FE A. BARTOLOME, MD, FPASMAP
Department of Microbiology
Our Lady of Fatima University
IMMUNOLOGICAL TOLERANCE
• State in which the individual is
incapable of developing an immune
response to a specific antigen
• Self-tolerance  lack of
responsiveness to an individual’s
antigens
• Central tolerance & peripheral
tolerance
CENTRAL TOLERANCE
• Clonal deletion of self-reactive T and B
lymphocytes during their maturation in
the central lymphoid organs
CENTRAL TOLERANCE
T cells
• T lymphocytes that bear high-affinity
receptors for self-antigens are
negatively selected or deleted 
undergo apoptosis
• occur during fetal development
CENTRAL TOLERANCE
B cells
• Also undergo clonal deletion
• Developing B cells encounter a
membrane-bound antigen within the
bone marrow  B cells undergo
apoptosis
• Occur throughout life
PERIPHERAL TOLERANCE
• Self-reactive T cells that escape
intrathymic negative selection are
deleted or muzzled in the
peripheral tissues
PERIPHERAL TOLERANCE
MECHANISMS:
1.Clonal deletion by activation-induced
cell death
2.Clonal anergy
3.Peripheral suppression by T cells
PERIPHERAL TOLERANCE
Clonal deletion by activation-induced cell
death
• Apoptotic death of activated T cells by
the Fas-FasL system
• Self-antigens abundant in peripheral
tissue (e.g. collagen, thyroglobulin) 
repeated & persistent stimulation of
self-antigen-specific T cells  activation
of Fas-mediated apoptosis
Clonal deletion in thymus
Antigen
A
A
A
Cell
death
B
B
B
Two immature T cells
(A and B) with different
antigen receptors
Binding of self
antigen to T-cell A in
thymus but not to Tcell B
Death of self-reacting Tcell A; survival of T-cell
B that reacts against
foreign antigen
PERIPHERAL TOLERANCE
Clonal anergy
• Prolonged or irreversible functional
inactivation of lymphocytes
• Induced by encounter with antigens
• T cells – due to absence of co-stimulatory
molecules on APCs, such as B7-1 & B7-2
• B cells – due to lack of T cell help for
antibody synthesis (T cell anergy or downregulation of surface IgM)
PERIPHERAL TOLERANCE
Antigen
Class II
MHC
Antigen
Class II
MHC
TCR
Helper T
cell
APC
B7
protein
CD28
protein
TCR
Helper T
cell
APC
CD28
protein
CD4
protein
CD4
protein
B7 protein on APC interacts
with CD28 on helper T cells.
Full activation of helper T
cells occur.
B7 protein on APC is not
produced. CD28 on helper T
cell does not give a costimulatory signal. Anergy
occurs.
PERIPHERAL TOLERANCE
Peripheral suppression by T cells
• Suppressor T cells – with ability to
down-regulate the function of other
autoreactive T cells
• Shift immune response from TH1 to TH2
• TH2 generally immunosuppressive 
down-modulate TH1 response
Factors Affecting ArtificiallyInduced Tolerance
1.Form, dose & route of administration
• Very simple molecules induce tolerance
more readily than a complex one
• Very high or very low doses of an antigen
may result in tolerance instead of an
immune response
• Purified polysaccharides or amino acid copolymers injected in very large doses
result in “immune paralysis”
Factors Affecting ArtificiallyInduced Tolerance
2.Immunologic “maturity” of the host
• E.g. neonates  immunologically immature 
do not respond well to foreign antigens
3.Chimerism
• Tolerance induced by inoculation of
allogeneic cells into hosts that lack immune
competence
4.Antibodies to CD4 and CD8
• Tolerance of transplanted tissues by
inoculating graft recipient with monoclonal
antibodies against CD4 and CD8
Factors Affecting ArtificiallyInduced Tolerance
5.Clonal exhaustion
• Repeated antigenic challenge
• Stimulate B and T cell to differentiate
into short-lived end cells
Factors Affecting ArtificiallyInduced Tolerance
6. Clonal anergy induced by anti-idiotypic
antibodies & antagonistic peptides
• Antibody combining site (idiotype) act as
antigen  induce formation of anti-idiotypic
antibodies  cross-link on B cells  prevent
interaction with Ag
• Antagonistic peptides  fit into Ag-binding
site of MHC  no activation of T cells
Other aspects of induction/maintenance of
tolerance
•
T cells become tolerant more readily and
remain tolerant longer than B cells.
