AUTOIMMUNE DESEASE

BY
Dr. Nova Kurniati.
 Autoimmunity
 An immunological paradox.
 Immune system has evolved to discriminate
between self and nonself or discriminate between
safe and dangerous signals.
 Ability developed during fetal life, during the
ontogeny of the immune system.
 Termed tolerance, a form of censorship of the
immune system.
 Deletion (clonal deletion) or functional inactivation
(clonal anergy) of developing lymphocytes that
possess antigenic receptors with high affinity for
self-antigens.
 Loss of Tolerance in Autoimmune Disease

Susceptibility genes Triggering factors

(usually multiple) (probably environmental)

Loss of tolerance

Auto reactive T cells Auto reactive B cells Inadequate regulatory

mechanism

Persistent pathogenic autoantibodies

Persistent pathogenic immune complexes
Persistent damaging autoreactive T cell
 Mechanism of Autoantibody Secretion

Uptake of
autoantigen
 Autoimmune Diseases
 Self-reactive lymphocytes (the forbidden clones)
should be eliminated from the immunological
repertoire.
 Diseases involving an immunological response to
normal tissue – termed autoimmunity or
autoimmune diseases.
 Original concept – the receptors of lymphocytes
with specificity for foreign antigens underwent
mutation – results in a new class of receptors
with specificity for self-antigens.
 It is now clear that autoantibodies and self-
reactive T cells are normal components of the
immune repertoire.
 Self-reactive Antibodies are a
Normal Component of Immunity
 Autoimmune Diseases

 Affect between 5 and 7% of the population, often

causing chronic debilitating illnesses.
 Have a substantial economic impact on the society
as a whole in addition to the personal effects of
the individual.
 Rheumatoid arthritis causes an annual economic
loss in the United States of $1 billion per year.
 Autoimmune diseases can be divided into two
categories:
 organ specific and systemic (non organ-specific).
 Autoimmune Diseases

Organ-specific
 Immune response to antigens unique to a single organ
or gland.
 Manifestations are largely limited to that organ.

Systemic (Organ Non-specific)

 Immune response to a broad range of target antigens.
 Involves a number of organs and tissues.
Proposed Mechanisms of
Autoimmunity
Release of Sequestered Antigens

 Some self-antigens are sequestered in specialized tissues

and cannot be expressed in the thymus or bone marrow.
 These are not seen by the developing immune system –
will not induce self-tolerance.
 Exposure of T cells to these normally sequestered/tissue-
specific self-antigens in the periphery results in their
activation.
Examples of Sequestered Antigens

 Myelin basic protein (MBP),

associated with MS.
 Lens and corneal proteins of the
eye following infection or trauma.
 Heart muscle antigens following
myocardial infarction.
 Cross-reacting Antigens
(Molecular Mimicry)

 Viruses and bacteria possess antigenic determinants that are

similar or identical, to normal host cell components.

 This phenomenon, known as molecular mimicry, occurs in a

wide variety of organisms.

 Molecular mimicry may be the initiating step in a variety of

autoimmune diseases.
Cross-reacting Antigens
(Molecular Mimicry)
Examples of Molecular Mimicry
 Inappropriate Expression of
Class II MHC Molecules
 The elimination of self-reactive T cells involves contact with
APC presenting self-peptides within the thymic
environment.
 Results in deletion or functional inactivation.
 Highly tissue specific proteins not expressed within the
thymus, do not induce clonal deletion or tolerance.
 T cells will not respond in the periphery if the tissue
expressing these specific proteins does not express class II
MHC molecules.
 Inappropriate Expression of
Class II MHC Molecules
 Class II MHC ordinarily expressed on antigen presenting cells,
such as macrophages, dendritic cells and B cells.
 The aberrant expression of MHC determinants allows the
recognition of these autoantigens by self-reactive T cells.
 Results from the local production of IFN-g, which is known to
increase class II MHC expression on a variety of cells.
 The inducer of IFN-g under these circumstances could be a
viral infection.
 Cytokine Imbalance

 An imbalance in the normal regulatory functions

that control cytokine secretion and the
expression of cytokine receptors.
 Perturbation of the regulation of expression of
IL-2 and its receptor (IL-2R) may have several
possible consequences.
 Cytokine Imbalance
Potential consequences include:
 Increased expression of IL-2 and IL-2R promotes T cell
activation.
 Results in overproduction of other cytokines and the
enhancement of T cell effector function – leads to tissue
damage.
 Elaboration of excessive cytokines from activated CD4 T cells.
 Results in excessive B cell activation and autoantibody
production.
 Autoreactive B cells differentiate into plasma cells without the
requirement for the corresponding autoreactive helper T cells.
 Increased expression of IL-2R on thymocytes - alter
development and allow self-reactive T cells to escape clonal
deletion.
 Polyclonal B Cell Activation
Viruses and bacteria can induce nonspecific polyclonal B cell
activation, including:

Certain gram negative bacteria

Herpes simplex virus.
Cytomegalovirus
Epstein Barr Virus
Human immunodeficiency virus (HIV)

 Induce the proliferation of numerous clones of B cells to

secrete IgM in the absence of a requirement for CD4 T cell
help.
 Polyclonal activation leads to the activation of self-reactive B
cells and autoantibody production.
 Patients with mononucleosis (caused by EBV) and AIDS
(HIV) have a variety of autoantibodies.
Pathology of Autoimmune Diseases

 Most of the autoimmune diseases attributed to

autoantibodies.

