Immunological Tolerance and Auto immune disease Flashcards
(142 cards)
1
Q
A state of Unresponsiveness for a particular antigen
A
Immunological Tolerance
2
Q
How does one get Immunological Tolerance
A
It is learned by a very specific and priorly exposed antigen
3
Q
What Immunological Tolerance lead to
A
Tolereance to a non-self antigen
4
Q
the physiological state in which the immune system does not react destructively against self tissue
A
Self Tolerance
5
Q
Normal immune response to A microbe
A
Proliferation and differentiation
6
Q
selftolerance immune response to a self antigen
A
Anergy (functionally unresponsiveness
Deletion (Cell death)
Cheng in specificity (receptor editin)
7
Q
Where may self-tolerance be induced
A
In immature self-reative lymphocytes in generative lymphoid organs or in mature lymphocytes in peripheral sites
8
Q
Self tolerance induced in mature lymphocytes in peripheral sites
A
Peripheral tolerance
9
Q
Self tolerance induced in immatuer self reactive lymphocytes in generative lymphoid organs
A
Central tolerance
10
Q
where does Central tolerance occur
A
In generative lymphoid organs (bone marrow/thymus)
11
Q
what cells does Central tolerance involve
A
Immature self-reactive lymphocytes recognizing self antigen
12
Q
Where does PEripheral Tolerance occur
A
In peripheral sites
13
Q
what cells does Peripheral Tolerance invovle
A
MAture self-reactive lymphocytes encountering self antigen
14
Q
Is immunologica tolerance a failure to recognize an antigen
A
no
15
Q
What is Immunological tolerance a response to
A
an active response to a particular epitope
16
Q
How specific is Immunological tolerance
A
just as specific as an immune response
17
Q
How can Immunological tolerance come to be
A
Natural(self tolerance, oral tolerance…)
induced (prevent allergies, graft rejections or autoimmunity)
18
Q
when does prevention of Reactivity to certain antigen develop
A
Occurs during development rather than being genetically pre-progammed
19
Q
What does Self tolerance prevent
A
prevents the body from mounting an immune attach against its own tissues
20
Q
T cells come out of the bone marrow in what state
A
A very immature state ( CD4-, CD8-, TCR-) -dont express any
21
Q
where do Immature T cells begin to Express CD4, CD8, and TCR
A
in the cortex of thymus(get one type of CD and one type of TCR)
22
Q
Where does T cells go through Positive and negatvei seelction
A
In the cortical region of thymus of positive selection
In the medullary region for negative selection
23
Q
What is central tollerance part of
A
The positive and negative selction process
24
Q
How do Cells leave the thymus
A
As a fully functioning cell
25
what types of cells leave the Thymus as a fully functioning cells
CD4+ helper T lymphocyte
CD8 cytotoxic T lympohocyte
Delta gamma T cell
26
What types of Lympohocytes area destined to die by apaoptosis
Those that do not bind MHC through their TCR
27
How does Positive selection and lineage commitment respond to antigen
Low avidity interaction with self antigen
28
Postiive selection leads to
MAturation of clonse and generation of subsets of lympohocytes and expansion and diferentiation
29
what mediates neagtive selection
by high avidity with self antigen
30
what happens to immature T cells that recognize antigens with high avidity during maturation in the thymus
They are deleated
31
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
32
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
33
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)
34
Recognition of self antigen by peripheral tolerance leads to
Anergy
Apoptosis (Deletion)
suppression
35
Recognition of self antigen by peripheral tolerance leads to
Anergy
Apoptosis (Deletion)
suppression
36
what type of B cells do Central tolerance and where
Immature B cells in the bone marros
37
why do Central tolerance in B cells
So that potentially autoreactive cells can be eliminated or inactivated by contact with self ag
38
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
39
What determines the Fate of B cells
NAture and concentration of the self Ag
40
What kind of Ag induces B cell death
Multivalent Ag( memebrane associated Proteins)
41
what concentration of Ag induces B cell death
High concentration of Ag
42
what induces functional anergy of B cells
Low concentrations of small, soluble self Ag
43
Functional anergy of B cells results in
Decreased membrane Ig
| Blocked signal transduction by membrane bound Ig
44
What is the mechanism of Peripheral tolerance
