolone,
dexamethasone) can be used to induce a remission or reduce the morbidity in
autoimmune diseases. Corticosteroids slow the proliferation of lymphocytes,
induce a transient lymphocytopenia by altering lymphocyte recirculation and
also induce lymphocyte death. The most important immunosuppressive effect
of corticosteroids is on T cell activation, by inhibition of the production of
cytokines and effector molecules. Cyclosporin A blocks signal transduction
mediated by the T cell receptor. This drug inhibits only antigen-activated T
cells while sparing non-activated ones.
•
Plasmapheresis is a very effective method to remove antigen-antibody complexes
from the blood providing a short-term reduction in symptoms.
•
Intravenous immunoglobulin therapy (IVIG): The beneficial effects of IVIG on
autoimmune disease require doses of 1–3 g per kilogram body weight in contrast with
the dose of 0.5 g/kg used for antibody replacement. This high dose is required because
21
IVIG alleviates autoimmune disease by complete saturation of the binding sites for
IgG on all the Fcγ receptors. This prevents the autoantibodies and their complexes
with antigen from engaging effector functions. IVIG has a generally suppressive effect
on immunoglobulin synthesis, therefore the production of autoantibodies is reduced.
IVIG attenuates the function of existing autoantibodies by decreasing their half-life in
the circulation and by preventing them from recruiting effector functions. It prevents B
cells and plasma cells from producing fresh supplies of existing autoantibodies, and it
suppresses the activation of naive autoreactive B cells.
•
Thymectomy is the removal of thymus from patients to decrease the activity of
autoimmune T helper lymphocytes. Thymectomy is most often used in patients with
myasthenia gravis.
3.2.New and more specific therapeutic approaches:
•
Monoclonal Antibody Treatments: Monoclonal antibodies recognize and attach to
specific proteins produced by cells. Each monoclonal antibody recognizes one
particular protein. They work in different ways depending on the protein they are
targeting. The major targets of monoclonal antibody therapy in autoimmunity are
cytokines, co-stimulatory molecules and B cells.
-monoclonal antibody against the TNF-alpha cytokine: Infusion with monoclonal
antibodies specific for TNF-α alleviates the symptoms of rheumatoid arthritis by
eliminating this inflammatory cytokine, which reduces joint swelling and pain. Widely
used anti-TNF-α antibodies are infliximab, a chimeric antibody, and adalimumab, a
human antibody.
-monoclonal antibody against the IL-6 cytokine receptor: Tocilizumab is a
recombinant monoclonal IgG1 anti-human IL-6 receptor antibody which is often used
in rheumatoid arthritis after treatment failure with anti-TNF. In patients with
rheumatoid arthritis, a high level of IL-6 is present in the blood and in the synovium of
involved joints. Injecting this antibody into the inflamed joints reduced the swelling
and the inflammatory response.
-monoclonal antibody against CTLA-4 molecule: Since co-stimulation is required
for T cell activation, blocking costimulatory pathways is an attractive potential
treatment for auto-immune disease. The chimeric CTLA-4-immunoglobulin combines
the extracellular domain of CTLA-4 with human IgG1. It is a soluble receptor fusion
protein that binds two potent costimulatory ligands on antigen-presenting cells, B7-1
22
and B7-2 (also called CD80 and CD86). Hence, CTLA-4-immunoglobulin inhibits the
ability of these molecules to bind to CD28 blocking the co-stimulation of CD28 on T
cells. Treatment with CTLA-4-immunoglobulin, namely abatacept has been shown to
be effective in both rheumatoid arthritis and psoriatic arthritis and has recently shown
promise in treating type 1 diabetes.
-monoclonal antibody against CD20 molecule: Anti-CD20 monoclonal antibody,
rituximab is also used as a treatment for rheumatoid arthritis. This antibody, which
binds to B cells and makes them targets for NK cell killing, reduces the population of
circulating B cells by 98% and gives major benefit to 80% of patients and some
benefit to another 30%. These clinical results show that antibodies make a significant
contribution to rheumatoid arthritis. As anti-TNF-α and anti-CD20 therapies are
increasingly prescribed, their side-effects, such as reduced resistance to infection, are
being observed and studied.
