Immunologic

Tolerance
& Autoimmunity

Singgih Wahono, BP Suryana, Handono

Kalim
Department of Internal Medicine,
Faculty of Medicine, Brawijaya
University, Malang
 What is immunologic tolerance ?

Immunologic tolerance is specific

unresponsiveness to an antigen induced by
exposure of lymphocytes to that antigen
Maintenance of self tolerance
( prevention of autoimmunity )
 Consequences of the encounter of
lymphocytes with antigens

Abbas, 2004
Immunologic Tolerance
• Central Tolerance
Central tolerance (negative selection) is induced by
the death of immature lymphocytes that encounter
antigens in the generative lymphoid organs

• Peripheral Tolerance
Peripheral tolerance results from the recognition
of antigens by mature lymphocytes in peripheral
tissues.
Central Mechanisms of the Induction of Tolerance
 Central T cell Tolerance

Abbas, 2004 In Thymus

Peripheral T cell Tolerance

• Peripheral tolerance is induced when mature T

cells recognize self antigens in peripheral tissues,
leading to functional inactivation (anergy) or
death, or when the self-reactive lymphocytes are
suppressed by regulatory T cells.
Peripheral Mechanisms of the Induction of
Tolerance
 T cell Anergy

Abbas, 2004
 Deletion: Activation-induced death of T
lymphocytes

Abbas, 2004
 T cell-mediated suppression of immune
responses

Abbas, 2004
 Central &Peripheral Tolerance

Abbas, 2004
Central B cell Tolerance
• When immature В lymphocytes interact strongly
with self antigens in the bone marrow, the В cells
are either killed (negative selection) or they
change their receptor specificity (receptor editing)
 Central B cell Tolerance

Abbas, 2004
Peripheral B cell Tolerance

• Mature В lymphocytes that encounter high concentrations

of self antigens in peripheral lymphoid tissues become
anergic and cannot again respond to that self antigen
• Anergic В cells may leave lymphoid follicles and are
subsequently excluded from the follicles. These excluded В
cells may die because they do not receive necessary
survival stimuli.
 Peripheral B cell Tolerance

Abbas, 2004
 Features of protein antigens that influence the choice
between T cell tolerance and activation.

Feature Tolerogenic self Immunogenic

antigens foreign antigens

Abbas, 2004
Causes of autoimmunity ( break down of self
tolerance, loss of tolerance )
 Causes of Autoimmunity
Susceptibility Triggering factors
genes (usually (probably
multiple) environmental)

Loss of tolerance
( break down of tolerance )

Auto reactive T Auto reactive B Inadequate

cells activation cells activation regulatory
mechanism

Tolerance can break down in the thymus ( genetic reason ) or

in the periphery ( environmental )
Postulated mechanisms of autoimmunity
/Environmental
Triggers

Abbas, 2004
Genetic factors in Autoimmunity
• Multiple genes predispose to autoimmune diseases, the
most important of these being MHC genes.

Particular MHC alleles may contribute to the development of

autoimmunity because
• they are inefficient at displaying self antigens, leading to
defective negative selection of T cells
• peptide antigens presented by these MHC alleles may fail
to stimulate regulatory T cells.
 The roles of some non-MHC genes in
autoimmunity
Gene(s) Disease assocoation Mechanism

Complement Lupus-like disease Defective clearance of

proteins immune complexes ?

Fas, FasL Lpr, gld mouse strains; human Defective elimination of

ALPS self-reactive T and and B
lymphocytes

AIRE Autoimmune polyendocrinopathy Defective elimination of

with candidiasis and ectodermal self-reactive T cells in the
dysplasia thymus

Abbas, 2004
 Association of autoimmune diseases with
alleles of the MHC locus

Abbas, 2004
Environmental factors in autoimmunity :
mechanisms
Environmental factors in autoimmunity :
mechanisms
Role of Infections in Autoimmunity

• Infections may activate self-reactive lymphocytes

and lead to the development of autoimmune
diseases.
 Role of Infections in Autoimmunity (contd)

Abbas, 2004
Induction of autoantibodies by cross-reactive
antigens
Mechanisms of autoimmune diseases
( tissue injury in autoimmunity )
 Loss of
Self Tolerance

Abnormal
AUTOIMMUNITY immune response

AUTOIMMUN Tissue injury

DISEASE
 Autoimmune diseases are hypersensitivity reactions in
which an exaggerated response is triggered by self-
antigen

Mechanisms of autoimmune diseases

• Antibody-mediated ( type II hypersensitive reactions)

: auto immune hemolytic anemia
• Immune-complex-mediated ( type III ) : SLE,
glomerulonephritis, vasculitis
• Cell-mediated ( type IV) : rheumatoid arthritis , type
I diabetes mellitus )
 Two types of autoimmune disease
Brain
Multiplesclerosis (?)

Thyroid
Hashimoto’s
primary myxedema
Muscle
thyrotoxicosis
dermatomyositis
Muscle
myasthenia gravis Kidney
SLE
Stomach Skin
Pernicious anemia Scleroderma
SLE
Adrenal
Addison’s disease
Joints
Pancreas
Rheumatoid arthritis
Insulin – dependent
diabetes mellitus
Grave’s Disease
Systemic Lupus Erythematosus
Myasthenia Gravis
Rheumatoid Arthritis
Ankylosing Spondylitis
Pemphigus Vulgaris
Scleroderma (Systemic Sclerosis)
 Summary
• Self tolerance is physiologically maintain : T and B cells are
prevented from responding to self.
• T and B cells tolerance is develop through central and
peripheral mechanisms
• Genetic factors and environmental factors play important role
in the development of autoimmunity
• Autoimmune diseases ( tissue injury ) can be classified in the
same way as the hypersensitivy ( excluding type I
hypersensitivity )