Mature T cels that recognize self antigens in peripheral tissues become incapable of responding to these antigens
45
Mech of peripheral tolerance
Clonal Deletion/apoptosis
Clonal Anergy
Suppression
Ignorance
46
What is Clonal Deletion/apoptosis of Peripheral Tolerance
Actual elimination from the cellular repertoire by activation induced cell death
47
What is Clonal anergy of peripheral tolerance
Mature cell is present but is functionally inactivated and can be reversed
48
INhibition of cellular activity through interaction with other cells
Suppression
49
What cells do the suppression
T regs (CD4+/CD25+ T cells, TGF-beta or IL 10 secreting REg T cells)
50
What is ignorance in peripheral tolerance
Co-existence of self-reactive clones and antigen
| cells do not respond to antigen
51
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
52
why do peripheral tolerance in B cells
Not all potentially reactive cells are eliminated or inactivated and enter peripheral circulation
53
what is follicular exclusion
keeps some cells from the follicles and eventually elads to apoptosis
54
what is needed for a functional b cell response
Helper T cells
55
where is IgG found
In circulation
56
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
57
what antibody is big in circulation
IgG
58
What do you look at with a titer
IgG
59
How do T cell affect the outcome of B cell activation in the peripher
via the Two signal hypothesis
60
what are the Signals of the two signal hypothesis
1: generated through the Ag receptor
2: mediated by AD40 and CD40L
61
What results if one of the signals from the two signal hypothesis is missing
B cell anergy
62
What do Anergic Cells show
show a Block in TCR-induced singal transduction
63
what costimulation occures in anergic cells
LAck costimulation by B7/B12
| Costimulation by inhibitory receptors (CTLA-4
64
CTLA-4 for Peripheral tolerance through anergy competes with what
Competes with CD28 for B71 and B72 by binding with higher affinity than CD28
65
Roll of CTLA-4
Keeps T cells in check
66
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)
67
Normal T cell response to an antigen
Recognition of foreign antigen with costimulation
| T cell proliferation and differentiation
68
T cell anergy antigen recognition
Recognition of self antigen
Signalling block or Engagement of Inhibitory receptors (CTLA-4)
Unresponsive (Anergic) T cell
69
what in peripheral tolerance can lead to apoptosis
Activation in the absence of IL-2
PErsistant Ag
Activation-induced cell death
70
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
71
Apoptosis due to elimination of antigen and other signals
Release of Mitochontrial cytochrome C, activation of caspase-9
Passive cell death (death by neglect)
72
T cell mediated suppression results in
Inhibition of T cell activation
| Inhibition of T cell effector function
73
How can the state of tolerance by maintained
Immune regulation
74
Il-10 inhibts
Inhibitions function of APCs: IL-12 secretion and B7 expression to step naive t cells drom recognizing antigens
75
TGF-beta inhibits
T cell proliferation
76
Il-4 inhibits
Actions of IFN-gamma stopping the effector function of T cells
77
Il-10, TGF-beta inhibit
Macrophage acivation
78
when self-reactive T cells ignore self antigen
Passive
79
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
80
How to preferentially induce tolerance rather than an immune response
Foreign antigens are administed
81
How are protein antigens administed to preferentiall induce tolerance
Subcutaneously or intradermally with adjuvants favor immunity
82
How are high doses of antigens administered to preferentially induce tolerance
Administered systemically without adjuvants
83
Can oral administration of Ag help with tolerance induction
Yes, it favors tolerance
84
what follows oral administration of an antigen
A state of immune hyporesponsiveness
85
What is the role of oral tolereance
Maintenance of homeostasis so no immune response to food antigen
86
why use oral tolerance
To abrogate autoimmune disease
lack or toxicity, ease to administrate over time
antigen-specific mech of action
87
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
```
88
How can the state of tolerance from oral administration be maintained
By the immune regulation
89
PRinciple site of Tolerance induction in T and B lymphocytes
T: Thymus (Cortex);periphery
B: bone marrow; periphery
90
Tolerance-sensitive stage of maturation of T and B lymphocytes