•
T cell vaccination: With the need to prevent side effects resulting from current
treatments and acquire better clinical remission, development of novel pharmaceutical
tools is extremely urgent. The concept of T cell vaccination (TCV) has been raised
based on the finding that immunization with attenuated autoreactive T cells is capable
of inducing T cell-dependent inhibition of autoimmune responses. TCV may act as an
approach to control unwanted adaptive immune response through eliminating the
autoreactive T cells. Over the past decades, the effect of TCV has been justified in
several animal models of autoimmune diseases including e.g. experimental
autoimmune encephalomyelitis (EAE), murine autoimmune diabetes in non-obese
diabetic (NOD) mice, collagen-induced arthritis (CIA). Meanwhile, clinical trials of
TCV have confirmed the safety and efficacy in corresponding autoimmune diseases
ranging from multiple sclerosis to systemic lupus erythematosus.
•
Peptide Blockade of MHC molecules: The major histocompatibility complex (MHC)
is a principal susceptibility locus for many human autoimmune diseases, in which selftissue antigens providing targets for pathogenic lymphocytes are bound to HLA
molecules encoded by disease-associated alleles. Copaxone (Cop 1) is a random
synthetic amino acid copolymer that reduces the relapse rate by about 30% in
relapsing-remitting multiple sclerosis patients. Its activity involves, as a first step,
binding to class II MHC proteins on the surface of antigen-presenting cell. Cop 1 was
shown to compete with myelin antigens, for activation of specific effector T cells
recognizing peptide epitopes derived from these proteins and/or induction of antigen23
specific regulatory T cells. After completion of phase 3 clinical trials, Cop 1 was
approved as a therapy for multiple sclerosis and is currently in wide use.
•
Oral antigen administration: Oral tolerance is classically defined as the suppression
of immune responses to antigens that have been administered previously by the oral
route. Multiple mechanisms of tolerance are induced by oral antigen. Low doses favor
active suppression, whereas higher doses favor clonal anergy or deletion. Oral antigen
induces anti-inflammatory Th2 and regulatory T cell responses. Oral and nasal
tolerance suppress several animal models of autoimmune diseases including
experimental allergic encephalomyelitis (EAE), uveitis, thyroiditis, myasthenia,
arthritis and diabetes in the non-obese diabetic (NOD) mouse, plus non-autoimmune
diseases such as asthma, atherosclerosis, colitis and stroke. Oral tolerance has been
tested in human autoimmune diseases including multiple sclerosis, arthritis, uveitis
and diabetes. Positive results have been observed in phase II trials and new trials for
arthritis, multiple sclerosis and diabetes are underway. Mucosal tolerance is an
attractive approach for treatment of autoimmune and inflammatory diseases because
of lack of toxicity, ease of administration over time and antigen-specific mechanism of
action. The successful application of oral tolerance for the treatment of human
diseases will depend on dose, developing immune markers to assess immunologic
effects, route (nasal versus oral), formulation, mucosal adjuvants, combination therapy
and early therapy.
•
Stem cell therapy: Cell therapy, pioneered for the treatment of malignancies in the
form of bone marrow transplantation, has subsequently been tested and successfully
employed in autoimmune diseases. Autologous haemopoietic stem cell transplantation
(HSCT) has become a curative option for conditions with very poor prognosis such as
severe forms of scleroderma, multiple sclerosis, and SLE, in which targeted therapies
have little or no effect. Autologous HSCT can re-establish immunological tolerance
leading to an increased number of regulatory T cells which are important in the
preservation of tolerance.
Regulatory T cells, found abnormal in several autoimmune diseases, have been
proposed as central to achieve long-term remissions. However mesenchymal stem
cells (MSC) of bone marrow origin have more recently been shown not only to be able
to differentiate into multiple tissues, but also to exert a potent anti-proliferative effect
that results in the inhibition of immune responses and prolonged survival of
haemopoietic stem cells. MSC derived from the bone marrow of patients with
24
autoimmune disease have consistently been shown to retain their immunosuppressive
activity. Important advantage of these cell therapies that the own (autologous)
haemopoietic or mesenchymal stem cells of the patient have been transplanted so there
is no need to search for a matching stem cell donor. Therefore, the treatment with own
stem cells may present a promising tool for the treatment of patients with autoimmune
syndromes.
