Transcript Document

Lecture outline
• Self-tolerance: concept, significance
• Mechanisms of central and peripheral
tolerance: deletion, anergy, regulatory T
cells
• Pathogenesis of autoimmunity: roles of
susceptibility genes and environmental
factors
The immunological equilibrium: balancing
lymphocyte activation and control
Activation 
Effector and
memory T cells
Normal: reactions against
pathogens
Pathologic: inflammatory
disease, e.g. caused by
reactions against self
Tolerance
Regulatory T cells
No response to self
Controlled response to
pathogens
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
What self antigens are seen in the
thymus?
• Ubiquitous cell-associated and circulating
proteins
• The thymus has a special mechanism for
displaying peripheral tissue antigens in
thymic medullary epithelial cells, where
they signal self-reactive thymocytes for
death
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”)
• Mouse knockout: autoantibodies against multiple
endocrine organs, retina
– Failure to express many self antigens in the
thymus --> failure of negative selection
Deletion of self-reactive T cells in the thymus:
how are self antigens expressed in the thymus?
AIRE (autoimmune
regulator) is a regulator
of gene transcription
that stimulates thymic
expression of many self
antigens which are
largely restricted to
peripheral tissues
Discovered as the
genetic cause of a
human autoimmune
disease (APS-1)
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
• 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
13
Peripheral tolerance
Costimulation
(signal 2)
Immunogenic
antigen
APC
(microbe,
TCR
vaccine) Antigen (peptide +
HLA): signal 1
Naïve
T cell
Effector and
memory cells
Tolerogenic
antigen (e.g.
self)
Tolerance: functional
inactivation or cell death,
or sensitive to suppression
T cell anergy
T cell anergy (“clonal anergy”)
• Induced by self antigens that are displayed
to the immune system without inflammation
or innate immune responses (prolonged signal
1, i.e. antigen, inadequate signal 2)
• Recognition of such antigens may lead to
signaling block and/or engagement of
inhibitory receptors
• Role of anergy in self-tolerance in humans is
unclear; therapeutic potential?
Regulatory T cells
Regulatory T cells
• Regulatory T cells are CD4+ cells that
express high levels of CD25 (IL-2
receptor a chain)
– Generated by self antigen recognition in the
thymus or peripheral tissues
– Generation requires a transcription factor
called Foxp3 (mutations in Foxp3 are the cause
of a severe autoimmune disease in humans and
mice)
Regulatory T cells
•
Regulatory T cells are CD4+ cells that express high levels of CD25
(IL-2 receptor a chain)
• Mechanism of action: may be multiple
– Secretion of immune-suppressive cytokines
– CTLA-4 on Tregs blocks B7 on APCs
• Significance for self-tolerance:
– Some autoimmune diseases may be associated
with defects in regulatory T cells or resistance
of responding cells to suppression
– Therapeutic potential of cellular therapy
(autoimmune diseases, graft rejection, etc)
“Activation-induced cell death”: death of mature
T cells upon recognition of self antigens
Deletion (activation-induced cell death)
• Stimulation of T cells by self antigen triggers
apoptosis by engagement of death receptors
(“death receptor pathway”) or imbalanced
expression of pro-apoptotic proteins
(“mitochondrial pathway”)
• Evidence for the importance of AICD in
maintenance of self-tolerance:
– Mice with mutations in Fas or Fas ligand develop a
lupus-like autoimmune disease
– Humans with mutations in Fas or enzymes involved in
death receptor-induced apoptosis (caspases): the
autoimmune lymphoproliferative syndrome (ALPS)
– Eliminating both death pathways in mice -->
“spontaneous” systemic autoimmune disease
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
– Engagement of inhibitory receptors
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 organ-specific; may be caused by different
types of immune reactions (antibody- or T cellmediated)
Autoimmunity
•
•
Definition: immune response against self (auto-) antigen
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 organ-specific; may be
caused by different types of immune reactions
• Challenges in understanding pathogenesis of
human autoimmune diseases:
– Failure to identify target antigens,
heterogeneous disease manifestations, disease
may present long after initiation
– Recent advances: identifying self antigens (MS,
type 1 diabetes); genetic analyses; improved
methods for studying immune system of patients
Pathogenesis of autoimmunity
Genetic basis of autoimmunity -- 1
• Genetic predisposition of autoimmune diseases
– Increased incidence in twins (more in monozygotic
than in dizygotic twins)
– 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 gene variants identified by genome-wide
association and linkage studies
– Many of these variant genes individually have
small effects on disease susceptibility, may
influence disease when present in combination
– Interactions with environmental factors
difficult to define
Genetic basis of autoimmunity -- 3
• Genome wide association studies are
revealing genetic polymorphisms associated
with autoimmune diseases
– 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, others:
• CD25 (IL-2 receptor): role in T cell activation and
maintenance of regulatory T cells
Genetics of autoimmunity: challenges
• Difficult to relate complex genotypes to
phenotypic and functional abnormalities, to
better understand pathogenesis
• Limitations of GWAS: detects frequency
of common variants, misses rare mutations
• Identified disease-associated
polymorphisms have small effects,
therefore little predictive value
• Because of small effects of any one gene,
targeting these genes therapeutically is
unlikely to have significant benefit
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 certain infections
– Type 1 diabetes, multiple sclerosis, others? - increasing incidence in developed countries
– Mechanism unknown; the “hygiene hypothesis”
Mechanisms by which infections may promote autoimmunity
Other environmental influences
• Hormones
– Gender bias of autoimmune diseases
– Mechanisms still not defined
• UV exposure
– SLE
Understanding autoimmunity
• Experimental models have been very
valuable for defining pathways of normal
and abnormal immune responses, BUT
they may have limited value for
understanding human diseases
• Need technologies for studying patients
• Emphasis should be on antigen-specific
immune responses