 Disease processes and tissue damage are due

to Type II and Type III hypersensitivity
reactions.

 Other autoimmune diseases have an

autoreactive T cell component.

 Disease process and tissue damage due to

Type IV hypersensitivity reactions.
 Antigen Recognized by Autoantibodies in Systemic
Autoimmune Diseases

Antinuclear Localization Recognized Antigen Disease

antibodies
Anti-ss-DNA antibody ss-DNA SLE etc.
Anti-ds DNA antibody ds-DNA SLE
Anti-polyADP ribose poly ADPribose SLE
antibody
Anti-Scl-70 antibody Chromatin DNA topoimerase l SSc
Anti-centromere antibody centromere CREST
Anti-histone antibody Histone Drug induce lupus
Anti-U1RNP antibody U1RNP MCTD
Anti-Sm antibody U1, U2, U4/U6, U5 RNP SLE
Anti-U2RNP antibody U2RNP Overlap syndrome
Anti-SS-A/Ro antibody Nucleus hY1~hY5 RNP SjS etc.
Anti-SS-B/La antibody RNA polymerase III trancription
termination factor SjS
DNA polymerase δ auxiliary factor
Anti-PCNA antibody DNA dependent protein kinase SLE
activation factor
Type II Hypersensitivity
Type II Hypersensitivity
Autoimmunity
Autoimmune Diseases due to
Type II Hypersensitivity
 Goodpasture’s Syndrome
 A disease caused by autoantibodies binding to
basement-membrane antigens of the kidney glomeruli
and the alveoli of the lungs.
 Complement activation leads to direct cell damage and
inflammation due to the release of complement
chemotactic factors (C5a).
 Damage to the kidney and lung basement membranes
leads to progressive kidney damage and pulmonary
hemorrhage.
 Death ensues several months after the onset of
disease.
 Biopsies of patients reveal linear deposits of IgG and
C3b along the basement membranes.
Goodpasture’s Syndrome
Fluorescent anti-IgG staining of
a kidney biopsy of a patient with
Goodpasture’s syndrome –
reveals deposits of
autoantibodies along the
basement membrane.

Mechanism of tissue damage

in Goodpasture’s Disease – the
deposition of immune
complexes in the kidney
glomeruli, the activation of
complement and the
recruitment of inflammatory
cells.
Type III Hypersensitivity
Type III Hypersensitivity
Autoimmunity
Autoimmune Diseases due to
Type III Hypersensitivity
Systemic Lupus Erythematosus
 Systemic lupus erythematosus (SLE) – prototypical
systemic autoimmune disease.
 Typically appears in females 13 to 40 years of age –
ratio of female to male is 10:1.
 Characterized by fever, weakness, arthritis, skin rashes,
pleurisy, and kidney dysfunction.
 Patients produce autoantibodies to DNA, histones,
erythrocytes, platelets, leukocytes, and clotting factors.
 Autoantibodies to erythrocytes or platelets can cause
hemolytic anemia or thrombocytopenia due to
complement-dependent cell lysis.
 Immune complex deposition along the walls of small
blood vessels results in a Type III hypersensitivity
reaction – causes damage to the endothelial cells,
resulting in vasculitis and glomerulonephritis.
Systemic Lupus Erythematosus
Systemic Lupus Erythematosus
 Systemic Lupus Erythematosus

Autoantibodies against Prevalence

Double stranded DNA (dsDNA) 30-90%
Single stranded DNA (ssDNA) 70-95%
Histones 50-80%
U1-nRNP 15-40%
Sm 5-30%
SS-A (Ro) 20-60%
SS-B (La) 10-20%
Cyclin I (PCNA) 3%
Ku 5-10%
Ribosomal P proteins 5-20%
Cardiolipin, β-2-glycoprotein 1 20-40%
 Criteria for Diagnosis of SLE
 Malar rash  Haematologic disorder
 Discoid rash – Haemolytic anemia
 Photosensitivity
– leukopenia
 Oral ulcers
 Arthritis – lymphopenia
 Serositis – thrombocytopenia
 Neurological disorder  Immunological disorder
– seizure
– anti-dsDNA
– psychosis
– anti-Sm
. Renal disorder
– proteinuria > 0.5g – anti-phospholipids
– Casts  ANA positivity
 Rheumatoid arthritis