Appendix:
1. Examples for autoimmune diseases
Autoimmune hemolytic anemia
Etiopathogenesis: Autoimmunity corresponding to the type II hypersensitivity reaction
frequently targets blood cells. In autoimmune hemolytic anemia, IgG and IgM antibodies bind
to components of the erythrocyte surface, where they activate the complement system via the
classical pathway. This leads to assembly of the membrane-attack complex and the lysis of
red cells. Alternatively, erythrocytes coated with antibody and C3b are cleared from the
circulation, principally by the Fc and complement receptors of phagocytes in the spleen.
These mechanisms induce a deficiency of red blood cells and the condition is called anemia.
White blood cells are also targets for autoantibodies and complement activation. Since
nucleated leukocytes are less susceptible to complement-mediated lysis than erythrocytes, the
main effect of complement fixation on leukocyte surfaces is opsonization. As the opsonized
leukocytes circulate through the spleen they are removed and degraded by the resident
macrophages. For example, patients who develop autoantibodies against neutrophil surface
antigens suffer a deficiency of circulating neutrophils which state is called neutropenia. Lysis
of nucleated cells by complement is less common because these cells are better defended by
complement regulatory proteins, which protect cells against immune attack by interfering
with the activation of complement components and their assembly into a membrane-attack
complex.
Symptoms: The signs and symptoms of hemolytic anemia will depend on the type and
severity of the disease. People who have mild hemolytic anemia often have no signs or
25
symptoms. More severe hemolytic anemia may cause many signs and symptoms, and they
may be serious. The most common symptom of all types of anemia is fatigue (tiredness).
Fatigue occurs because your body doesn't have enough red blood cells to carry oxygen to its
various parts. A low red blood cell count also can cause shortness of breath, dizziness,
headache, coldness in your hands and feet, pale skin, and chest pain. A lack of red blood cells
also means that your heart has to work harder to move oxygen-rich blood through your body.
This can lead to arrhythmias (irregular heartbeats), a heart murmur, an enlarged heart, or even
heart failure. The hemoglobin is broken down into a compound called bilirubin, which gives
the skin and eyes a yellowish color. Bilirubin also causes urine to be dark yellow or brown.
Gallstones or an enlarged spleen may cause pain in the upper abdomen. High levels of
bilirubin and cholesterol (from the breakdown of red blood cells) can form into stones in the
gallbladder.
Therapy: The first-line therapy for this disease is corticosteroids, which are effective in
70–85% of patients and should be slowly tapered over a time period of 6–12 months. For
refractory/relapsed cases, the current sequence of second-line therapy is splenectomy,
rituximab,
and
thereafter
any
of
the
immunosuppressive
drugs
(azathioprine,
cyclophosphamide, cyclosporin, mycophenolate mofetil). Since leukocytes opsonized with
antibody and complement are still functional, after removal of the spleen, opsonized
leukocytes survive longer in the circulation. Additional therapies are the administration of
large quantities of nonspecific intravenous immunoglobulins - which among other
mechanisms inhibits the Fc receptor-mediated uptake of antibody-coated cells - or plasmaexchange.
Goodpasture's syndrome
Etiopathogenesis: Antibody responses to extracellular matrix molecules are infrequent,
but they can be very damaging when they occur. In Goodpasture's syndrome, an example of a
type II hypersensitivity reaction, antibodies are formed against the alpha 3 chain of basement
membrane collagen (type IV collagen). These antibodies bind to the basement membranes of
renal glomeruli and, in some cases, to the basement membranes of pulmonary alveoli, causing
a rapidly fatal disease if untreated. The autoantibodies bound to basement membrane ligate
Fc-gamma receptors, leading to the activation of monocytes, neutrophils, and tissue basophils
and mast cells. These cells then release chemokines that attract a further influx of neutrophils
into glomeruli, causing severe tissue injury. The autoantibodies also cause a local activation
of complement, which may amplify the tissue injury.
