Immunological Tolerance and Auto immune disease Flashcards
A state of Unresponsiveness for a particular antigen
Immunological Tolerance
How does one get Immunological Tolerance
It is learned by a very specific and priorly exposed antigen
What Immunological Tolerance lead to
Tolereance to a non-self antigen
the physiological state in which the immune system does not react destructively against self tissue
Self Tolerance
Normal immune response to A microbe
Proliferation and differentiation
selftolerance immune response to a self antigen
Anergy (functionally unresponsiveness
Deletion (Cell death)
Cheng in specificity (receptor editin)
Where may self-tolerance be induced
In immature self-reative lymphocytes in generative lymphoid organs or in mature lymphocytes in peripheral sites
Self tolerance induced in mature lymphocytes in peripheral sites
Peripheral tolerance
Self tolerance induced in immatuer self reactive lymphocytes in generative lymphoid organs
Central tolerance
where does Central tolerance occur
In generative lymphoid organs (bone marrow/thymus)
what cells does Central tolerance involve
Immature self-reactive lymphocytes recognizing self antigen
Where does PEripheral Tolerance occur
In peripheral sites
what cells does Peripheral Tolerance invovle
MAture self-reactive lymphocytes encountering self antigen
Is immunologica tolerance a failure to recognize an antigen
no
What is Immunological tolerance a response to
an active response to a particular epitope
How specific is Immunological tolerance
just as specific as an immune response
How can Immunological tolerance come to be
Natural(self tolerance, oral tolerance…)
induced (prevent allergies, graft rejections or autoimmunity)
when does prevention of Reactivity to certain antigen develop
Occurs during development rather than being genetically pre-progammed
What does Self tolerance prevent
prevents the body from mounting an immune attach against its own tissues
T cells come out of the bone marrow in what state
A very immature state ( CD4-, CD8-, TCR-) -dont express any
where do Immature T cells begin to Express CD4, CD8, and TCR
in the cortex of thymus(get one type of CD and one type of TCR)
Where does T cells go through Positive and negatvei seelction
In the cortical region of thymus of positive selection
In the medullary region for negative selection
What is central tollerance part of
The positive and negative selction process
How do Cells leave the thymus
As a fully functioning cell
what types of cells leave the Thymus as a fully functioning cells
CD4+ helper T lymphocyte
CD8 cytotoxic T lympohocyte
Delta gamma T cell
What types of Lympohocytes area destined to die by apaoptosis
Those that do not bind MHC through their TCR
How does Positive selection and lineage commitment respond to antigen
Low avidity interaction with self antigen
Postiive selection leads to
MAturation of clonse and generation of subsets of lympohocytes and expansion and diferentiation
what mediates neagtive selection
by high avidity with self antigen
what happens to immature T cells that recognize antigens with high avidity during maturation in the thymus
They are deleated
what happesn to some self-reactive CD4+ t cells that see self antigens in the thymus that are not delected
Differentiate into regulatory T cells
What determines the choice between lymphocyte activation and tolerace
The properties of the antigens
The state of matuation of the antigen-specific lymphocytes
Types of stimuli ereceived when these lympohocytes encournter self antigen
recognition of self antigen by central tolerance leads to
Apoptosis (deletion)
Change in receptors (receptor editing B cells)
Development of regulatory T lymphocytes (CD4+ T cells only)
Recognition of self antigen by peripheral tolerance leads to
Anergy
Apoptosis (Deletion)
suppression
Recognition of self antigen by peripheral tolerance leads to
Anergy
Apoptosis (Deletion)
suppression
what type of B cells do Central tolerance and where
Immature B cells in the bone marros
why do Central tolerance in B cells
So that potentially autoreactive cells can be eliminated or inactivated by contact with self ag
steps of receptor editing in B cells
strong Ligation of IgM by self antigen
Arrest of B-cell development and continued light chain rearrangement: Low celL surface IgM
New Receptor specificty is expressed
If new receptor is still self reactive, B cell does Apoptosis
IF no longer self reactive, immature B cell migrates to the periphery and matures
What determines the Fate of B cells
NAture and concentration of the self Ag
What kind of Ag induces B cell death
Multivalent Ag( memebrane associated Proteins)
what concentration of Ag induces B cell death
High concentration of Ag
what induces functional anergy of B cells
Low concentrations of small, soluble self Ag
Functional anergy of B cells results in
Decreased membrane Ig
Blocked signal transduction by membrane bound Ig
What is the mechanism of Peripheral tolerance
Mature T cels that recognize self antigens in peripheral tissues become incapable of responding to these antigens
Mech of peripheral tolerance
Clonal Deletion/apoptosis
Clonal Anergy
Suppression
Ignorance