•
Administration of a cross-reacting antigen
tends to terminate tolerance.
•
Administration of immunosuppressive
drugs enhances tolerance.
•
Tolerance is maintained best if the antigen
to which the immune system is tolerant
continues to be present.
AUTOIMMUNITY
• Immune reaction against self-antigens
• Requirements:
1.Presence of an autoimmune reaction
2.Clinical or experimental evidence
that reaction is not secondary to
tissue damage but is of primary
pathogenetic significance
3.Absence of another well-defined
cause of the disease
AUTOIMMUNITY
• Most important step in production of
autoimmune disease: activation of
self-reactive CD4 T cells
• Most are antibody-mediated
AUTOIMMUNITY
GENETIC FACTORS
• (+) genetic predisposition
• Strong association with HLA
specificities, especially class II genes
• Class I MHC-related: ankylosing
spondylitis & Reiter’s syndrome; more
common in men
• Class II MHC-related: RA, Grave’s
disease, SLE; more common in women
AUTOIMMUNITY
HORMONAL FACTORS
• Approximately 90% occur in women
• Estrogen can alter the B-cell
repertoire and enhance formation of
antibody to DNA
AUTOIMMUNITY
ENVIRONMENTAL FACTORS
• Exposure to an environmental agent
can trigger a cross-reacting immune
response against some component of
normal tissue
• Example: S. pyogenes & rheumatic
fever
AUTOIMMUNITY: Mechanisms
Defects in clonal deletion mechanisms
• Thymic defects that lead to
proliferation of self-reactive T cells
• Failure of central tolerance
AUTOIMMUNITY: Mechanisms
Polyclonal lymphocyte activation
• Microorganism-derived mitogens
stimulate lymphocytes
• Microbial products (e.g. LPS)  act as
superantigens  activate a large pool
of T and B cells
AUTOIMMUNITY: Mechanisms
Molecular mimicry
• Microbial antigens with similar
structure to self-antigens  activate
autoreactive T cells
• Cross-reactivity-induced immune
response
• Example: M protein of S. pyogenes
and myosin of cardiac muscle
AUTOIMMUNITY: Mechanisms
Release of sequestered antigens
• Immunologically privileged sites
(brain, ant. eye chamber, ovary,
placenta, testis, pregnant uterus) 
not exposed to immune system
• Damage  release of antigens  elicit
immune response
AUTOIMMUNITY: Mechanisms
Defects in the regulation of TH1 and
TH2 cells
• Impaired T suppressor cell
immunoregulation
Microbial infections associated with autoimmune
diseases
Microbe
Autoimmune disease
BACTERIA
Streptococcus pyogenes
Campylobacter jejuni
Escherichia coli
Chlamydia trachomatis
Shigella sp.
Yersinia enterocolitica
Borrelia burgdorferi
Rheumatic fever
Guillain-Barre syndrome
Primary biliary cirrhosis
Reiter’s syndrome
Reiter’s syndrome
Grave’s disease
Lyme arthritis
VIRUSES
Hepatitis B virus
Hepatitis C virus
Measles virus
Cytomegalovirus
Multiple sclerosis
Mixed cryoglobulinemia
Allergic encephalitis
Scleroderma
ORGAN-SPECIFIC AUTOIMMUNE DISEASES
Type of Immune
Response
Autoimmune Disease
Target of Immune
Response
Antibody to
receptors
Myasthenia gravis
Grave’s disease
Acetylcholine receptor
TSH receptor
Antibody to cell
components
other than
receptors
Pernicious anemia
Intrinsic factor and
parietal cells
BM of kidney & lung
Islet cell
Adrenal cortex
Sperm
Desmoglein in tight
junctions of skin
Thyroglobulin
Thyroid peroxidase
Goodpasture’s synd.
IDDM
Addison’s disease
Male infertility
Pemphigus
Hashimoto’s
Primary myxedema
NON-ORGAN SPECIFIC AUTOIMMUNE DISEASES
Type of Immune
Response
Antibody to cell
components
other than
receptors
Autoimmune Disease
Target of Immune
Response
Rheumatoid arthritis
IgG in joints
SLE
dsDNA, histones
Sjogren’s syndrome
(Sicca syndrome)
RNP antigens (SSA/Ro and SS-B/La)
Guillain-Barre synd.
Myelin protein