Download Peripheral tolerance

AUTOTOLERANCE
AND
AUTOIMMUNITY
The problem of self-nonself discrimination
• The immune system responds to many foreign
(microbial) antigens but not to self antigens
• Developing lymphocytes express a large number of
antigen receptors, not biased by specificity
• Therefore, all individuals produce lymphocytes with
the ability to recognize self antigens
• Self antigens have access to the immune system
• Therefore, self-reactive lymphocytes must be
selected against (eliminated or inactivated) to
prevent autoimmunity
Immunological tolerance
• Definition:
– specific unresponsiveness to an antigen that is
induced by exposure of lymphocytes to that
antigen (implies antigen specificity, in contrast to
“non-specific immunosuppression”)
• Significance:
– All individuals are tolerant of their own antigens
(self-tolerance); breakdown of self-tolerance
results in autoimmunity
– Therapeutic potential: Inducing tolerance may be
exploited to prevent graft rejection, treat
autoimmune and allergic diseases, and prevent
immune responses in gene therapy, perhaps stem
cell transplantation
Central and peripheral tolerance
The principal fate
of lymphocytes that
recognize self antigens
in the generative organs
is death (deletion), BUT:
Some B cells may change
their specificity (called
“receptor editing”)
Some T cells may
differentiate into
regulatory (suppressor)
T lymphocytes
Mechanisms of unresponsiveness to self antigens
• Central tolerance: Immature self-reactive
lymphocytes that recognize self antigens in
generative (“central”) lymphoid organs die by
apoptosis; other fates
• Peripheral tolerance: Mature self-reactive
lymphocytes that recognize self antigens in
peripheral tissues are inactivated (anergy), killed
(deletion) or suppressed
• “Clonal ignorance”: Mature self-reactive lymphocyte clones do
not encounter or respond to self antigens
• In normal individuals it is not known which self
antigens induce tolerance by which mechanism
Central T cell tolerance
Deletion of self-reactive T cells in the thymus:
how are self antigens expressed in the thymus?
AIRE (autoimmune
regulator) is a putative
transcription factor
that stimulates thymic
expression of many self
antigens, which were
thought to be restricted
to peripheral tissues
Discovered as the
genetic cause of a
human autoimmune
disease (APS-1)
Consequences of AIRE mutation
• Human disease: autoimmune polyendocrinopathy with
candidiasis and ectodermal dysplasia (APECED), also
called autoimmune polyendocrine syndrome (APS-1)
– Associated gene identified by positional cloning,
named AIRE (“autoimmune regulator”)
Central tolerance: fates of immature selfreactive lymphocytes
• Induced by antigen in generative lymphoid organs
(thymus for T cells, bone marrow for B cells),
and high-affinity (“strong”) recognition of the
antigens (dangerous lymphocytes)
• Immature lymphocytes undergo apoptosis upon
encounter with antigens (negative selection)
– Eliminates high-affinity self-reactive (potentially most
dangerous) lymphocytes
• Some self-reactive T cells that encounter self
antigens in the thymus develop into regulatory T
cells and immature B cells in the bone marrow
change their receptors (rendered harmless)
Peripheral tolerance
Normal T cell
response
Anergy
APC
CD28
T cell
TCR
APC
TCR
Off signals
Activated
T cell
Deletion
APC
Activated
T cells
Functional
unresponsiveness
Apoptosis
(activation-induced
cell death)
Block in
activation
Suppression
APC
Regulatory
T cell
T cell anergy
From Abbas, Lichtman and Pillai. Cellular and Molecular Immunology 6th ed, 2007
“Activation-induced cell death”: death of mature
T cells upon recognition of self antigens
ALPS
Regulatory T cells
From Abbas, Lichtman and Pillai. Cellular and Molecular Immunology 6th ed, 2007
Tolerance in B lymphocytes
• Central tolerance:
– Deletion of immature cells by high-affinity
antigen recognition in the bone marrow
– Some immature cells may change their antigen
receptors when they encounter antigens in the
bone marrow (“receptor editing”)
• Peripheral tolerance:
– Anergy
– Exclusion from lymphoid follicles, death because
of loss of survival signals
AUTOIMMUNE DISEASES
Frequency:
The most
frequent
diseases
5% of population
Reumatoid arthritis
Graves disease
Type I diabetes mellitus
Pernicious anemia
Systemic lupus erithematosus
Multiple sclerosis
Autoimmunity
• Definition: immune response against self (auto-)
antigen, by implication pathologic
• General principles:
– Pathogenesis: The development of autoimmunity reflects a
combination of susceptibility genes and environmental
triggers (usually infections)
– Different autoimmune diseases may be systemic or organspecific; may be caused by different types of immune
reactions (antibody- or T cell-mediated)
• Problems in understanding pathogenesis of human
autoimmune diseases:
– Failure to identify target antigens, heterogeneous disease
manifestations, disease may present long after initiation
GENETIC
PREDISPOSITION
- MHC genes
- non MHC genes
Environmental factors
AUTOIMMUNITY
- infection
- drugs
Genetic basis of autoimmunity -- 1
• Genetic predisposition of autoimmune diseases
– Increased incidence in twins (more in monozygotic)
– Identification of disease-associated genes by
breeding and genomic approaches
• Multiple genes are associated with
autoimmunity
– Most human autoimmune diseases are multigenic
– Single gene mutations and mouse knockouts reveal
critical pathways
Genetic basis of autoimmunity -- 2
• MHC genes
– Major genetic association with autoimmune
diseases (relative risk of disease in individuals
with particular HLA haplotypes)
– Disease-associated alleles are present in
normal individuals
• Non-MHC genes:
– Many loci identified by whole genome
association and linkage studies
– Most are chromosomal locations; actual genes
and roles in disease are largely unknown
Genetic basis of autoimmunity -- 3
• Genome wide association studies are being
done to define genes
– Crohn’s disease:
• NOD-2: microbial sensor in intestinal epithelial and
other cells
• IL-23 receptor: involved in TH17 responses
– Rheumatoid arthritis, others:
• PTPN-22 (tyrosine phosphatase): may control kinasedependent lymphocyte activation
– Multiple sclerosis:
• CD25 (IL-2 receptor): required for maintenance of
regulatory T cells
– Difficult to define pathways and target them for
therapies
Infections predispose to autoimmunity
Genes encoding antigen receptor
specific for a myelin antigen
Transgenic mouse with
myelin-specific T cells
Normal mouse colony
CNS disease
Pathogen-free mouse colony
No disease
Infections and autoimmunity
• Infections trigger autoimmune reactions
– Clinical prodromes, animal models
– Autoimmunity may develop after infection is
eradicated (i.e. the autoimmune disease is
precipitated by infection but is not directly
caused by the infection)
– Some autoimmune diseases are prevented by
infections (type 1 diabetes, multiple sclerosis,
others? -- increasing incidence in developed
countries): mechanism unknown; similar
protection suggested for asthma
• The “hygiene hypothesis”
Immune-mediated inflammatory
diseases
• Immune-mediated inflammatory diseases
develop because the normal controls on
immune responses fail
• These diseases often become selfperpetuating
• The phenotype of the disease is
determined by the nature of the immune
response