This document discusses autoimmunity and provides examples of several autoimmune diseases. It begins by defining autoimmunity as an inappropriate immune response directed against self-components. It then discusses how failure to eliminate self-reactive lymphocytes during development can lead to autoimmunity. Several autoimmune diseases are described in detail, including the mechanisms, symptoms, and treatments. Animal models of autoimmune diseases are also discussed.

1. AUTOIMMUNITY
BY SAIMOON TEHSEEN

2. Autoimmunity
 Inappropriate response against self components
 In 1960, self reactive lymphocytes eliminated during
development in bone marrow and thymus and failure to
eliminate them cause Autoimmunity
 In 1970, not all self reactive lymphocytes deleted during
B andT cell maturation
 Normal persons have seen re-circulating mature self
reactive lymphocytes

3.  Damage to self-cells causes:
 Antibodies
 T-cells
Antibodies:
 Common cause of autoimmunity is tissue injury byType-2
hypersensitivity. E.g.
 Autoimmune hemolytic anemia:
 Ag on RBC’s recognized by auto Abs And cause destruction
of RBC’s and results in anemia
 Hashimoto’sThyroiditis:
 Abs react with tissue specific Ags such as thyroid
peroxidase and thyroglobulin and results in severe tissue
damage

4.  T-cells:
 Tissue destruction byT-cells
 Rheumatoid arthiritis:
 Self-reactiveT-cells attack the tissue joints causing an
inflammatory resoponse
 Multiple sclerosis:
 Diabetes mellitus type-1

5.  Auto immunity effects:
 Organ Specific
 Systemic Autoimmune Disease
 Organ specific:
 Immune response directed to single organ or
gland so action limited to organ
 Also involve humoral response or cell
mediated cell response

6. AutoimmuneDiseaseMediatedByDirectCellularDamage
 Direct cellular damage due to lymphocytes and Ab bind to cell
membrane Ag causing cellular lysis or inflammatory response
 Hashimoto’s Thyroiditis:
 Ab dependent cell mediated cytotoxic response
 Middle aged women
 Individual produces Auto-Ab and sensitizedTH1 cells specific
for thyroid gland
 DTH response characterized by intense infiltration of thyroid
gland by lymphocytes, macrophages
 Inflammatory response cause goitre
 Abs form against many thyroid proteins like thyroid
peroxidase, thyroglobulin and cause hypothyroidism

7. Autoimmune Anemia
(Autoantibodies)
 Prenecious anemia
 Autoimmune Hemolytic anemia
 Drug induced Hemolytic anemia
 Prenecious anemia:
 Intrinsic factor required for absorption ofVB12 i.e important to make
RBC’s
 But body fail to make Intrinsic factor
 Auto Abs bind to Intrinsic factor, and results in VB12 absorption failure
 Absorption ofVB12 decrease means no. of RBC’s decreases
 Treatment:
 It is treated by Injections ofVB12

8. Pernicious Anemia
Ab against
intrinsic factor

9. Autoimmune Hemolytic anemia
 Autoantibodies against RBC’sAg trigering Ab
mediated opsonization and phagocytosis of RBC’s
 Reason:
 Certain drugs like penicillin or anti-hypersensitive
agent methyldopa interact with RBC’s
-RBC’s become antigenic
 DiagnosticTest:
 Coombs test
 RBC’s incubated with anti-human IgG antiserum
 If IgG auto-antibodies are present on RBC’s, the cells
are agglutinated by antiserum

10. Insulin Dependent Diabetes mellitus
 Also due to auto-antibodies
 0.2 percent population
 Due to autoimmune attack on pancreas
against specialized insulin producing Beta-
cells located in Islets of langerhans
 Beta-cell destroyed by autoimmune attack
 Decrease Insulin production, high blood
glucose level

11. Factors in Beta Cell
Destruction
 CytotoxicT-cells migrate into an Islets and attack the
Beta cells (Insulitis)
 Local cytokines production induces IFN-gamma,
TNF-alpha, IL-1
 Insulitis followed by release of cytokines and
presence of auto-antibodies, which lead to cell-
mediated DTH
 Beta cell destruction due to cytokines release during
DTH and by lytic enzyme by macrophages
 Beta cell destruction by auto-antibody due to Ab and
complement lysis or Ab dependent cell-mediated
lysis

12. Adipocyte
Insulin receptor
Insulin in blood
Pancreaticcells
various intracellular
processes
Adipocyte
Insulin receptor
Insulin Pancreaticcells
YYYY
YY
Auto Ab against
insulin receptors

