Tolerance & Autoimmunity Flashcards
Self-antigens
an individual’s own antigens
Immunologic tolerance
unresponsiveness to self-antigens
Tolerogens
antigens that induce tolerance
Immunogens
antigens that induce an immune response
Autoimmunity
failure of self-tolerance and resulting immune reaction to self-antigens
Location: Tolerogenic self antigens
presence in generative organs (some self antigens) induces negative selection and other mechanisms of central tolerance
Location: Immunogenic foreign antigens
presence in blood and peripheral tissues (most microbial antigens) permits concentration in secondary lymphoid organs
Tolerogenic self antigens and Accompanying costimulation
Deficiency of costimulators may lead to T cell anergy or apoptosis, development of Treg, or sensitivity to suppression by Treg
Immunogenic foreign antigens and Accompanying costimulation
Expression of costimulators, typically seen with microbes, promotes lymphocyte survival and activation
Tolerogenic self-antigens and Duration of antigen exposure
Long-lived persistence (throughout life); prolonged TCR engagement may induce anergy and apoptosis
Immunogenic foreign antigens and Duration of antigen exposure
Short exposure to microbial antigen reflects effective immune response
3 Characteristics of Tolerance
Induced
Antigen-specific
Induced during central tolerance OR peripheral tolerance
Generative (central) tolerance occurs
in central lymphoid organs
Central tolerance for T cells occurs in
thymus
Central tolerance for B cells occurs in
bone marrow
Mechanisms of Central Tolerance for T cells
Deletion (- selection)
Regulatory T cells
Mechanisms of Central Tolerance for B cells
Receptor editing
Anergy
Deletion
Peripheral Tolerance occurs in
peripheral tissues
-spleen, lymph nodes, etc.
Mechanisms of Peripheral Tolerance for T cells
Suppression
Anergy
Deletion
Mechanisms of Peripheral Tolerance for B cells
Suppression
Anergy
Deletion
Positive selection occurs in the
cortex of thymus with assistance of cTECs (cortical epithelial cells)
Negative selection occurs in the
medulla of thymus with assistance of mTECs (medullary epithelial cells)
Type of cells that undergo positive selection in thymus
Double positive (CD4+/CD8+) thymocytes
Weak recognition of class II MHC + peptide
results in Mature CD4+ T cell
Weak recognition of class I MHC + peptide
results in Mature CD8+ T cells
Strong recognition of either class I or class II MHC + peptide
results in apoptosis (negative selection)
T cells surviving negative selection
exist as Mature, Single Positive CD4+ or CD8+ T cells and leave the thymus
AIRE (Autoimmune Regulator Protein)
TF that resides in mTECs
Controls expression of peripheral tissue self-antigens
Critical role in negative selection and self-tolerance
Expression of air leads to
protective immunity
Deficiency of air leads to
Autoimmunity (APS-1 disease)
AIRE deficiency and regulatory T cells
Even in the absence of AIRE, you still get development of Tregs!
Central T lymphocyte Negative Selection
Deletion of immature lymphocytes that interact strongly with self antigen
but, Imperfect Process
APECED
aka APS1
Autosomal recessive inheritance
Mutations in AIRE gene (chromosome 21q22.3)
Triad: “HAM”
APECED triad (symptoms)
“HAM”
Mucocutaneous candidiasis
Adrenal insufficiency
Hypoparathyroidism
T cell Central Tolerance: Regulatory T cell Development
Some self-reactive CD4+ T cells will not be deleted, but instead will differentiate into regulatory T cells
Are all self-reactive T cells deleted following failure of Negative selection?
No, some self-reactive CD4+ T cells become Tregs
Development of Tregs is independent of
AIRE
Tregs exit thymus and enter the periphery in order to
inhibit responses against self-antigens
Important for inhibiting responses against self-antigens
Tregs
CD markers on Tregs
CD3+ CD4+ CD25 (high) and FoxP3+
Cytokines produced by Tregs
IL-10 and TGF-beta
Natural Tregs
made in thymus
APECED Clinical Manifestations
Candidiasis Hypoparathyroidism Adrenal failure Hypothyroidism DM Alopecia Vitilligo Gastritis/Pernicious anemia Immune hepatitis
Anergy defiintion
Functional unresponsiveness
Suppression definition
Block in activation
Deletion definition
apoptosis
Two signal hypothesis
-T cell proliferation and differentiation requires antigen-induced signals and costimulators
Best characterized pathway in T cell activation
B7: CD28 family of costimulators
CD28 expressed on
T cells
B7 expressed on
APCs
CTLA-4 expressed on
activated T cells and Tregs
CTLA-4 function
negative regulation of immune responses; self-tolerance
2 Mechanisms by which T cells become Anergic (unresponsive)
(1) block in signaling from TCR complex
(2) engagement of inhibitory receptors
2 Drugs involved in therapeutic manipulation of CTLA-4
Ipilimumab
Abatacept
Ipilimumab
Monoclonal antibody against CTLA-4
enhances T cell activation and antitumor immunity
Abatacept
consists of EC domain of CTLA4 and Fc region of IgG1
binds CD80/86 (B7) on APC
interrupts CD28-mediated costimulation
causes T cell anergy
What cells do the drugs Ipilimumab and Abatacept bind?