26
Symptoms: The targeted basement membranes are essential for the blood-filtering
mechanism of the kidney. The immune system attacks a particular molecule that is found in
the kidney and the lung. It can be both lung and kidney disease, or kidney disease alone, or
(rarely) lung disease alone. Commonly the first lung symptoms develop days, weeks or
months before kidney damage becomes evident, although they may occur at any time. As IgG
and inflammatory cells accumulate, kidney function becomes progressively impaired, leading
to kidney failure and death if not treated. The kidney disease primarily involves the glomeruli
(filtering units). It is usually only recognized when an explosive acceleration of the disease
process occurs, so that kidney function can be lost in days (rapidly progressive
glomerulonephritis, RPGN; also known as crescentic nephritis). Blood leaks into the urine,
the amount of urine passed declines, and fluid and urea and other waste products are retained
in the body. This is renal failure. Renal failure only causes symptoms when 80% or more of
the total function of the kidney has been lost, and at first symptoms may be very vague: loss
of appetite moves on to sickness, and when kidney damaged is advanced, breathlessness, high
blood pressure, and swelling caused by fluid retention. Lung haemorrhage may cause shortage
of oxygen so that intensive care and artificial ventilation are needed. In occasional patients
relatively mild symptoms may go back over many years. Coughing up of blood may be a poor
guide to how severe the lung disease is, but as with the kidney disease, and often at the same
time, deterioration may occur very rapidly. It is often only at this stage that the patient seeks
medical attention. Sometimes patients are anaemic because of bleeding episodes into the
lungs over many weeks or months.
Therapy: Treatment involves plasma exchange to remove existing antibodies, together
with immunosuppressive drugs to stop new ones from being made.
Graves’ diseases
Etiopathogenesis: Graves’ disease is caused by an autoimmune response that affects the
thyroid gland, and is thus an example of an organ-specific or tissue-specific autoimmune
disease. The thyroid is an endocrine gland that regulates the basal metabolic rate of the body
through the secretion of two related hormones, tri-iodothyronine and tetra-iodothyronine
(thyroxine), small iodinated derivatives of the amino acid tyrosine. When increased cellular
metabolism is required, for example when the ambient temperature drops, signals from the
nervous system induce the pituitary, another endocrine gland, to secrete thyroid-stimulating
hormone (TSH). Thyroid epithelial cells express receptors that bind TSH, which induces the
production and secretion of thyroid hormones. The hormones induce cellular metabolism that
27
raises the body temperature. This in turns feeds back to the pituitary and shuts down further
release of TSH. Graves’ disease is caused by agonistic autoantibodies specific for the TSH
receptor. By mimicking the natural ligand, the antibodies bound to the TSH receptor cause
chronic overproduction of thyroid hormones that is independent of regulation by TSH and
insensitive to the metabolic needs of the body.
Symptoms: This hyperthyroid condition causes heat intolerance, nervousness,
irritability, warm moist skin, weight loss, and enlargement of the thyroid. Other aspects of
Graves’ disease are outwardly bulging eyes and a characteristic stare (called exophthalmus).
This condition, called Graves’ ophthalmopathy, is due to autoantibodies that bind to the eye
muscles. These antibodies were made against a thyroid protein and they cross-react with an
eye-muscle protein.
Therapy: Short-term treatment for Graves’ disease is provided by methimazole and
propylthiouracil. These drugs inhibit the production of thyroid hormones by reducing the
uptake of iodine by the thyroid. In the long term, the disease is treated by completely stopping
thyroid function, either by surgical removal of the gland or by its irradiation on administration
of the radioactive iodine isotope. Thyroid function is then replaced by daily doses of synthetic
thyroid hormones.
Myasthenia gravis
Etiopathogensis: Myasthenia gravis is an autoimmune disease in which signaling from
nerve to muscle across the neuromuscular junction is impaired. Antagonistic autoantibodies
bind to the acetylcholine receptors on muscle cells, inducing their endocytosis and
intracellular degradation in lysosomes. The loss of cell-surface acetylcholine receptors makes
the muscle less sensitive to neuronal stimulation.
Symptoms: Patients with myasthenia gravis suffer progressive muscle weakening as
levels of autoantibody rise; the name of the disease means severe (‘gravis’) muscle (‘myo’)
weakness (‘asthenia’). Early symptoms of the disease are droopy eyelids and double vision.
With time, other facial muscles weaken and similar effects on chest muscles impair breathing.
This makes patients susceptible to respiratory infections and can even cause death.
Therapy: Treatment for myasthenia gravis is the drug pyridostigmine, an inhibitor of
the enzyme cholinesterase, which degrades acetylcholine. By preventing acetylcholine
degradation, pyridostigmine increases the capacity of acetylcholine to compete with the
autoantibodies
for
the
receptors.
During
28
crises
of
severe
muscle
weakening,
immunosuppressive drugs, principally azathioprine but also others, are used to inhibit
production of the autoantibodies.