13. Abnormalities in glucose
metabolism
 Abnormalities in glucose metabolism cause:
 Ketoacidosis
 High thirst and more urination
 At late stage, Artherosclerotic vascular
lesions leads to renal failure and blindness
 If left untreated then it can lead to death
 Therapy:
 Insulin Injection

14. Autoimmune Diseases Caused By
Stimulating or Blocking Auto-
Abs
 Ab act as Agonist
 Increase the response
 Chemical binds to receptor and activates
receptor to produce biological response
 Auto-Ab act as Antiagonist
 Bind with receptor and prevent the activation
E.g. Grave’s Disease

15. Grave’s Disease
 Thyroid stimulating hormone (TSH) produced
by pituitary gland, regulates thyroid hormone
 Binding ofTSH to receptor on thyroid cell
activates adenylate cyclase and stimulate
synthesis of twoThyroid hormones:
 Thyroxin
 Triiodothyronine

16. Grave’s Disease
 Grave’s disease patient produce auto-antibodies
that bind withTSH and mimic normal action of
hormone production
 But the problem is auto-antibody over stimulate
the thyroid that’s why auto-Ab called long acting
thyroid stimulating antibodies
 In Grave’s disease, increase size of thyroid
(goiter) effect the eyes and make them bulging,
muscle weakness, skin, heart and nervous
system etc.

17. Myasthenia Gravis
 Mediated blocking Ab
 In this auto-Ab binds with acetylcholine
receptor on motor end-plates of muscles,
blocking the binding of acetylcholine and also
induce complement mediated lysis
 Results of weakening of muscles
 Ultimately Abs destroy the cells bearing
receptor
 Dropping eyelids and weakening of jaws

18. Systemicautoimmunediseases
 In this the response is directed toward a
broad range of target antigens and tissues.
 Tissue damage is wide spread and mediated
both from cell mediated immune response
and from direct cellular damage caused by
auto-antibodies.

19. Systemic lupus erythmatosus
 Typically in women 20-40 years.
 Female to male ratio, 10:1
 Characteristics: fever, weakness, arthritis,
skin rashes, kidney dysfunction.
 Affected individuals produce ab against
vast array of tissue ag like, DNA, histone,
RBC’s, platelets, clotting factor.
 Auto-antibodies against RBC’s and platelets can lead to
complement lysis and cause hemolytic anemia and
thrombocytopenia.
 Type 3 hypersensitive reaction due to the depositon of
the auto anti bodies complex along the walls of small
blood vessels.

20.  Excessive complement activation produces elevated serum
levels of the complement split products C3a and C5a
 C5a induces increased expression of CR3 on neutrophils,
facilitating neutrophil aggregation and attachment to the
vascular endothelium.
 Neutrophils attach to small blood vessels, the number of
circulating neutrophils declines and various blockage of the
small blood vessels develop, widespread tissue damage occur.
 Laboratory diagnosis of SLE
focuses on the characteristic antinuclear antibodies, which are
directed against double stranded or single-stranded DNA,
nucleoprotein, histones, and nucleolar RNA.

21. Type III Hypersensitivity--->Lupus
Ab
Ag
activate C
platelets
Basophil
mediators
Increased vascular
permeability
Ab
Ag
activate C
enzyme release
Immune
complexes
are deposited
BloodVesselWall
Neutrophil

22. Multiple Sclerosis
 most common cause of neurologic disability
Symptoms:
 may be mild, such as numbness in the limbs, or severe, such as
paralysis or loss of vision.
 diagnosed between the ages of 20 and 40.
In this disease produce auto reactiveT cells that participate in the
formation of inflammatory lesions along the myelin sheath of nerve
fibers.
The cerebrospinal fluid of patients with active MS contains activatedT
lymphocytes, which
 infiltrate the brain tissue and cause characteristic inflammatory
lesions, destroying the myelin.
 The cause of MS, like most autoimmune diseases, is not well
understood. However, there are some suggestions that infection by
certain viruses may predispose a person to MS.

23. Rheumatoid Arthritis
 affecting women from 40 to 60 years old.
 major symptom is chronic inflammation of the joints,
although the hematologic, cardiovascular, and
respiratory systems are also frequently affected.
Rheumatoid arthritis produce a group of auto-antibodies
called rheumatoid factors that are reactive with
determinants in the Fc region of IgG.The classic
rheumatoid factor is an IgM antibody.
Such auto-antibodies bind to normal circulating IgG,
forming IgM-IgG complexes that are deposited in the
joints.These immune complexes can activate the
complement cascade.Which leads to chronic
inflammation of the joints.

