Immunological Tolerance Flashcards
Immunological Tolerance
A state of unresponsiveness for a particular antigen
– LEARNED, very specific and induced by prior exposure to antigen
– Includes tolerance to non-self antigen
• Self tolerance – physiological state in which the
immune system does not react destructively against self tissue
Self-tolerance may be induced in
immature self-reactive lymphocytes in generative lymphoid organs (central tolerance), or in mature lymphocytes in peripheral sites (peripheral tolerance)
Central Tolerance-
occurs in generative lymphoid organs (bone marrow/thymus) involving immature self-reactive lymphocytes recognizing self antigen
Peripheral Tolerance-
in peripheral sites involving mature self-reactive lymphocytes encountering self antigen
- Immunological tolerance is NOT simply a failure to recognize an
antigen
Immunological tolerance is
ItISanactiveresponsetoaparticularepitope and is just as specific as an immune response
Tolerancecanbe
natural(selftolerance,oral tolerance)…or induced (e.g.- prevent allergies, graft rejection or autoimmunity)
Reactivity is prevented by
y processes that occur during development rather than being genetically pre- programmed.
• The most important aspect of tolerance is
self tolerance, which prevents the body from mounting an immune attack against its own tissues.
Those lymphocytes that do not bind MHC through their TCR are destined to
die by apoptosis.
• During maturation in the thymus, most immature T cells that recognize antigens with high avidity are
deleted
Some self-reactive CD4+ T cells that see self antigens in the thymus are not
deleted but instead
differentiate into regulatory T cells
choice between lymphocyte activation and tolerance is determined by:
the properties of the antigens
– state of maturation of the antigen-specific lymphocytes
– types of stimuli received when these lymphocytes encounter self antigens
Central tolerance in B cells: Occurs in
immature B cells in the bone marrow
Potentially autoreactive cells can be
eliminated or inactivated by contact with self Ag
• Nature and concentration of the self Ag
determine the fate of
B cells
Multivalent Ag (membrane associated proteins) induce
B cell death
– High concentrations of Ag induce
B cell death
Lower concentrations of small, soluble self Ag induce
functional anergy
Peripheral tolerance is the mechanism by which
mature T cells that recognize self antigens in peripheral tissues become incapable of responding to these antigens
PT: Clonal deletion/apoptosis-
Actual elimination from the cellular repertoire by activation induced cell death
PT: Clonal anergy-
mature cell is present but is functionally inactivated (can be reversed)
PT Suppression- i
inhibition of cellular activity through interaction with other cells
– T regs (CD4+/CD25+ T cells, TGF-β or IL-10 secreting reg T cells)
Ignorance- co-existence of
self-reactive clones and antigen; cells do not respond to antigen
Peripheral tolerance in B cells- Not all potentially reactive cells are
eliminated or inactivated and enter peripheral circulation
• TWO SIGNAL HYPOTHESIS - how T cells affect B cell activation
Signal one: Generated through the Ag receptor
Signal two: mediated by CD40 and CD40L
B cell anergy results if one of the signals is mis
Anergic cells show a block in
TCR-induced signal transduction
- Lack of costimulation by B7/B72
- costimulation by inhibitory receptors
- e.g. CTLA-4
-CTLA-4 competes with CD28 for
B71 and B72 -binds with higher affinity than CD28
-CTLA-4 keeps T cells in
check
-knockout mice lacking CTLA-4 develop
- uncontrolled lymphocyte activation
- massively enlarged lymph nodes and spleen
- fatal multiorgan lymphocytic infiltrates (suggestive of systemic autoimmunity)
– Activation in the absence of IL-2 can lead to
death
Self-reactive cells may be ‘deleted’ from the repertoire.
Activation in the absence of IL-2 can lead to death – Persistent Ag
– Activation-induced cell death
The state of tolerance may be maintained by
immune regulation
How does ignorance happen?
Antigen is expressed in a privileged site/sequestered.
- T cells cannot get to the antigen across an endothelial barrier
- Perhaps the antigen is not expressed in the context of MHC molecules.