Ipilimumab binds up T cells (binds at CTLA4)
Abatacept binds up APCs (binds at CD80/86)
Tregs require ______ for growth
IL-2
CD25
receptor for IL-2
Tregs require _______ for function; expression is induced by ________
FoxP3
TGF-beta
3 Mechanisms by which Induced Peripheral T regs suppress immune responses
(1) Production of inhibitory cytokines (IL-10, TGF-beta) to inhibit effector T cell functions
(2) Expression of CTLA-4 (to inhibit naive T cell activation)
(3) Expression of IL-2 receptor and capture of IL-2
IPEX
mutations in FoxP3 gene
X-linked recessive
Triad: EDE
IPEX triad (symptoms)
EDE
Enteropathy (diarrhea)
Dermatitis (eczemous rash)
Endocrine disease (diabetes/thyroid)
2 Mechanisms of Peripheral T cell Deletion (apoptosis)
(1) Deficiency of survival signals (expression of pro-apoptotic proteins induces apoptosis)
(2) Engagement of death receptors (FasL binding Fas induces apoptosis)
Fas ligand expressed on
T cells
ALPS
disorder of apoptosis
mutations in Fas, FasL, caspase 8/10
chronic accumulation of lymphoid cells
defective lymphocyte apoptosis in vivo
ALPS symptoms
(1) Lymphoproliferation
- splenomegaly
- hepatomegaly
- lymphadenopathy
(2) Autoimmunity to RBCs
- autoimmune hemolytic anemia
- autoimmune thrombocytopenia
- autoimmune neutropenia
(3) Increased risk for lymphomas
B lymphocyte tolerance important for maintaining unresponsiveness to
(1) nonprotein, T-independent antigens (e.g. polysaccharides, lipids, nucleic acids)
(2) protein self-antigens
Defective B lymphocyte tolerance may contribute to
autoantibody production in autoimmune disorders
In response to lipids, polysaccharides, etc. (non-protein antigens), B cells…
become (short-lived) IgM secreting plasma cells
2 responses to High-Avidity self-antigen recognition by Central B cells
(1) Receptor editing: expression of new Ig V region –> non-self reactive B cell
(2) Apoptosis –> deletion
Response to Low-Avidity self-antigen recognition by Central B cells
(1) Reduced receptor expression, signaling –> anergic B cell
3 Mechanisms of Peripheral B Cell Tolerance in response to self-antigen binding
(1) Functional inactivation –> anergy
(2) Apoptosis –> deletion
(3) inhibitory receptors –> regulation/suppresion by inhib receptors
Failure of Self-tolerance results in
Self-reactive lymphocytes
Reaction to environmental stimuli in Autoimmunity
Environmental stimuli
Tissue injury and inflammation
Activation of tissue APCs
Activation of self-reactive lymphocytes
Self-reactive effector lymphocytes cause tissue injury: autoimmune disease
Single Gene Defects that cause autoimmunity
AIRE
FOXP3
FAS
SLE
- Systemic autoimmune disorder (multi-organ)
- Loss of immunological tolerance to multiple self antigens (defective B and T cell tolerance)
- Autoantibodies primarily to nuclear constituents
- Predominantly affects women of childbearing age
Genetic influences of SLE
family history
complement deficiency (C1q, C2, C4)
TREX1
HLA-DR2 and DR3
Antinuclear antibodies in SLE
Anti-dsDNA antibody
Anti-Smith antibody
SLE symptoms
Malar rash
Phostosensitivity
Oral or nasal mucocutaneous ulcerations
Nonerosive arthritis
Nephritis
Encephalopathy (seizures, psychosis)
Immunological self tolerance
unresponsiveness to specific antigenes INDUCED by exposure of lymphocytes to that antigen
