Tolerance & Autoimmunity Flashcards
(60 cards)
1
Q
Tolerance
A
The avoiding of recognition and damage of self-tissues
2
Q
Response to viral infection
A
Burst of interferons -> NK cell activation whilst adaptive immunit unfolds
3
Q
How is tolerance come about?
A
Acquired not hard-wired
4
Q
Self vs non-self?
A
No, really dangerous vs non
5
Q
Adjuvant
A
Mixture that enhances body’s response to antigen
6
Q
How do adjuvants work?
A
- Convert soluble protein into particulate material for ingestion by APCs
- May contain bacterial products that stimulate macrophages or dendritic cells through PRRs
7
Q
Two types of tolerance and difference?
A
Central - occurs during lymphocyte dev
Peripheral - occurs after left primary organs
8
Q
T cell tolerance (Central)
A
T cells must be able to recognise MHC proteins with non-self
peptides
Clonal selection: positive selection if some affinity for self MHC
Negative selection if too high affinity for self-peptides + MHC
9
Q
Central tolerance B cells
A
B cells that react to peptides on self cells are eliminated
10
Q
Experimental evidence?
A
x
11
Q
Anergy
A
Absence of immune response to particular antigen
12
Q
Why is peripheral tolerance needed?
A
- Many self-peptides not expressed in thymus or bone marrow
- Does not eliminate T cells with weak response to self
- Some not present until matures
13
Q
Outline the 4 mechanisms for peripheral
self-tolerance
A
- Ignorance - potentially self-reactive T cells not activated because the antigens are in
immunologically priviledged sites (hidden) - Split tolerance - Many pathways in immune system are interdependent
e.g. if T cell tolerance has been establish then an autoreactive B cell can still be present
as it needs the T cell for co activation - Anergy - non-responsiveness state -T cells become anergic in absence of co-stimulation
- Suppression - T cells can be prevented from reacting by other T cells
Tregs. These have intermediate affinity for self and express Fox3P
to distinguish.
14
Q
Treg mechanisms and the two types
A
1. Natural (from thymus) 2. Inducible (in periphery) On contacting self-antigen on MHC class 2 - Tregs suppress prolieration of naïve T cells responding to autoantigens on same APC
15
Q
What favours Fox3P induction?
A
x
16
Q
4 factors that affect tolerance
A
- Timing
- Dose of antigen
- Amount of co-stimulation
- Location
17
Q
Explain why graft accepted if bone marrow
injected at birth but not later?
A
Chimerism established if injected at birth - tolerise developing thymocytes to the foreign
18
Q
Special case of lack of immune response
and reasons why no immune response
A
Placenta and fetus which share child’s genotype not mother’s
1. Physical barrier to mother’s T cells
2. Lack of MHC class 1 expression on outer placenta cells ->
not targets for cytotoxic T cells
19
Q
Experimental tolerance
A
- Peptide sniffing
2. Co-receptor blockade
20
Q
Evasion of immune recognition by microbes
A
- Varying their surface antigens by genetic variation or rearrangement
- Hiding - fungi have immunologically inert coat
- Flu - antigenic drift or shift
21
Q
Original antigenic sin
A
Refers to propensity of body’s immune system to react preferentially with antibodies from last infection
e.g. using immunological memory instead of solely to new infection (limiting effectiveness of response
therefore)
During the second reaction, only those epitopes common to the first and seconday strain
stimulate antibody production
(This is for e.g. influenza virus which has different antigens each time)
22
Q
Bacterial super-antigens
A
Secrete toxins that indiscriminately activate T cells so failure to mount specific response
23
Q
Lecture 10// Autoimmunity
A
x
24
Q
What is autoimmunity and what can it be
attributed to?
A
Autoimmunity - when immune system attacks host components causing a pathological change
Attributed to failure of self tolerance
25
Common targets for organ specific and
| reasons for?