• Foreign antigens may be administered in ways that preferentially
induce tolerance rather than immune responses
protein antigens administered subcutaneously or intradermally with adjuvants
favor immunity
high doses of antigens administered systemically without adjuvants tend to
induce tolerance
• Oral administration of Ag favors
tolerance induction
• A state of immune hyporesponsiveness follows
oral administration of an antigen
Oral tolerace is
Responsible for maintenance of homeostasis
– No immune response to food antigens
Human disease trials utilizing fed proteins to abrogate autoimmune disease
lack of toxicity, ease of administration over time, and antigen-specific mechanism of action
• MS (glatiramer acetate/cop1 - resembles human myelin (4 a.a) • Uveitis (peptide B27PD – resembles retinal autoantigen protein) • Type 1 Diabetes (Human insulin)
• T cells (Cell mediated responses)–
Recognize processed antigen in the context of MHC to irradicate infection
– Effector functions include cytokine production and release of cytotoxic factors
B cells (Humoral responses)-
Recognize free antigen via Ig receptor to irradicate infection
Effector functions include antibody mediated destruction of antigen
What is Autoimmune Disease?
Group of more than 80 serious, chronic illnesses/syndromes that can involve almost every organ system
– includes diseases of the nervous, gastrointestinal, and endocrine systems as well as skin and other connective tissues, eyes, blood, and vasculature.
• Occurs when the immune system
becomes dysregulated and attacks the
very organs it was designed to protect
- AUTOIMMUNITY RESULTS WHEN CENTRAL AND PERIPHERAL TOLERANCE IS
broken
Mechanisms that lead to autoimmunity
remain unclear
Genetic Factors: •Autoimmune diseases tend to occur in
families and this concordance is largely genetic.
•Greater concordance between identical twins for some diseases.
•Strong HLA/MHC association.
Many autoimmune diseases affect
women much more commonly than men
Severity/course of autoimmune disease may also differ between
sexes
Rheumatoid arthritis is typically more aggressive in
females
Multiple Sclerosis can differ in clinical course between females and males
- Females tend to have a relapsing-remitting disease course
* Males tend to exhibit a chronic progressive disease course
What initiates an autoimmune response???
Incomplete deletion of self reactive cells
• Aberrant stimulation of “normally” anergic self reactive cells
• Altered regulation of anergic self reactive cells
Systemic
Immune cells target multiple organ systems and tissues
– Thought to be due to aberrant regulation of many clones of lymphocytes
Organ Specific
Immune cells target specific organs or tissue
– Thought to be due to failure of self tolerance in only a few clones of cells which react to a limited number of antigens
Systemic Lupus Erythematosus (SLE) –
A systemic disorder in which a variety of autoantibodies (DNA, nucleoproteins, platelets, lymphocytes) can cause multisystem damage
Multiple Sclerosis (MS) –
Immune System targets Central Nervous System via myelin specific T cells
SLE Clinical Features
• Multisystem disorder characterized by a variety of autoantibodies • Increased risk associated with HLA DR2 and HLA DR3 • Female/male predominance 10:1 • Initial onset of symptoms typically occurs between 15-25 years of age • Typical symptoms include – Fatigue – Fever – Alopecia – Mucosal ulceration – Butterfly rash – Joint and muscle pain • Severe complications – Kidney, Heart, lung, CNS
SLE Pathogenesis
Immune complex disease (type III hypersensitivity)
Large amounts of autoantibodies produced against
SLE pathogenesis
self antigens
– DNA
– Nucleoproteins – Platelets
– Lymphocytes
SLE pathogenesis: • Immune complexes deposit in
kidneys, joints and vessel walls
Nonsteroidal anti-inflammatory drugs (NSAIDS) are used to treat
arthritic symptoms of lupus
• Corticosteroid creams are used to treat
skin rashes
Antimalarial drugs sometimes used for
skin and arthritis symptoms.
Corticosteroid therapy or cytotoxic (anti-proliferative) drugs may be used in
severe or life-threatening manifestations of the disease
• Kidney transplant indicated for
advanced Lupus nephritis
MS Clinical Features
The most common inflammatory disorder of the central nervous system
• Increased risk associated mainly with HLA DR2
• Female/male predominance is 3:2
• Those affected can exhibit a relapsing-remitting or a chronic progressive disease
• Pathologic hallmark is the CNS plaque with loss of myelin and depletion of oligodendrocytes with or without axon loss
• Typical onset
– women of childbearing years
– In men onset is typically >40 years of age
• Symptoms include
– Impaired vision (optic neuritis)
– Ataxia
– Spasticity
– Bladder dysfunction
– Weakness/Paralysis of one or more limbs – Sensitivity to temperature
– Cognitive impairment
MS Pathogenesis
• T cell mediated autoimmune disease in which T cells are specific for components of the myelin sheath
MS: Also evidence of macrophage and microglial cell involvement in
myelin degradation
MS: • Damage to/loss of myelin impairs
nerve conduction
MS Treatments
Immunomodulatory Drugs • Corticosteroids
• Immunosupressive therapy