Systemic lupus erythematosus (SLE)
Etiopathogensis: Systemic lupus erythematosus (SLE) is a disease in which IgG is
made against a wide range of cell-surface and intracellular self-antigens that are common to
many cell types. The immune complexes formed by these antigens and antibodies are
deposited in various tissues, where they cause inflammatory reactions resembling type III
hypersensitivity reactions. The main self-antigens are three types of intracellular
nucleoprotein particles: the nucleosome subunits of chromatin, the spliceosome, and a small
cytoplasmic ribonucleoprotein complex containing two proteins known as Ro and La (named
after the first two letters of the surnames of the two patients in whom autoantibodies against
these proteins were discovered). For these autoantigens to participate in immune-complex
formation, they must become extracellular. SLE can also be attributed to the failure to clear
immune complexes. The autoantigens are derived from dead and dying cells and are released
from injured tissues. Thus large quantities of antigen are available, therefore large amounts of
small immune complexes are produced continuously and are deposited in the walls of small
blood vessels in the renal glomerulus, in glomerular basement membrane, in joints, and in
other organs causing the symptoms of SLE.
Symptoms: The deposits of the immune complexes can cause glomerulonephritis in the
kidneys, arthritis in the joints, and a butterfly-shaped skin rash on the face, which gave the
disease its name. Since the rash, or erythema, gives the face an appearance of a wolf’s head
(lupus is Latin for wolf) the disease was first described clinically as “lupus erythematosus”.
Later, with appreciation of its systemic nature, the name was expanded to “systemic lupus
erythematosus”. The disease presents in diverse ways, with only a proportion of patients
getting the facial rash. SLE can be a very severe disease, in which the unwanted reactions of
autoimmunity stimulate further autoimmunity that sends the immune system careering down a
path of ever-increasing and uncontrolled destruction.
Therapy: While there is no cure for lupus, early diagnosis and treatment can help in
managing the symptoms and lessening the chance of permanent damage to organs or tissues.
The goal of treatment is to ease symptoms. Treatment can vary depending on how severe the
symptoms are and which parts of the body affects. Mild forms of the disease can be treated
with non-steroidal anti-inflammatory drugs (NSAIDs) which are helpful in reducing
inflammation and pain in muscles, joints, and other tissues. Low doses of corticosteroids, such
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as prednisone are very effective for skin and arthritis symptoms as well as some corticosteroid
creams for skin rashes. Interestingly, hydroxychloroquine (Plaquenil) is an antimalarial
medication found to be particularly effective for SLE people with fatigue, skin involvement,
and joint disease. Treatments for more severe SLE displaying major organ manifestations may
include high-dose corticosteroids and consider immunosuppressive agents (eg, azathioprine,
mycophenolate mofetil, methotrexate).
Type 1 diabetes or insulin-dependent diabetes mellitus (IDDM)
Etiopathogensis: Type 1 diabetes, also called insulin-dependent diabetes mellitus
(IDDM) or juvenile-onset diabetes, is caused by the selective autoimmune destruction of the
insulin-producing cells of the pancreas. The pancreas contains about half a million islets, each
consisting of a few hundred cells. Each islet cell is programmed to make a single hormone: α
cells make glucagon, β cells make insulin, and δ cells make somatostatin. In patients with
type 1 diabetes, autoantibody and T cell responses are made against insulin, glutamic acid
decarboxylase, and other specialized proteins of the pancreatic β cell. Which responses cause
the disease remains uncertain. Antigen-specific CD8+ T cells are believed to mediate β cell
destruction, gradually reducing the number of insulin-secreting cells. Individual islets become
successively infiltrated with lymphocytes, a process called insulitis. The β cells comprise
about two-thirds of the islet cells; as they die, the architecture of the islet degenerates. A
healthy person has about 108 β-cells, providing insulin-making capacity much greater than the
body needs. Because of this excess, and the low rate of β-cell destruction, disease symptoms
do not manifest until years after the autoimmune response begins. Disease commences when
there are insufficient β-cells to provide the insulin necessary to control the level of blood
glucose.
Symptoms: The following symptoms may be the first signs of type 1 diabetes or they
may occur when blood sugar is high: being very thirsty, feeling hungry, feeling tired all the
time, having blurry eyesight, feeling numbness or tingling in feet, losing weight, urinating
more often. Without treatment, the glucose level becomes very high and acids form in the
bloodstream (ketoacidosis). If this persists patients will become dehydrated and are likely to
lapse into a coma and die.
Therapy: For patients with type 1 diabetes, the usual treatment is daily injection with
synthetic human insulin.
