Beni-Suef University

Faculty of Medicine

Department: Microbiology GROUP

Student ID# Number
Final Grade
(Pass /Fail) 26
1. 09905222201316
2. 29812202201095
3. 29909102201547
4. 29907232201538
5. 29911242200537
Title: Autoimmune diseases
Corresponding student ID: 29905222201316
Student ID# Student Role
1. 29905222201316 - searching and writing about graves'
diease and diagnosis of RA
- writing the introduction
- organization of the word
2. 29812202201095 - searching and writing about the
mechanisms of immunological tolerance
- writing the abstract
3. 29909102201547 - Searching and writing about causes of
autoimmune diseases and pathogenisis of
Rheumatoid arthritis
- writing the conclusion
4. 29907232201538 - searching and writing about treatment of
autoimmune diseases and the pathogenesis
of SLE
- shared in introduction
5. 29911242200537 - searching and writing about the
definition of autoimmune diseases and the
diagnosis of SLE
Date of submission: 3/6/2020
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Title:
Autoimmune diseases
Aims:
The aims of this research are illustration of the meaning of autoimmune
diseases, the mechanism of immunological tolerance, the causes of
autoimmune diseases, and talking about 3 of these diseases in details by
mentioning their pathogenesis and diagnosis, and targeting to know how
we can treat some of these diseases.
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Abstract
Autoimmunity is an adaptive immune response to self-antigens leading to
production of autoantibodies and self-reactive T cells attacking the self-molecule
due to a breakdown of immune tolerance to auto-reactive immune cells which may
causes autoimmune diseases.
Tolerance mechanisms have evolved to distinguish self and non-self, and block the
development of growth, or differentiation of autoreactive lymphocytes.
Immunological tolerance to different autoantigens may be induced when immature
lymphocytes recognize these antigens in the generative (central) lymphoid organs,
a process called central tolerance, or when mature lymphocytes encounter
autoantigens in peripheral (secondary) lymphoid organs or peripheral tissues,
called peripheral tolerance. Tolerance induction and maintenance mechanisms vary
between the B and T cells and the central and peripheral lymphoid. The failure of
that auto-tolerance may result in autoimmune disease.
Factors that evolve into autoimmune disease include genetic predisposition,
structural modification of tissue protein, cross reactivity and breakdown in the
immune network.
Autoimmune disorders are a spectrum of diseases ranging from organ-specific
diseases in which antibodies and T cells respond to self-antigens found in a single
specific tissue (such autoimmune thyroid diseases: Grave’s disease, myxedema and
Hashimoto's disease) to systemic diseases characterized by reactivity to a common
antigen or antigens distributed across the body's various tissues (such that occurs in
SLE and rheumatoid arthritis).
In Rheumatoid arthritis, the pathogenesis of such disease is complex with multiple
genetic, environmental, immunologic, and other factors contributing to the
development and expression of disease. Diagnosis of Rheumatoid arthritis disease
can be done by blood test, imaging tests, ELISA Test and Multiplex
cytofluorimetric test which is more sensitive and specific.
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In Graves' disease, there is a generalized over-activity of the entire thyroid gland

caused by auto-antibodies to TSHR. B-cells and T-cells play an important role in
such cases. Diagnosis of Grave’s disease is done by Physical examinations to the
eye and thyroid gland, blood tests, radioactive iodine uptake, Ultrasound waves
and Imaging tests.
In Systemic lupus erythematosus, it is characterized by the production of
autoreactive antibodies and cytokines. It may be due to genetic or environmental
causes. It ranges from relatively benign disease to rapidly progressive and even
fatal disease. IL-1, Gelatinase B or MMP-9 and antibody play a significant role in
such disease.
Treatment of autoimmune disease includes NSAIDs, Corticosteroids, Disease-
modifying anti-rheumatic drugs (DMARDs), Biologics (A relatively new class of
DMARDs made of synthetic proteins), Intravenous Immunoglobulin,
Plasmapheresis (a process that clears the plasma from autoantibodies) and Surgery
to cope with certain autoimmune disease complications.
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Introduction
Autoimmune diseases mean abnormal responses
done by the immune system to normal body parts and the cause of these responses
is generally unknown. there is common symptoms in different autoimmune
diseases. The severity of these symptoms differ according to the site and the type
of the autoimmune response. The person may suffer from more than one disease at
the same time. Fatigue, low graded fever, malaise, rash on different areas of the
body, and muscle and joints pain.(1)
When immature lymphocytes recognize the auto antigens in central lymphoid
organs, it undergoes central tolerance, but when mature lymphocytes recognize
these antigens in peripheral tissue or lymphoid organs, it undergoes peripheral
tolerance. We classified the mechanism of tolerance into central and peripheral T
and B cells tolerance. In central T cell tolerance, some of the developing T cells are
deleted and the remaining develop into regulatory T cells. In central B cell
tolerance, When immature B cells in the bone marrow encounter auto-antigens
with high avidity, either the B cells change their specificity (receptor editing) or
they are killed (deletion). Self-antigen recognition by mature T cell induce
peripheral tolerance in peripheral tissues, resulting in functional irresponsiveness)
T cell anergy(or death, or make T cells sensitive to suppression by regulatory T
cells. Mature B lymphocytes that recognize self-antigens in peripheral tissues in
the absence of specific T helper cells may become functionally irresponsive or die
by apoptosis.(3)(4)
There is some genetic and environmental causes of these diseases. Till now we
can't isolate the exact genes responsible for these autoimmune diseases, but there is
several experimental methods as the genome-wide association scan are used in
identifying the genetic risk factors. For example, in case of rheumatoid arthritis
there isn't complete genetic mapping, but there is several genes that we think they
have a role in this condition. There is a receptor associated factor located on
chromosome 9q33-34 known as TNF receptor association factor 1 (TRAF1) which
is found in the genes that influence the human immune system and there is an
increased concentration of HLA-DRB1 alleles in B1 gene in the human genome.
Both of them are commonly seen in rheumatoid arthritis patients.(8)
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There is a lot of environmental factors which may