Stomach, thyroid
| 1. Well vascularised 2. Make organ specific proteins
26
Pathogenesis
Manner of disease development
27
Autoantibody
Antibody produced by organism in response to constituent of its own tissue
28
Mechanisms
1. Direct antibody-mediated disease - autoantibodies already present in body e.g. in Grave's
disease - antibodies to TSH receptor - so they bind to it and lead to it being attacked and destroyed
similar to type 2 hypersensitivity
2. Immune complex mediated effects - SLE - result from autoantibody-antigen complexes
and their consequences - type 3 hypersentivity
3. T cell mediated effects e.g. MS - T cell mediated damage leads to tissue destruction without
requiring autoantibody production - MS - T cells cross the blood brain barrier get activated by myelin
and secrete cytokines which induces an immune response against the myelin and destroys it (lets in
more immune cells from the bb barrier)
29
Factors affecting autoimmune diseases
Environmental - e.g. after infection
Genetic - HLA complex is region of chromosome that encodes for MHC proteins - if have problem
with one of HLA then can lead to a specific autoimmune disease
30
Initiation and perpetuation of autoimmune
| reactions after infection
1. Release of sequestered antigen
2. T cell tolerance bypass: 1. Modification - binding of self-peptide to pathogen which results in breaking o
tolerance to a self antigen. 2. Inflammation - activated APCs leads to anergic T cell activation
4. Molecular mimicry - antibodies or T cells generated in response to an infection
cross react with self
31
Animal models of autoimmunity
Spontaneous or induced - spontaneuous autoimmune disease models - requires some
treatment to trigger the response
32
Immunoregulation
Some autoimmune conditions can resolve themselves - restore tolerance - regulation of CD4+ cells
33
How to identify different subsets of T cells?
Staining for different associated transcription factors
34
Lecture 11// Hypersensitivity
x
35
Hypersensitivity
Immune responses that are damaging rather than helpful to the host
36
Type 1 hypersensitivity
- Allergy
- Contact with allergen which host has pre-existing IgE antibody
- Taken up by APC and presented to T cells which cause it to differentiate and release cytokines that
cause antibody class switching in B cells and cause them to secrete IgE antibodies
- Mast cells activated by cross-linking FcRI receptors to release histamine (IgE antibodies can do
this)
- Secondary inflammatory mediators released in late response - more leukocytes recruited
37
What do allergens have in common?
Easily diffusible, proteins proteases?
38
Systemic anaphylaxis
Extreme over-reaction when injected into bloodstream
39
Genetic susceptibility
Some population much more susceptible -> tropical conditions
40
Asthma
Chronic inflammation of the airways: overeactivity due to Th2 cells
1. Dendritic cells present allergen peptides to T cells which causes them to differentiate and secrete
cytokines -> IL-4 and IL-5
2. IL-4 causes antibody class switching of B cells to produce IgE antibodies which bind to Mast cells
and stimulate them to release histamine
3. IL-5 stimulates eosinophils to degranulate
41
Aetiology
Set of causes of a disease
42
Type 2 hypersensitivity
Cytotoxic hypersensitivity - antibody mediated destruction of T helper cells
- self-reactive B cells produce IgM or IgG antibodies which bind to antigens on host cells
- These antibodies can activate the complement system which will kill the host cell :( (by recruiting
the complement components set up a chemotactic gradient that can attract
neutrophils that degranulate and release enzymes that kill)
-Another mechanism is the formation of a membrane attack complex or ADCC where NK cells are
recruited which secret perforins
43
Blood groups
Genetically variable structures (polymorphic) on red blood cells
44
ABO system
- consists of core H antigen
- A and B add different sugars onto the core H whereas O is unmodified
Immune system doesn't create antibodies against the ones it has otherwise the antibody would bind
to the rbc and attack it. This is why important to only have blood transfusions of the same type (as
then the body may have an antibody against it and then immune response)
45
Rhesus reaction
Difference in blood type between mother and baby - say if mother is RH -ve then can create antibodies
against Rh and so if baby is Rh +ve then mother can attack baby - is treatable
46
Difference between antigens in type 2 and 3
| hypersensitivities
Some antigens are soluble and float around whereas some antigens are bound to cell surfaces.