Hashimoto's thyroiditis
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Etiopathogensis: The CD4+ Th2 response that mediates Graves’ disease produces little
inflammation or lymphocytic infiltration of the thyroid tissue, which retains its normal
morphology. By contrast, chronic thyroiditis, also called Hashimoto’s disease, is caused by a
CD4+ Th1 response, which produces both antibodies and effector CD4+ T cells that are
specific for thyroid antigens. Targets for the autoantibodies are the proteins thyroglobulin,
thyroid peroxidase, the TSH receptor, and the thyroid iodide transporter, all of which are
uniquely expressed in thyroid cells. Lymphocytes infiltrate the thyroid, causing a progressive
destruction of the normal thyroid tissue and a corresponding loss of the capacity to make
thyroid hormones. A characteristic feature of Hashimoto’s disease is that the lymphocytes and
other cells infiltrating the thyroid gland become organized into structures resembling the
typical microanatomy of secondary lymphoid organs. These structures, called ectopic
lymphoid tissues or tertiary lymphoid organs, contain T cell and B cell areas, dendritic cells,
follicular dendritic cells, and macrophages. The process by which they form, termed lymphoid
neogenesis, resembles the formation of secondary lymphoid tissues and is similarly driven by
lymphotoxin. Unlike a lymph node, the ectopic lymphoid tissue is not encapsulated, lacks
lymphatics, and is exposed to the inflammatory environment of the autoimmune response.
Ectopic lymphoid tissue also functions like a secondary lymphoid tissue. Within the organized
structure, B cells and T cells are stimulated by antigen to give effector cells, and in germinal
center reactions B cells undergo isotype switching and somatic hypermutation to produce
plasma cells making high-affinity autoantibodies.
Symptoms: Hashimoto's thyroiditis is the most common cause of hypothyroidism
because it impairs the thyroid's ability to produce adequate amounts of thyroid hormone.
Without enough thyroid hormone the followings are the typical symptoms: fatigue, weight
gain, increased sensitivity to cold, dry skin, nails, and hair, constipation, drowsiness, muscle
soreness and increased menstrual flow.
Therapy: Treatment for Hashimoto’s disease is replacement therapy with synthetic
thyroid hormones taken orally on a daily basis.
Rheumatoid arthritis (RA)
Etiopathogensis: Rheumatoid arthritis is the most common rheumatic disease. The
disease involves chronic and episodic inflammation of the joints, usually starting between 20
and 40 years of age. Some 80% of patients with rheumatoid arthritis make IgM, IgG, and IgA
antibodies specific for the Fc region of human IgG - rheumatoid factor is the name given to
these anti-immunoglobulin autoantibodies. The synovium of an arthritic joint is infiltrated
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with leukocytes. These include neutrophils, macrophages, CD4+ and CD8+ T cells, B cells,
lymphoblasts, and plasma cells producing rheumatoid factor. Prostaglandins and leukotrienes
are the major mediators of the inflammation. Neutrophils also release lysosomal enzymes into
the synovial space, causing tissue damage and inducing proliferation of the synovium.
Dendritic cells activate autoimmune CD4+ T cells, and they in turn activate macrophages. The
activated macrophages accumulate in the inflamed synovium, where they secrete
inflammatory cytokines that recruit additional effector cells into the joints, all of which adds
to the tissue erosion. Proteinases and collagenases produced by inflammatory cells in a joint
can extend the damage to cartilage, to supporting structures such as ligaments and tendons,
and eventually to the bones. In some patients with rheumatoid arthritis, the autoimmune
response is directed toward self-proteins and self-peptides in which arginine residues were
converted into citrulline residues by inducible enzymes called peptidyl-arginine deiminases
(PAD). Citrullinated proteins provide a source of peptide antigens to which the T cell
repertoire is not tolerant. Presentation of citrullinated self-peptides by MHC class II molecules
could therefore activate specific CD4+ T cells. Citrullination makes proteins more susceptible
to proteolysis, which also enhances their capacity to stimulate an autoimmune response. In
patients with rheumatoid arthritis who produce antibodies against citrullinated epitopes, the
association with HLA-DR4 is strong, but in those who lack such antibodies there is no
association.