have a direct effect or act as a catalyst in many autoimmune
diseases. About 70% of these disease are due to environmental factors as:
chemicals, diet, and infection. We can find chemicals direct or in for of drugs as
hydrazine, hair dyes, and trichloroethylene. UV may be a possible cause of
dermatomyositis (an autoimmune disease), exposure to pesticides has a role in
development of rheumatoid arthritis, and vitamin D plays a role in preventing
immune dysfunction in older people.(8)
In this research we will discuss in details 3 of the most common autoimmune
disease which are graves' disease, rheumatoid arthritis, and systemic lupus
erythematosis.
Graves' disease is an autoimmune disease which affects thyroid gland leads to an
increase in thyroid hormones secretion which control how our body uses energy. In
this disease, there is formation of antibodies which recognize and activate thyroid-
stimulating hormone receptor, which its function is growth and activation of
thyroid gland to secret its hormones. There is a condition called graves'
ophthalamopathy, at which the patient suffers from retro-orbital inflammation due
to a buildup of certain carbohydrates in the muscles and the tissue behind the eye,
this condition is accompanied with pre-tabial myxedema. We can diagnose this
disease by physical test of the eye to see if there is any inflammation, or by doing
blood test to search for the antibodies, or doing radioactive iodine uptake test.(11)(12)
Rheumatoid arthritis is a non organ specific autoimmune disease which is
associated with systemic complications, progressive disability, and early death.
There is some genetic and environmental factors that play a role in developing the
disease. The risk of developing the disease in monozygotic twins is more than the
risk in the dizygotic twins. One of the causes of the disease is a defect in immune
regulatory factor. some studies on genetic-environmental interaction found that
smoking and other bronchial stress increases the risk of rheumatoid arthritis in
person with HLA-DR4 alleles. Hyperplastic synovium is the cause of cartilage
damage and bone erosion that occur in rheumatoid arthritis patients. Synovial
cytokines promote osteoclast differentiation and invasion of the periosteal surface
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adjacent to articular cartilage. Osteoclasts have the

ability to destroy mineralized cartilage and sub-chondral bone
which lead to deep resorption pits which is filled by inflammatory tissue. It's
difficult to diagnose rheumatoid arthritis as there is no blood or physical tests to
confirm the diagnosis, but doing blood test, imaging test, and ELISA may help in
the diagnosis.(16)
Systemic lupus erythematosis is characterized by production of autoreactive
antibodies and cytokines. One from every 10 females suffers from SLE, in some
cases it's benign, but it can be rapidly progressive and fatal. There's genetic and
environmental causes for the disease as UV radiation causes photosensitive lupus
rash. The genes that causes SLE are located in HLA region on chromosome 6,
where mutation may occur. Diagnosis of SLE is difficult as symptoms vary from
person to another. There is no single test can diagnose SLE but some signs ,
symptoms and tests will help in the diagnosis as CBC, ANA test, urine analysis,
and erythrocyte sedimentation rate. We also can use imaging tests as chest X-ray,
and echocardiogram.(19)(20)