What is Clonal Deletion/apoptosis of Peripheral Tolerance
Actual elimination from the cellular repertoire by activation induced cell death
What is Clonal anergy of peripheral tolerance
Mature cell is present but is functionally inactivated and can be reversed
INhibition of cellular activity through interaction with other cells
Suppression
What cells do the suppression
T regs (CD4+/CD25+ T cells, TGF-beta or IL 10 secreting REg T cells)
What is ignorance in peripheral tolerance
Co-existence of self-reactive clones and antigen
cells do not respond to antigen
Factors determining which mechanisms are operative for peripheral tolerance
Concenration of self antigen in generative lymphoid organs
Affininty of antigen receptor for antigen
Nature of antigen
Concentration and availability of co-stimulatory molecules
why do peripheral tolerance in B cells
Not all potentially reactive cells are eliminated or inactivated and enter peripheral circulation
what is follicular exclusion
keeps some cells from the follicles and eventually elads to apoptosis
what is needed for a functional b cell response
Helper T cells
where is IgG found
In circulation
How do B cells work
Freely floating antigen that binds up a receptor on surface of Naive b Cell
This activates it and the B cell Clonally expands
genes then rearrange and some are spliced out to never return
Isotype switching all get IgM and some get other antibodies
what antibody is big in circulation
IgG
What do you look at with a titer
IgG
How do T cell affect the outcome of B cell activation in the peripher
via the Two signal hypothesis
what are the Signals of the two signal hypothesis
1: generated through the Ag receptor
2: mediated by AD40 and CD40L
What results if one of the signals from the two signal hypothesis is missing
B cell anergy
What do Anergic Cells show
show a Block in TCR-induced singal transduction
what costimulation occures in anergic cells
LAck costimulation by B7/B12
Costimulation by inhibitory receptors (CTLA-4
CTLA-4 for Peripheral tolerance through anergy competes with what
Competes with CD28 for B71 and B72 by binding with higher affinity than CD28
Roll of CTLA-4
Keeps T cells in check
What do knockout mice that lack CTLA-4 develop
Uncontrolled lymphocyte acitvation
massively enlarged lymph nodes and spleen
Fatal multiorgan lymphocytic infiltrates ( suggestive of systemic autoimmunity)
Normal T cell response to an antigen
Recognition of foreign antigen with costimulation
T cell proliferation and differentiation
T cell anergy antigen recognition
Recognition of self antigen
Signalling block or Engagement of Inhibitory receptors (CTLA-4)
Unresponsive (Anergic) T cell
what in peripheral tolerance can lead to apoptosis
Activation in the absence of IL-2
PErsistant Ag
Activation-induced cell death
Apoptosis due to persistence of antigen repeated stimulation leads to
FAS and FASL bind on the T cell
This activates Caspase-8
Activation-induced cell death
Apoptosis due to elimination of antigen and other signals
Release of Mitochontrial cytochrome C, activation of caspase-9
Passive cell death (death by neglect)
T cell mediated suppression results in
Inhibition of T cell activation
Inhibition of T cell effector function
How can the state of tolerance by maintained
Immune regulation
Il-10 inhibts
Inhibitions function of APCs: IL-12 secretion and B7 expression to step naive t cells drom recognizing antigens
TGF-beta inhibits
T cell proliferation
Il-4 inhibits
Actions of IFN-gamma stopping the effector function of T cells
Il-10, TGF-beta inhibit
Macrophage acivation
when self-reactive T cells ignore self antigen
Passive
How does Ignorance happen
Antigen is expressed in a privileged site/sequestered
T cells Cannot get to the antigen acorss and endothelial barrier
Perhaps the antigen is not expressed in the context of MHC molecules
How to preferentially induce tolerance rather than an immune response
Foreign antigens are administed
How are protein antigens administed to preferentiall induce tolerance
Subcutaneously or intradermally with adjuvants favor immunity
How are high doses of antigens administered to preferentially induce tolerance
Administered systemically without adjuvants
Can oral administration of Ag help with tolerance induction
Yes, it favors tolerance
what follows oral administration of an antigen
A state of immune hyporesponsiveness
What is the role of oral tolereance
Maintenance of homeostasis so no immune response to food antigen
why use oral tolerance
To abrogate autoimmune disease
lack or toxicity, ease to administrate over time
antigen-specific mech of action
How is Oral tolerance induce
ORal administration of Ag GALT 1. high dose Deletion or anergy of Th1 and Th2 cells Clonal deletion/anergy 2. Low dose INduction of Th2 (IL-4/IL-10) and secretion of TGF-beta Active suppression Both:: oral tolerance induction
How can the state of tolerance from oral administration be maintained
By the immune regulation
PRinciple site of Tolerance induction in T and B lymphocytes
T: Thymus (Cortex);periphery
B: bone marrow; periphery
Tolerance-sensitive stage of maturation of T and B lymphocytes
T: CD4+CD8+(double positive) thymocyte)