The former is for type 2 mediated and the latter and type 3 mediated.
47
Type 3 hypersensitivity
Antigen-antibody complexes deposit in blood vessel walls -> inflammation and tissue damage
Mediated by immune complexes (antigen-antibody)
B cells normally secrete IgM but via T helper cell can switch to making IgG antibodies (crosslinking of
receptors on B cells can cause presentation of antigen on MHC to T cell and costimulation with T cell
can cause it to secrete cytokines and cause antibody class switching of the B cell)
Type 3 is with soluble antigens
Immune complexes form between the IgG antibodies and the (auto)antigen and deposit in basal blood
vessels which can activate the complement system in large amounts rapidly
48
Type 4 hypersensitivity
T cell mediated hypersensitivity
| T cells activated (by dendritic cells) -> release cytokines to recruit macrophages etc to the area to cause inflammation
49
TB skin test
Inject with TB and if have been exposed to TB before then Th1 cells are recruited to the area ->
inflammatory response in area
50
Lecture 12// Transplantation
x
51
Two situations where allogeneic cells contact
Iatrogenic - blood transfusion
| Natural - placenta
52
Problem with transplanting tissue
Most cells express polymorphic surface antigens encoded by MHC - variation between donor and recipient
at MHC results in rejection
53
Why is second rejection to the same graft
more rapid than for the first time? (Allogeneic
transplants)
Immunological memory - Memory T cells are produced alongside the effector
T cells during the first reaction
54
Rejection mechanisms - 3 types
Recognition of transplanted tissue can be caused by antibody or T cells (indirect or direct)
1. Hyperacute rejection: rapidly, results from pre-existing antibody -> xenotransplants
Complement activation = tissue damage (normally complement is disabled on self-tissue by DAF but
this doesn't work on xenografts)
2. Acute graft rejection: main barrier to allografts - not problem for blood transfusion as rbc have no
MHC. Via T cell recognition of transplanted tissue. Can be direct or indirect. Former: MHC regions dominates
histocompatibility -> region is highly polymorphic and so most transplants are performed across
differences in MHC so direct is due to T cell recognition of allo-MHC molecules
Indirect recognition - recognition of minor transplantation antigen - APC process donor peptides
and goes to lymph nodes to activate Th cells - slower rejection that direct but additive -> fast
3. Chronic rejection - can occur 30 years after - maybe due to IgG antibodies against allogeneic
HLA class 1 molecules on the graft -> forming immune complexes that can deposit in the blood vessels
of transplanted organ
Indirect recognition - uptake of allogeneic proteins by recipient APC and presentation to T cells -
among some of the graft-derived peptides may be some non-MHC 'minor' or H antigens -
55
Influence of HLA matching on allograft survival
Depends on tissue
56
HLA
Human Leukocyte Antigen complex is set of genes encoding MHC proteins
57
Microcytoxicity test
- Known anti-HLA antibodies that specifically recognise allomorphs of particular
HLA loci = serum
- This serum in mixed with donor blood -> if antibodies recognised epitope on MHC then cells lysed
and turn blue
58
Cross-matching
Need to determine if recipient has any preformed antibodies to potential donor HLA alloantigens
59
Problems with conventional transplantation
Not enough organs
60
SLE
SLE = autoimmune disease - cells undergo damage that can causes apoptosis, this exposes the
inside of the cell as apoptotic bodies -> people with genetic susceptibility to SLE will be less able to
clear the apoptotic bodies by macrophages (so there will be more of them around) and their B cells
may be more likely to recognise the apoptotic bodies as foreign (as antigens) -> the B cells may then
start creating antibodies to the apoptotic bodies e.g. DNA and then the antibodies will form antibody-
antigen complexes with the antigens which can deposit in tissue -> this can cause inflammation via
the complement system and can result in cell lysis and tissue damage. When tissues become damaged
as a result of such complexes, type 3 hypersensitivity reaction