There is a lot of therapies are taken to treat autoimmune diseases. We can use non-
steroidal anti-inflammatory drugs in multi-system autoimmune diseases. And we
can use corticosteroids in the treatment as they have immunosuppressive and anti-
inflammatory effects on both the acquired and innate immunity. Disease-
modifying anti-rheumatic drugs are used in treatment of rheumatoid arthritis.
Intravenous IV immunoglobulin (IVIG) in autoimmune diseases has several
probable mechanisms of action in inflammatory and autoimmune processes
suppression. We can clear the plasma from auto-antibodies and non-specific
inflammatory mediators by a process known by plasmapheresis. In rare cases, to
cope with certain autoimmune disease complications such as intestinal obstruction
in Crohn’s disease or joint damage in juvenile idiopathic arthritis we can do
surgery.(21)
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Review
Definition of autoimmune diseases:
Autoimmunity Is an adaptive immune response to self antigens leading to
production of auto antibodies and self reactive T cells attacking the self molecule
due to a breakdown of immune tolerance to auto-reactive immune cells which may
causes autoimmune diseases.(1) Multiple autoimmune disorders have been strongly
related with Genetic, infectious and/or environmental predisposing factors.
Includes various conditions and signs, from organ-specific to systemic,
autoimmune diseases include insulin-dependent mellitus diabetes, rheumatoid
arthritis, systemic lupus Scleroderma, erythematosus, thyroiditis and multiple
sclerosis. Normally, The immune system represents a complex collection of
Cellular, mechanical, and soluble protein components designed to protect the body
Overseas substances, including infections-Tough agents, and tumor cells, but not
Self-molecules react. Outside or Abroad Self-molecules (usually carbohydrates or
proteins-Drates) which evoke different immune systems Responses are called
antigens. Immune cells are present all over the body .Skin, or discreetly
encapsulated Organs such as spleen and thymus or as diffuse lymphoid and
myeloid cell accumulations as found in combination with the skin and digestive
tract, where they are strategically placed to monitor the entry of foreign
substances . Optimum immune response requires that immune cells and cell
products interact sequentially with each other. The immune system mechanism
depend upon specific recognition molecules present on the surface of immune
competent cells, in particular, T and B lymphocytes.
Tolerance mechanisms have evolved to distinguish self and non-self, and block the
development growth, or differentiation of auto reactive lymphocytes. If the
tolerance is acquired early in life probably in uteri it is auto tolerance.(1)
It occurs through a mechanism of the following three :
A) clonal depletion which requires physical removal of auto reactive lymphocytes;
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b) clonal anergy requiring functional removal of auto

reactive lymphocytes via down-regulation of responsiveness; and
c) suppression or inhibition of auto reactive lymphocytes via association with
other types of cells such as cytotoxic T lymphocytes or NK cells.
The failure of that auto-tolerance may result in autoimmune disease. Autoimmune
disorders are a spectrum of diseases ranging from organ-specific diseases in which
antibodies and T cells respond to self-antigens found in a single specific
tissue(such autoimmune thyroid diseases : Graves' disease, myxedema and
Hashimoto's disease) to systemic diseases characterized by reactivity to a common
antigen or antigens distributed across the body's various tissues (such that occurs in
SLE and rheumatoid arthritis). In organ specific diseases ,Th cytokines, like IL-2
and IFN-y predominate and the effector responses tend to occur via cell-mediated
immune responses such as killing by cytotoxic T cells through the release of
cytokines or through IgG and IgM antibodies directed toward cell-surface antigens,
triggering Fc receptor-mediated killing.
In Systemic autoimmune disorders ,there's an elevation level of Th2 cytokines such
as IL-4, IL-5, and IL-10 and the widespread circulation of auto-antibodies and
immune complex deposition, opsonization with antibody, and cell damage via
complement-mediated lysis.
autoimmunity have been associated with recurrent spontaneous abortion, male &
female infertility, endometriosis, premature ovarian failure, and abnormal sperm
maturation.(2)

Mechanisms of Immunological Tolerance

Immunological tolerance to different auto antigens may be induced when immature
lymphocytes recognize these antigens in the generative (central) lymphoid organs,
a process called central tolerance, or when mature lymphocytes encounter auto
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antigens in peripheral (secondary) lymphoid organs