B: Immature (IgM+IgD-) B lymphocyte
Central stimuli for tolerance induction of T and B lymphocytes
T: high-avidity recognition of antigen in thymus
B: Recognition of multivalent antigen in bone marrow
Peripherial stimuli for tolerance induction ofT and B lymphocytes
T: antigen presentation by APCs lacking costimulators; repeated stimulation by self antigen
B: antigen recognition without T cell help or second signals
Pricniple mech of Central tolerance of T and B lymphocytes
T: Deletion (Apoptosis); development of regulatory T cells
B: Deletion (apoptosis); recetpor editing
Principle mech of Peripheral tolerance of T and B lymphocytes
T: Anergy, apoptosis, suppression
B: block in signal transduction (anergy); failure to enter lymphoid follicles; apoptosis
What type of Response do T cells do
Cell meidated Response
Roll of T cells
Recognize processed antigen in the context of MHC to irradicate infection
effector function of T cells
Cytokine production and release of cytotoxic factors
what type of response to B cells do
Humoral responses
roll of B cells
Recognize Free antigen via Ig Receptor to irradiacte infection
Effector function of B cells
Antibody mediated destruction of antigens
What all can Autoimmune diseases involve
NErvous GI Endocrin Skin connective tissue Eyes blood vasvulature
when does and autoimmune disease occur
When the immune system becomes dystregulated and attacks the very organs it was deisnged to protext
when does autoimmunity occure
When central and peripheral tolerance is broken
How common are autoimmune disease
each one is individually rare
collectively 5% of us pop(2% of globe)
14 million people
how does Autoimmunity happen
Unclear
Factors that can predispose an individual to arious autoimmune disease
MHC associations Familial concordance Gender Climate Chemical agents Infectious agents Immune sytregulation
Genetic factors for autoimmune disease
tend to occur in families
GReater concordance between ideantical twins
Strong HLA/MHC association
do men and women get more autoimmune disease
WOmen
is Rheymatoid arthritis more aggressive in male or female
female
course of Multiple sclerosis in males and femals
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
induction of costimulators on APCs/bystander activation
Molecular mimicry
Categories of autoimmune disease
Systemic
Organ specific
Systemic Autoimmune disease targets
Immune cels target multiple organ systems and tissues
What does a systemic autoimmune disease result for
Aberrant regulation of many clones of lymphocytes
ORgan specific autoimmune diseases target
Specific organs or tissues
how does ORgan specific autoimmune disease occure
Due to a failure of self tolerance in only a few clones of cells which react to a limited number of antigens
what is Systemic Lupus Erythematosus
A systemic disorder in which a variety of autoantibodies (DNA, nucleoproteins, plateltes, lymphocytes) can cause multisystem damge
What is Multiple sclerosis (MS)
Immunse system targets Central NErvous system via myelin specific T cells
What does SLE have increased risk associated with it
HLA DR2
HLA DR3
Female/Male predominacne of SLE
10:1
when does SLE symptoms occur
15-25 years old
Symptoms of SLE
Fatigue Fever Alopecia Mucosal ulceration Butterfly rash Joint and muscle pain
Severe complications of SLE
Kidney, heart, lung, CNS
what type of disease is SLE
Immune complex disease (type III hypersensitivity)
Autoantibodies produced by SLE attack
DNA
Nucleoproteins
Platalets
Lympohcotes
Where doe Immune complexes for SLE deposit
In kdneys
Joints
Vessel walls
TReat SLE
Nonsteroidal anti-inflammatory drugs (NSAIDS) to treat arthritic symptoms of lupus
Corticosteroid creams used to treat skin rashes
Antimalarial drugs used for skin and arthritis symptoms
Corticosteroid therapy or cytotoxic (anti-proliferative) drugs may be used in severe or life-threatening manifestation of the disease
WHen would someone need a kidney transplant for SLE
Advanced Lupus nephritis
what is the most common inflammatory disorder of the CNS
MS
what is the increased risk for MS
HLA DR2
Female/male predomininace of MS
3:2
what kind of Disease pattern of MS
Both Relapsing-remitting
Chronic progressive disease
what happens to the CNS due to MS
CNS plaque with loss of myelin and depletion of logodendrocytes with or without axon loss
when do women get MS
Childbearing years
when do men get MS
greater than 40 years of age
Symptoms of MS
Impaired vision (optic neuritis) Ataxia Spasticity Bladder Dysfunction Weakness/Paralysis of one or more limbs Sensitivity to temperature Cognitive impairment
How does The MS attach only the Myelin sheath
T cell mediated auto immune disease in which T cells are specific
also evidence of macrophage and microglial cells
What happens because of Damage to/loss of myelin
IMpairs nerve conduction
treating MS
Immunomodulatory drugs
Corticosteroids
Immunosupressive therapy
Inter-realtion of autimmune disease
can develop more than 1 autoimune disease
Can overlap too
2 common systemic Autoimmune diseases
Systemic Lupus Eryhtematosus
Rheumatoid arthritis
2 common organ specific Auto immune diseases
Insulin Dependant Diabetes Mellitus (IDDM)
Multiple Sclerosis m