Autoantibodies against Prevalence

Histones Rare
Single stranded DNA (ssDNA) 8%
RANA 90-95%
Rheumatoid factors 65-90%
Fillagrin (keratin) 50%
 ACR 1987 CLASSIFICATION CRITERIA
FOR RHEUMATOID ARTHRITIS
Requires four out of the seven criteria:
1. Morning stiffness*
2. Arthritis of three or more joints*
3. Arthritis of hand joints*
4. Symmetric arthritis*
5. Rheumatoid nodules
6. Serum rheumatoid factor
7. Radiographic changes
*Must have been present for at least six weeks
 Grave’s Disease
 A disease associated with the overproduction of
thyroid hormones.
 Production of thyroid hormones is normally tightly
regulated by thyroid stimulating hormone (TSH)
produced by the pituitary gland – feedback
mechanisms downregulate TSH production if thyroid
hormone levels are high.
 Patient with Graves’ Disease produces autoantibodies
that bind to and constitutively stimulate the TSH
receptor – activates adenylate cyclase and the
overproduction of thyroid hormones.
 Because the production of thyroid hormones is
unregulated in Graves’ Disease, the autoantibodies are
designated long-acting thyroid-stimulating (LATS)
antibodies.
Grave’s Disease
 Myasthenia Gravis
 Myasthenia gravis is the prototypical autoimmune
disease with blocking autoantibodies.
 The patient produces autoantibodies that bind to the
acetylcholine receptor on the motor end plates of
muscles.
 Binding of the autoantibodies blocks the normal binding
of acetylcholine – also induces complement-mediated
degradation of the receptors – results in the weakening
of skeletal muscles.
 Ultimately, the autoantibodies destroy the receptors –
early signs of disease include drooping eyelids and the
inability to retract the corners of the mouth.
Myasthenia Gravis
Myasthenia Gravis
Type IV Hypersensitivity
Autoimmune Diseases due to
Type IV Hypersensitivity
Insulin-dependent Diabetes Mellitus
(IDDM – Type I Diabetes)
 Disease affects 0.2% of the population.
 Caused by an autoimmune attack on the pancreas.
 Directed against the insulin-producing b-cells located in
spherical clusters called the islets of Langerhans.
 The autoimmune response destroys the b-cells – results in
decreased insulin production, leading to elevated levels of
blood glucose.
 Islet cell destruction occurs by waves of immunological
attack.
 CD8+ T cells (CTL) Initial infiltration of activated, which
destroy the islet cells by direct lysis.
 A local increase in IFN-g, TNF-a and IL-1 occurs as a
consequence of the response.
 The initial infiltration of CD8+ T cells and the activation of
macrophages – referred to as insulitis.
Type I Diabetes
Islet of Langerhans in
normal pancreas.

Islet of Langerhans from

individual with insulin-
dependent diabetes
mellitus. Note the intense
lymphocyte infiltration into
the islet (insulitis).
 Type I Diabetes

 The cytokine release further activates infiltrating CD4+ T

cells.
 Together, both CD4+ and CD8+ T cells destroy remaining
islet cells by DTH mechanisms
 Involves both cytokine release and the effect of lytic
granules released by activated macrophages.
 Autoantibodies to the islet cells contribute to cell
destruction by antibody-dependent cell-mediated
cytotoxicity (ADCC).
 The abnormalities in glucose metabolism result in
serious metabolic problems, including ketoacidosis and
increased urine production.
Type I Diabetes
 Multiple Sclerosis
 An autoimmune disease affecting the central nervous system
– most common cause of neurological disability associated
with disease in Western Hemisphere.
 Symptoms range from mild (numbness of limbs) to severe
(paralysis, loss of vision).
 MS diagnosed between ages of 20 to 40 years of age.
 MS is more common in the Northern Hemisphere, particularly
the United States.
 Suggests there is an environmental factor associated with the
acquisition of MS.
 Also a genetic component, as the children or siblings of
individuals with MS have a 1 in 50 chance of developing
disease, compared to 1 in 1000 in the general population –
identical twins of MS patients have a 1 in 3 chance of
developing disease.
 MS affects women 3 times more frequently than men.
 Multiple Sclerosis

 Disease associated with autoreactive T cells –

form inflammatory lesions along the myelin
sheath of nerve fibers.
 The cerebrospinal fluid of patients contain
activated T cells that recognize antigens
derived from myelin, and destroy the myelin
sheath – the breakdown of the myelin sheath
leads to neurological dysfunction.
Progressive systemic sclerosis (diffuse form)
Autoantibodies against Prevalence
Single stranded DNA (ssDNA) 30-60%
Fibrillarin (U3 nRNP) 5-10%
PM-Scl 3%
Scl-70 25-75%
RNA Polymerase I 4%
7-2 RNP (To) Rare
NOR (NOR- 90) Rare

Progressive systemic sclerosis (limited form)

Autoantibodies against Prevalence
Centromeres 80-95%