or peripheral tissues, called peripheral tolerance.(3)
Tolerance induction and maintenance mechanisms vary between the B and T cells
and the central and peripheral lymphoid organs.
Central T cell Tolerance
During their thymus maturation, many developing T cells that encounter antigens
with high affinity are deleted and some of the remaining cells in the CD4+ strain
develop into regulatory T cells.(4)
 Deletion is a mechanism by which self-reactive T cells are eliminated by
undergoing apoptosis. For immature T cells, thymic deletion is the principal
mechanism of negative selection. Thymocytes expressing TCRs that interact
with high avidity with self-antigens–major histocompatibility complex (MHC)
molecule complexes (expressed on thymic dendritic cells and medullary
epithelial cells) undergo rapid deletion, on the other hand Thymocytes that
express TCR with lower avidity for self-peptide-MHC molecule complexes
survive (positive selection).(5)
 Autoimmune regulator (AIRE) protein has a significant role in central T cell
tolerance. It’s responsible for the thymic expression of peripheral tissue
antigens such as those expressed in the pancreas and central nervous system.
Thus, the negative selection of self-reactive T cells unique to self-molecules
produced by peripheral tissues occurs in normal individuals.(3)(5)
 Antigens which induce negative selection may include abundant proteins, such
plasma proteins and common cell proteins.(3)

Central B cell Tolerance

When immature B cells in the bone marrow encounter auto-antigens with high
avidity, either the B cells change their specificity (receptor editing) or they are
killed (deletion).(3)
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 Receptor-editing

Some developing B cells that encounter self-antigens

in the bone marrow undergo a 2nd round of re-arrangement of antigen receptor
genes and then express new receptors that are no longer self-reactive.(6)

 Deletion

If editing fails, developing B lymphocytes that strongly interact with auto-antigens

receive death signals and die by apoptosis.(3)
 Anergy

Some auto-antigens, like soluble proteins, may be identified in the bone marrow
with low affinity. B lymphocytes unique to these antigens survive, but expression
of antigen-receptor is diminished, and the cells become functionally irresponsive
(anergic).(3)
Peripheral T cell Tolerance
Self-antigen recognition by mature T cell induce peripheral tolerance in peripheral
tissues, resulting in functional irresponsiveness) T cell anergy(or death, or make T
cells sensitive to suppression by regulatory T cells.(3)
 Anergy

Exposure of mature CD4+ T cells to an antigen in the absence of co-stimulation or

innate immunity may make the cells incapable of responding to that antigen.
Anergic cells show a block in TCR-induced signal transduction, as in some cases
self-antigen recognition either activate cellular ubiquitin ligases, which
ubiquitinate TCR-associated proteins and target them for proteolytic degradation in
proteasomes or lysosomes, or engage inhibitory receptors of the CD28 family
associated antigen 4 (CTLA-4, or CD152) or (PD-1), whose function is to
terminate T cell responses.(4)
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 Suppression by regulatory T cells

Regulatory T cells are a subdivision of CD4+ T cells
whose function is to suppress immune responses and maintain self-tolerance by
several mechanisms.(4)
I. Production of immunosuppressive cytokines (e.g., TGF-β and IL-10), which
inhibit the activation of dendritic cells, lymphocytes, and macrophages.(3)
II. Expressions of CTLA-4, which may block or remove B7 molecules made by
APCs and make these APCs incapable of providing co-stimulation via CD28
and activating T cells.(3)
III. Other mechanisms of suppression by regulatory T cells that have been
reported include consumption of IL-2, thus reducing the availability of this
essential growth factor for responding lymphocytes, and killing of
responding T cells.(4)
- The development and maintenance of functional CD4 + regulatory T cells require
both IL-2 and FOXP3. (6)
 Deletion by apoptosis
T cells that recognize self-antigens may receive signals that promote their death by
apoptosis. Two mechanisms of deletion of mature T cells have been suggested.
I. If T cells recognize self-antigens, they upregulate Bim, a pro-apoptotic
member of the Bcl-2 family, which induces apoptosis by the mitochondrial
pathway.(6)
II. Repeated activation of T cells results in the co-expression of death receptors
(Fas) and their ligands (FasL), and their interaction (Fas-FasL) induces
apoptotic death.(6)
 Immunological ignorance
Certain self-antigens are sequestered from the immune system, because the tissues
in which these antigens are situated do not communicate with the blood and lymph,
for example, antigens that only present in the eye, testis, and brain (immune
privileged sites). These antigens fail to evoke immune responses.(6)
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Peripheral B cell Tolerance

Mature B lymphocytes that recognize self-antigens
in peripheral tissues in the absence of specific T helper cells may become
functionally irresponsive or die by apoptosis (Fas-FasL interaction).(4)