24. AnimalModelsforAutoimmune
Diseases

25. AutoimmunityCanDevelop
SpontaneouslyinAnimals
Autoimmune diseases that develop spontaneously in animals
exhibit important clinical and pathologic similarities to certain
autoimmune diseases in humans.
 New Zealand Black (NZB) mice and F1 hybrids of NZB and New
ZealandWhite (NZW) mice spontaneously develop
autoimmune diseases that closely resemble systemic lupus
erythematosus. NZB mice spontaneously develop autoimmune
hemolytic anemia between 2 and 4 months of age, at which
time various auto-antibodies can be detected, including
antibodies to erythrocytes, nuclear proteins, DNA, andT
lymphocytes. F1 hybrid animals develop glomerulonephritis
from immune-complex deposits in the kidney and die
prematurely by 18 months.As in human SLE, the incidence of
autoimmunity in the (NZB NZW)F1 hybrids is greater in
females.

26.  Another important animal model is the nonobese diabetic (NOD)
mouse, which spontaneously develops a form of diabetes that
resembles human insulin-dependent dia- betes mellitus (IDDM). Like the
human disease, the NOD mouse disease begins with lymphocytic
infiltration into the islets of the pancreas.Also, as in IDDM, there is a
strong association between certain MHC alleles and the development of
diabetes in these mice. Experiments have shown thatT cells from
diabetic mice can transfer diabetes to nondiabetic recipients. For
example, when the immune system of normal mice is destroyed by
lethal doses of x-rays and then is reconstituted with an injection of
bone-marrow cells from NOD mice, the reconstituted mice develop
diabetes.Conversely, when the immune system of still healthy NOD
mice is destroyed by x-irradiation and then reconstituted with normal
bone-marrow cells, the NOD mice do not develop diabetes.Various
studies have demonstrated a pivotal role for CD4+T cells in the NOD
mouse, and recent evidence implicates theTH1 subset in disease
development

27. Autoimmunity Can Be Induced
Experimentally in Animals
 Autoimmune dysfunctions similar to certain human
autoimmune diseases can be induced experimentally
in some animals .
 One of the first such animal models was discovered
accidently in 1973 when rabbits were immunized
with acetylcholine receptors purified from electric
eels.The animals soon developed muscular
weakness similar to that seen in myasthenia gravis.
This experimental autoimmune myasthenia gravis
(EAMG) was shown to result when antibodies to the
acetylcholine receptor blocked muscle stimulation
by acetylcholine in the synapse.

28. Autoimmunity Can Be Induced
Experimentally in Animals

29.  Experimental autoimmune thyroiditis (EAT) can be
induced in a number of animals by immunizing with
thyroglobulin in complete Freund’s adjuvant.
 Both humoral antibodies andTH1 cells directed
against the thyroglobulin develop, resulting in
thyroid inflammation. EAT appears to best mimic
Hashimoto’s thyroiditis. In contrast to both EAE and
EAT, which are induced by immunizing with self-
antigens, autoimmune arthritis (AA) is induced by
immunizing rats with Mycobacterium tuberculosis in
complete Freund’s adjuvant.
 These animals develop an arthritis whose features
are similar to those of rheumatoid arthritis in
humans.

30. Proposed Mechanisms for
Induction
of Autoimmunity

31. Release of Sequestered
Antigen
 Sequestered antigen is antigen that is normally hidden from the
immune response.
 A good example would be myelin basic protein (MBP). This protein is in
thymus to mediate negative selection ofT cells but also it is floating
around in the circulation for presentation toT cells. Even if some of it is
present in the circulation as soluble protein there is no reason for the
immune system to mount an immune response to it since it presents no
danger to the body.
 If, a viral infection damages the nervous tissue, now MBP could be
released in large quantities and under conditions of inflammation. The
local dendritic cells would now be seeing large amounts of a protein they
are not used to seeing in an environment where damage is occurring and
an active anti-viral immune response is being initiated. In this context
the dendritic cells could present the MBP antigen toT cells with the
appropriate co-stimulation to initiate an immune response to MBP.

32. Molecular Mimicry May Contribute
to Autoimmune Disease
 When the immune response makes a vigorous response to a
pathogen, antibodies and cell-mediated responses are highly
activated. These responses are specific to a particular antigen
but it is possible that other antigens, some of them self
antigens, could look so similar to some of the antigens from the
pathogen that “cross-reaction” occurs.
 One of the most obvious examples of this cross-reaction is
rheumatic fever. When a person is infected with Streptococcus
bacteria a vigorous anti-Strep antibody response is
mounted. This helps clear the bacteria and prevent re-
infection. Unfortunately, one of the dominant Strep antigens is
very similar to an antigen on human cardiac myocytes. Thus,
when a very vigorous antibody response is made to Strep then
the antibody can also recognize the cardiac myocytes and
cause myocyte cell death.