T: CD4+CD8+(double positive) thymocyte)
B: Immature (IgM+IgD-) B lymphocyte
91
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
92
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
93
Pricniple mech of Central tolerance of T and B lymphocytes
T: Deletion (Apoptosis); development of regulatory T cells
B: Deletion (apoptosis); recetpor editing
94
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
95
What type of Response do T cells do
Cell meidated Response
96
Roll of T cells
Recognize processed antigen in the context of MHC to irradicate infection
97
effector function of T cells
Cytokine production and release of cytotoxic factors
98
what type of response to B cells do
Humoral responses
99
roll of B cells
Recognize Free antigen via Ig Receptor to irradiacte infection
100
Effector function of B cells
Antibody mediated destruction of antigens
101
What all can Autoimmune diseases involve
```
NErvous
GI
Endocrin
Skin
connective tissue
Eyes
blood vasvulature
```
102
when does and autoimmune disease occur
When the immune system becomes dystregulated and attacks the very organs it was deisnged to protext
103
when does autoimmunity occure
When central and peripheral tolerance is broken
104
How common are autoimmune disease
each one is individually rare
collectively 5% of us pop(2% of globe)
14 million people
105
how does Autoimmunity happen
Unclear
106
Factors that can predispose an individual to arious autoimmune disease
```
MHC associations
Familial concordance
Gender
Climate
Chemical agents
Infectious agents
Immune sytregulation
```
107
Genetic factors for autoimmune disease
tend to occur in families
GReater concordance between ideantical twins
Strong HLA/MHC association
108
do men and women get more autoimmune disease
WOmen
109
is Rheymatoid arthritis more aggressive in male or female
female
110
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
111
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
112
Categories of autoimmune disease
Systemic
| Organ specific
113
Systemic Autoimmune disease targets
Immune cels target multiple organ systems and tissues
114
What does a systemic autoimmune disease result for
Aberrant regulation of many clones of lymphocytes
115
ORgan specific autoimmune diseases target
Specific organs or tissues
116
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
117
what is Systemic Lupus Erythematosus
A systemic disorder in which a variety of autoantibodies (DNA, nucleoproteins, plateltes, lymphocytes) can cause multisystem damge
118
What is Multiple sclerosis (MS)
Immunse system targets Central NErvous system via myelin specific T cells
119
What does SLE have increased risk associated with it
HLA DR2
| HLA DR3
120
Female/Male predominacne of SLE
10:1
121
when does SLE symptoms occur
15-25 years old
122
Symptoms of SLE
```
Fatigue
Fever
Alopecia
Mucosal ulceration
Butterfly rash
Joint and muscle pain
```
123
Severe complications of SLE
Kidney, heart, lung, CNS
124
what type of disease is SLE
Immune complex disease (type III hypersensitivity)
125
Autoantibodies produced by SLE attack
DNA
Nucleoproteins
Platalets
Lympohcotes
126
Where doe Immune complexes for SLE deposit
In kdneys
Joints
Vessel walls
127
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
128
WHen would someone need a kidney transplant for SLE
Advanced Lupus nephritis
129
what is the most common inflammatory disorder of the CNS
MS
130
what is the increased risk for MS
HLA DR2
131
Female/male predomininace of MS
3:2
132
what kind of Disease pattern of MS
Both Relapsing-remitting
| Chronic progressive disease
133
what happens to the CNS due to MS
CNS plaque with loss of myelin and depletion of logodendrocytes with or without axon loss
134
when do women get MS
Childbearing years
135
when do men get MS
greater than 40 years of age
136
Symptoms of MS
```
Impaired vision (optic neuritis)
Ataxia
Spasticity
Bladder Dysfunction
Weakness/Paralysis of one or more limbs
Sensitivity to temperature
Cognitive impairment
```
137
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
138
What happens because of Damage to/loss of myelin
IMpairs nerve conduction
139
treating MS
Immunomodulatory drugs
Corticosteroids
Immunosupressive therapy
140
Inter-realtion of autimmune disease
can develop more than 1 autoimune disease
| Can overlap too
141
2 common systemic Autoimmune diseases
Systemic Lupus Eryhtematosus
| Rheumatoid arthritis
142
2 common organ specific Auto immune diseases
Insulin Dependant Diabetes Mellitus (IDDM)
| Multiple Sclerosis m