Causes of Autoimmunity:
- There are more than 100 autoimmune diseases.
Generally they have unknown cause but some run familiarly and in a certain cases,
may triggered by environmental factors or infection such occurs in systemic lupus
erythrematosus .
- Heredity: Certain genes passed down by parents make certain kids vulnerable to
an autoimmune disease.
- External /Environmental factors: An autoimmune disease can not show itself until
something like an infection or exposure to other toxins or medications has caused it
.this including: chemicals, infection, diet, and gut dysbiosis.
- Hormonal factors: Since many autoimmune disorders continue to affect young
women and children, certain female hormones may also play a role in when these
illnesses flare up.(7)
- Genetic predisposition related to specific human leukocytic antigens which are
important in presentation of antigens to T cells may cause autoimmunity.
E.g. systemic lupus erythrematosus with DR3, rheumatoid arthritis with DR4 and
ankylosing spondylitis with B27.
- Exposure of the immune system to antigens normally sequestered within the
organ like sperms and eye lens because the lymphocytes specific to such antigens
were not exposed to them during development so they weren't detected.
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Ex: In the testicular infection the sperm antigens will

release. The immune is triggered and the antibodies
formed and react with testicular tissue and inhibit
spermatogenesis.
- structural modification of tissue proteins by drug or virus so such antigens are no
longer recognized as self antigens.
E. g. Autoimmune hemolytic anemia may be caused by Alfa methyl dopa which is
thought to modify proteins on the surface of red blood cells.
- cross reactivity between the antibodies formed to streptococcal M proteins and
antigens of joints and heart leading to acute rheumatic fever .
- Interference with the mechanisms normally suppress surviving self reactive T
cells.
- self reaction polyclonal activation of lymphocytes by viruses or bacteria.
- Overproduction of IL2 by Th1 cells which breaks down the immune network
causing autoimmune diseases.(1)
- UV radiation is found to be a possible cause of the autoimmune dermatomyositis
disease
- Pesticide exposure plays a part in the development of rheumatoid arthritis
- T-cell activators are considered infectious agents, a step needed to activate
autoimmune diseases.
they are one of the latest hypotheses To describe autoimmune disorders caused by
infection such as Guillain-Barr syndrome and rheumatic fever.(8)
Now we are going to take about 3 diseases of autoimmune diseases which are
graves' disease, rheumatoid arthritis, and systemic lupus erythematosis.
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Graves' disease:
It's an autoimmune disease which causes
hyperthyroidism. In this disease, the immune system attacks thyroid gland causing
more secretion of thyroid hormones, which control how our body uses energy, so
they affect approximately all the body. If we don't treat this disease it can cause a
lot of problems with muscles, bones, eye, heart, and fertility.(9)

Pathogenesis:
- it’s the most common cause of hyperthyroidism in US. It affects about 1 from
every 200 person.
- people at age of 30 to 50 are the most affected by graces' disease.
- the disease is 7 to 8 times more common in women than men.
- if one of the family members suffers from the disease, it increases the chance of
developing graves' disease to other family members.
- people with autoimmune diseases as rheumatoid arthritis, pernicious anemia,
lupus, and vitiligo are more likely to develop the disease.
- the mechanism of the disease:
There is production of thyroid-stimulating antibodies which recognize and activate
thyroid-stimulating hormone receptor, the function of these receptors is stimulating
the growth and the function of follicular cells of thyroid which lead to increase of
production of thyroid hormones (both T3 and T4). There's heterogeneous
lymphatic infiltration of the thyroid parenchyma and retro-orbital region.
There is hyper mutation of B-cell in lymph nodes which allow the survive of self-
specific B-cells which secrete antibodies for TSHR. These cells can present thyroid
auto antigen to T-cells which secret pro-inflammatory cytokines. Accordingly we
can find auto reactive T-cells in patients serum. Therefore, B-cells and T-cells play
an important role in producing thyroid stimulating hormone receptors antibodies
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and the chronic inflammation changes that we see in

thyroid gland and retro-orbital region.
There is 3 different types of TSHR-Ab were found in most of patients of the
disease; stimulating antibodies, blocking antibodies, and neutral antibodies.
Stimulating antibodies bind to only natural TSHR, increasing cAMP synthesis and
inhibit any simultaneous TSH-mediated activation of thyroid functions. Blocking
antibodies block binding of TSH to the receptors which cause a decrease in thyroid
hormones and they also have a weak against effect on TSHR. Neutral antibodies
don't block TSH binding or its action and don't increase cAMP generation. These
antibodies only bind with linear epitopes and they are directed to unique region of
the receptor.(10)
- graves' ophthalmopathy:
This condition is caused due to a buildup of certain carbohydrates in the muscles
and the tissue behind the eye. there's no unique genetic etiology for the retro-
orbital inflammatory response that occur with graves' disease and it seems that it's
just a manifestation of a more severe form of the disease. The eye disorders are
always accompanied with pre-tabial myxedema so both of them have common
characteristics. The immunopathology of these disorders is the local immune
response of widely expressed TSHR on fibroblasts and adipocytes in retro-orbital
and pre-tabial regions.(11)