33. Polyclonal B Cell Activation
 A number of viruses and bacteria can induce nonspecific
polyclonal B-cell activation. Gram-negative bacteria,
cytomegalovirus, and Epstein-Barr virus (EBV) are all known to
be such polyclonal activators, inducing the proliferation of
numerous clones of B cells that express IgM in the absence ofTH
cells. If B cells reactive to self-antigens are activated by this
mechanism, auto-antibodies can appear
 EBV (epstin barr virus), a variety of auto-antibodies are produced,
including autoantibodies reactive toT and B cells, rheumatoid
factors, and antinuclear antibodies.
 Many AIDS patients also show high levels of nonspecific
antibody and auto-antibodies to RBCs and platelets.These
patients are often coinfected with other viruses such as EBV and
cytomegalovirus, which may induce the polyclonal B-cell
activation that results in auto-antibody production.

34. Treatment of Autoimmune
Diseases
 Ideally, treatment for autoimmune diseases should be aimed at
reducing only the autoimmune response while leaving the rest of
the immune system intact
 Current therapies for autoimmune diseases are not cures but
merely palliatives, aimed at reducing symptoms to provide the
patient with an acceptable quality of life.
 Immunosuppressive drugs (e.g., corticosteroids, azathioprine,
and cyclophosphamide) are often given with the intent of
slowing proliferation of lymphocytes
 By depressing the immune response in general, such drugs can
reduce the severity of autoimmune symptoms.
 More selective approach employs cyclosporin A or FK506 to
treat autoimmunity.These agents block signal transduction
mediated by theT-cell receptor; thus, they inhibit only antigen-
activatedT cells

35.  Patients with Graves’ disease, myasthenia gravis,
rheumatoid arthritis, or systemic lupus
erythematosus may experience short-term benefit
from plasmapheresis. In this process, plasma is
removed from a patient’s blood by continuous-flow
centrifugation.The blood cells are then resuspended
in a suitable medium and returned to the patient.
 Plasmapheresis has been beneficial to patients with
autoimmune diseases involving antigen-antibody
complexes, which are removed with the plasma.
Removal of the complexes, although only
temporary, can result in a short-term reduction in
symptoms.

36. T-Cell Vaccination Is a
Possible Therapy
 The basis forT-cell vaccination as a therapy for some autoimmune
diseases came from experiments with the EAE animal model.When rats
were injected with low doses (<10–4) of clonedT cells specific for MBP,
they did not develop symptoms of EAE.
 Instead they became resistant to the development of EAE when later
challenged with a lethal dose of activated MBP-specificT cells or MBP in
adjuvant. Later findings revealed that the efficacy of these autoimmune
T-cell clones as a vaccine could be enhanced by crosslinking the cell-
membrane components with formaldehyde or glutaraldehyde.
 When crosslinkedT cells were injected into animals with active EAE,
permanent remission of symptoms was observed.The crosslinkedT cells
apparently elicit regulatoryT cells specific forTCR variable-region
determinants of the autoimmune clones. Presumably these regulatoryT
cells act to suppress the autoimmuneT cells that mediate EAE.

37. Use of Regulatory T cells
Isolate lymphocytes
from blood
lymphocytes
+IL-2
Immunotherapy of autoimmune disease
Purify regulatoryT cells
(Foxp3+)

38. Peptide Blockade of MHC Molecules Can
Modulate Autoimmune Responses
 Identification and sequencing of various
autoantigens has led to the development of new
approaches to modulate autoimmuneT-cell activity.
In EAE, for example, the encephalitogenic peptides
of MBP have been well characterized. Synthetic
peptides differing by only one amino acid from their
MBP counterpart have been shown to bind to the
appropriate MHC molecule. Moreover, when
sufficient amounts of such a peptide were
administered along with the corresponding
encephalitogenic MBP peptide, the clinical
development of EAE was blocked. Presumably, the
synthetic peptide acts as

39. Summary of Autoimmunity
 Cause: Multiple—genetic, environmental,
nutrition, infections, etc
 Breakdown in self-tolerance.
 Organ specific or Systemic.
 Majority are caused by autoAb production
 Treatment: Immunosuppressive drugs, Abs
againstTCR, cytokines, adhesion molecules,
etc.