Symptoms: Patients with rheumatoid arthritis suffer chronic pain, loss of function, and
disability. In the early stages, people with RA may not initially see redness or swelling in the
joints, but they may experience tenderness and pain. These following joint symptoms are
clues to RA: joint pain, tenderness, swelling or stiffness for six weeks or longer, morning
stiffness for 30 minutes or longer and more than one joint is affected. Along with pain, many
people experience fatigue, loss of appetite and a low-grade fever. High levels of inflammation
can cause problems throughout the body:
•Eyes: dryness, pain, redness, sensitivity to light and impaired vision.
•Mouth: dryness and gum irritation or infection.
•Skin: rheumatoid nodules – small lumps under the skin over bony areas.
•Lungs: inflammation and scarring that can lead to shortness of breath.
•Blood Vessels: inflammation of blood vessels that can lead to damage in the nerves, skin and
other organs.
Therapy: Treatment usually combines physiotherapy with anti-inflammatory and
immunosuppressive drugs. Infusion with monoclonal antibodies specific for TNF-α alleviates
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the symptoms of arthritis by eliminating this inflammatory cytokine, which reduces joint
swelling and pain. For a few patients, anti-TNF-α therapy has terminated their arthritis
disease. Widely used anti-TNF-α antibodies are infliximab, a chimeric antibody, and
adalimumab, a human antibody.
Multiple sclerosis
Etiopathogensis: Multiple sclerosis is an example of a T cell-mediated chronic
neurological disease that is caused by a destructive immune response against several brain
antigens, including myelin basic protein (MBP), proteolipid protein (PLP), and myelin
oligodendrocyte glycoprotein (MOG). It takes its name from the hard (sclerotic) lesions, or
plaques, that develop in the white matter of the central nervous system because autoimmune
effector cells attack the myelin sheath of nerve cells to produce sclerotic plaques of
demyelinated tissue in the white matter of the central nervous system. These lesions show
dissolution of the myelin that normally sheathes nerve cell axons, along with inflammatory
infiltrates of lymphocytes and macrophages, particularly along the blood vessels. The effects
of activated CD4+ Th1 cells and the IFN-γ they secrete are the cause of multiple sclerosis,
which resembles a T cell-mediated type IV hypersensitivity reaction. CD4+ Th1 cells are
enriched in the blood and cerebrospinal fluid. They activate macrophages that release
proteases and cytokines, which cause the demyelination and sclerotic plaque formation.
Symptoms: Patients with multiple sclerosis develop a variety of neurological symptoms,
including muscle weakness, ataxia, impaired vision and blindness, lack of coordination and
paralysis of the limbs. Like SLE, multiple sclerosis is a highly variable disease. It can take a
slow progressive course or it can alternate between acute attacks of exacerbating disease and
periods of gradual recovery. In its extreme form, severe disability or death occurs within a
few years, whereas some patients with mild disease experience little neurological impediment.
Therapy: Disease attacks are treated with high doses of immunosuppressive drugs and
regular subcutaneous injection of IFN-β1 reduces the incidence of disease attacks and the
appearance of plaques.
Celiac disease
Etiopathogensis: Celiac disease is an autoimmune disease caused by an immune
response in the gut lymphoid tissue that damages the intestinal epithelium and reduces the
capacity of those affected to absorb nutrients from their food. The major environmental factor
that determines the onset of celiac disease is dietary gluten. For this reason the condition is
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also called gluten-sensitive enteropathy. Celiac disease is caused by an adaptive immune
response to the proteins of gluten, a major component of grains such as wheat, barley, and
rye, which are dietary staples for some human populations. Moreover all patients with celiac
disease make IgG or IgA autoantibodies specific for tissue transglutaminase. Infiltrating the
lamina propria are CD4 T cells that respond to gluten-derived peptides presented by HLADQ2 or HLA-DQ8 allotypes in the gut-associated lymphoid tissues activate tissue
macrophages, which secrete pro-inflammatory cytokines that induce inflammation and tissue
damage in the small intestine. The intestinal epithelial cells are attacked and destroyed, but
basal membrane is left intact and there are no ulcerations of the tissue.
Symptoms: With persistent intake of gluten, the inflammation becomes chronic and
eventually causes atrophy of the intestinal villi, malabsorption of nutrients, stomach pains and
diarrhea. Children with the disease fail to thrive; adults can become anemic, depressed, and
prone to other diseases, including intestinal cancer.
Therapy: The symptoms of celiac disease disappear when patients adopt a strict glutenfree diet, but quickly come back if they consume gluten again.
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