Diagnosis:
Physical test:
Examination of the eye to see if there an irritation or protrusion and to see if there
is an enlargement in the thyroid gland as this disease increases the metabolism.
Blood test: This test is done to determine TSH and thyroid hormones levels. In
graves' disease patients, the level of TSH is lower than normal and the level of
thyroid hormones is more than normal.
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Radioactive iodine uptake:

The patient takes a small amount of radioactive iodine and later we use a
specialized scanning camera to measure the amount of it in the thyroid gland, so
we are able to determine the rate at which the thyroid gland uptakes the iodine.
Accordingly, we can know if the graves' disease is the cause of the
hyperthyroidism or another condition according to the amount of radioactive
iodine up taken by the thyroid gland.
Ultrasound waves:
These waves are with high frequency which can penetrate the body and show if
there is an enlargement in the gland specially in the patients that can't undergo
radioactive iodine uptake, as pregnant women.
Imaging tests:
if the doctor can't diagnose graves' ophthalmopathy, he order an imaging test as CT
scan. MRI which uses magnetic field and can create a cross-sectional or 3D
images, also may be used.(12)

Rheumatoid arthritis :
Rheumatoid arthritis is a non organ specific autoimmune disease which is
associated with systemic complications, progressive disability, and early death.
Despite of not knowing the cause of the disease, there's a development of new
therapeutics with improved outcome due to advances in understanding the
pathogenesis of it.(13)

Pathogenesis:
- Genetic and environmental factors:
a study on twins proved that about of 15-30% of monozygotic twins suffers from
rheumatoid arthritis, while only 5% of dizygotic twins suffers from it. Now, it's
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clear that immune regulatory factor defect is one of

causes of the disease. some predisposing T-cell repertoire selection, antigen
presentation, or alteration in peptide affinity has a role in promoting autoreactive
adaptive immune responses. The long-established association with the human
leukocyte antigen (HLA)–DRB1 locus has been confirmed in patients who are
positive for rheumatoid factor or ACPA; alleles that contain a common amino acid
motif (QKRAA) in the HLA-DRB1 region, termed the shared epitope, confer
particular susceptibility.
some studies on genetic-environmental interaction found that smoking and other
bronchial stress increases the risk of rheumatoid arthritis in person with HLA-DR4
alleles. Some infectious agents as E-coli and Epstein-Barr virus are also linked
with rheumatoid arthritis. Women have a greater risk more than men.(14)

- Synovial immunologic processes and inflammation:

Synovial cell hyperplasia and endothelial cell activation are early events that lead
to uncontrolled inflammation and cartilage and bone destruction. Genetic factors
and immune system abnormalities contribute to disease propagation.
Endothelial activation in synovial vessels enables leukocytes migration, which lead
to adhesion molecules and chemokines expression, accordingly neoangiogenesis
and lymphangiogenesis are characteristic features of early and established
synovitis.
We can find macrophages, mast cells, and NK cells in synovial membrane, while
neutrophils are in synovial fluid. Macrophages are activated by TLRs and NLRs
which recognize bacterial, viral, and putative endogenous ligands. They also be
activated by cytokines, interaction with T-cells, and immune complexes.
Neutrophils helps in synovitis through synthesizing of proteases, PGs, and reactive
oxygen intermediates. Mast cells produce high levels of vasoactive amines,
cytokines, chemokines, and proteases. These evidences prove that activation of
innate immunity plays a role in synovitis.
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Production of cytokines from synovial cells is one of

the causes of rheumatoid arthritis. TNF-α plays an important role as it activates
cytokine and chemokine expression, expresses endothelial-cell adhesion
molecules, protects synovial fibroblasts, promotes angiogenesis, suppresses
regulatory T cells, and induces pain. Interleukin-1 are expressed in large amounts
in rheumatoid arthritis.(15)

- Structural damage:
The most cause of cartilage damage in rheumatoid arthritis is hyperplastic
synovium. Losing the normal protective effect of synovium increases protein
binding characteristics of cartilage surface, which promotes FLS adhesion and
invasion. Synthesis of MMPs promotes destroying of type II collagen network and
degradation of collagenous cartilage matrix.

Bone erosion occurs to 80% of the patients within one year after diagnosis.
Synovial cytokines promote osteoclast differentiation and invasion of the periosteal
surface adjacent to articular cartilage. Osteoclasts have the ability to destroy
mineralized cartilage and sub-chondral bone which lead to deep resorption pits
which is filled by inflammatory tissue.(16)

Diagnosis:
It's difficult to diagnose rheumatoid arthritis in early stages because the signs and
symptoms are like many other diseases. There is no blood test or physical findings
to confirm the diagnosis.

During physical exam, doctor will check the joints for swelling, redness, and
warmth. He may check reflexes and muscle strength.

- Blood test:
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Patients often have an elevated erythrocyte
sedimentation rate or C-reactive protein (CRP),
which indicates the presence of inflammation
process in the body.

Other common blood tests search for rheumatoid factor and anti-cyclic
citrullinated peptide (anti-CCP) antibodies.

- Imaging tests:

X-ray helps in tracking the progression of the disease in joints over time. MRI and
ultrasound tests can help to know the severity of the disease.

- ELISA Test:
To detect anti-CCP antibodies.

- Multiplex cytofluorimetric test:

Which is more sensitive and specific.(17)

Systemic lupus erythematosis:

Pathogenesis:
Systemic lupus erythematosus characterized by the production of autoreactive
antibodies and cytokines
- Predominantly affects females almost 9 to 1
- The disease can affect all ages but commonly from 20-45
- The natural history of SLE ranges from relatively benign disease to rapidly
progressive and even fatal disease
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- The disease course is milder and survival rate
higher in persons with isolated skin and
musculoskeletal diseases than in those with renal
disease

- The cellular accumulation of hydrogen peroxide is facilitated by the myriad of

stimuli causing increased cellular bioenergetic activity which recognized SLE
exacerbating factors
The causes of SLE
- Genetic causes
The genes causing SLE are located in HLA region on chromosome 6, where
mutation may occur.(18)
-Environmental causes
These factors not exacerbate SLE but trigger the initial onset
They include certain medications as (antidepressants &antibiotics), hormones,
infections and extreme stress
UV radiation has been shown to trigger the photosensitive lupus rash
It was found that women with silicone gel-filled breast implant have produced
antibodies to their own collagen, these antibodies may cause connective tissue
disease such SLE
Drug induced lupus is a reversible condition that occur in people being treated for
a long time illness
Some people the immune system attacks nuclear-related proteins and produce
antibodies against them
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These antibodies complex damage blood vessels in
some areas as glomeruli of kidney that may cause
SLE
Drugs such as hydralazine ,methyldopa ,minocycline
can induce lupus not associated with anti-dsDNA

When antigen across the blood capillary and reaches extracellular space, the
antigen is taken inside macrophage cell & broken into smaller fragments or
epitopes
The antigen after broken combines with another protein called major MHC-
complex this combination is brought to cell surface to be presented T-helper cell or
B-cell
- Effect of IL-1 in SLE
play an important role in the immunopathology of systemic lupus erythematosus.
(IL-1ra) exhibits a dose-responsive inhibition of IL-effects. IL-1cause an increase
in the production of nitric oxidesynthase which responsible of vessels dilatation.
The end result of IL-1 is activation & migration of leukocytes and lymphocytes
from blood into inflammatory tissues.(19)
- Gelatinase B or MMP-9
Breakdown of extracellular collagen & elastin help cells to move and reach site of
inflammation
- Role of antibody
Antibody prepared the antigen for eating by phagocytes. Bacteria and other
pathogens covered with antibodies are be attacked by proteins from complement
system. Activation of complement cause cell lysis. In SLE antibodies react with
normal antigens from normal cells. Presence of auto antibodies determined by
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ANA test. dsDNA are important in pathogenesis of
systemic lupus erythematosis are observed in 60-
70% of patients with SLE.(19)

Diagnosis:
Diagnosis of SLE is difficult as symptoms vary from person to another. There is no
single test can diagnose SLE but some signs , symptoms and tests will help in
diagnosis of disease.

1- Laboratory tests:

Complete blood count: in SLE patients we can find the presence of anemia , low
platelet and WBCs count

Erythrocyte sedimentation rate: if the rate of sedimentation of RBC is faster

than the normal then the patient suffers from a systemic disease, as SLE. But it's
not a specific test for one disease.

Kidney and liver assessment: Lupus affects the function of these organs.

Urine analysis: if you are a lupus patient, then the result will show an increase in
protein level and RBCs in the urine.

ANA test: it's a positive test for presence of antibodies formed by the immunity
system which proves the activation of the immunity system. Most lupus patients
have positive ANA test, while most people with positive ANA tests don't have
lupus. So if the result of the test is positive the doctor asks for more specific
antibody test.

2- Imaging tests:
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Chest X-ray: it may suggests presence of fluid and
inflammation in the lung if there is abnormal
shadows in the image.

Echocardiogram: this test is done by using o sound

waves which produce real-time image of the heart. It can check for problems with
your valves and other portions of your heart.(20)

Therapies commonly used for autoimmune disease include:

 Non-steroidal anti-inflammatory drugs

Commonly, NSAIDs are used in multi-system autoimmune diseases to treat

constitutional symptoms, fever, serositis, arthritis, and headache.

 Corticosteroids

GCs have a wide variety of immunosuppressive and anti-inflammatory effects on

both the acquired and innate immunity. Organ threatening symptoms of disease in
SLE, multiple sclerosis, large and small vessel vasculitis, and dermatomyositis
frequently need pulse IV steroids as part of the initial induction therapy for acute
flare control.
 Disease-modifying anti-rheumatic drugs (DMARDs)

Group of drugs commonly used in people with rheumatoid arthritis. The most
common DMARDs include methotrexate, hydroxychloroquine, leflunomide,
sulfasalazine, and minocycline.

 Biologics

A relatively new class of DMARDs made of synthetic proteins. They can be

classified on the basis of their mechanism of action; cytokine-targeted therapies, B-
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cell-targeted therapies and T-cell-targeted therapies.
The major categories within biologics are tumor
necrosis factor (TNF) inhibitors, which
downregulate inflammatory cytokines and inhibit
immune-regulatory functions of TNF.
 Intravenous Immunoglobulin

Intravenous IV immunoglobulin (IVIG) in autoimmune diseases has several

probable mechanisms of action in inflammatory and autoimmune processes
suppression, including interfering with Fc receptors on effector cells, supply of

anti-idiotypical antibody activity against serum auto-antibodies, inhibition of

reticuloendothelial clearance of antibody-covered platelets via Fc receptors, and
suppression of various inflammatory mediators, including cytokines, chemokines,
and metalloproteinases.
 Plasmapheresis

Plasmapheresis is a process that clears the plasma from autoantibodies,

complement, immune complexes, and non-specific inflammatory mediators. It’s
primarily used in severe autoimmune or cytotoxic diseases.
 Surgery

In rare cases, to cope with certain autoimmune disease complications such as

intestinal obstruction in Crohn’s disease or joint damage in juvenile idiopathic
arthritis.(21)
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Conclusion
Autoimmune disease occurs when the immune system attacks self-molecules as a
result of a breakdown of immunologic tolerance to autoreactive immune cells.
Many autoimmune disorders were strongly associated with predisposing factors
such as genetic, infectious, and/or environmental or breakdown of immune
network by Overproduction of IL2 by Th1 cells ,Interference with the mechanisms
normally suppress surviving self reactive T cells. .Spectrum of autoimmune
diseases Includes various conditions and signs, from organ-specific to systemic,
autoimmune diseases include insulin-dependent mellitus diabetes, rheumatoid
arthritis, systemic lupus Scleroderma, erythematosus, thyroiditis and multiple
sclerosis. Tolerance mechanisms have evolved to distinguish self and nonself, and
block the development growth, or differentiation of autoreactive lymphocytes. If
the tolerance is acquired early in life probably in uteri it is auto-tolerance which
occurs through clonal depletion, clonal anergy and inhibition of autoreactive
lymphocytes via association with other types of cells such as cytotoxic T
lymphocytes or NK cells. The failure of that auto-tolerance may result in
autoimmune disease.
The mechanism of tissue damage in autoimmune hemolytic anemia is cytotoxic
reaction, in ulcerative colitis is cell mediated reactions,
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In SLE which characterized by the production of
autoreactive antibodies and cytokines ,the
mechanism of tissue damage is hypersensitivity type
III. It occurs by mutation in the gene of SLE that
located in HLA in chromosome 6
In rheumatic fever, which occurs by Genetic predisposition related to specific
human leukocytic antigens specifically rheumatoid arthritis with DR4,the damage
is caused by immune complex deposition or hypersensitivity type III after the
endothelial activation causing synovitis.
In Graves' disease, anti-thyroid antibodies attack thyroid stimulates secretion of
excess thyroxin lead to thyrotoxicosis. There's heterogeneous lymphatic infiltration
of the thyroid parenchyma and retro-orbital region. There is hyper mutation of

B-cell in lymph nodes which allow the survive of self-specific B-cells which
secrete antibodies for TSHR. These cells can present thyroid auto antigen to T-
cells which secret pro-inflammatory cytokines. Accordingly we can find auto
reactive T-cells in patients serum.
In All autoimmune diseases doctors use Connor therapies such as NSAID
,Corticosteroids, Disease-modifying anti-rheumatic drugs (DMARDs), Biologics
which is a relatively new class of DMARDs made of synthetic proteins.,
Plasmapheresis which is a process that clears the plasma from auto-antibodies and
Surgery in rare complicated cases.
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