Autoimmunity and Hypersensitivity Flashcards
How common are autoimmune reactions
Mostly short-lived, self-resolving sequelae of infection. However in some 2-3%
of individuals the reaction is chronic, debilitating and even life-threatening.
What is autoimmunity considered to be generally
a failure of self tolerance
Describe the different types of molecule involved in an autoimmune reaction
Antibodies (autoantibodies) or T cells (autoimmune T cells) are
directed to antigens on target tissues, known as autoantige
What is an explanation for the increase in autoimmune conditions in developed countries
hygiene hypothesis:
immune system is no longer conditioned by early exposure to infection
What has decreased while autoimmunity has increased?
infections
such as measles, mumps and TB
What may cause autoimmunity
some autoimmune
conditions are caused by infectious organisms that have not been identified: the Cryptic Infection
hypothesis.
Name an autoimmune disease that is highly tissue specific
Name one that is systemic
Graves’ disease
SLE (lupus)
Name 2 autoimmune diseases that attack the thyroid
Graves’ disease
Hashimoto’s thyroiditis
What is pernicious anaemia
Lack of intrinsic factor due to autoimmune attack on parietal cells and a resulting lack of B12
Which autoimmune disease can target the following:
skin
kidney
joints
How can these diseases be considered
skin (scleroderma),
kidney (SLE)
joints (RA)
non-organ specific autoimmune diseases
How do the 3 general autoimmune mechanisms parallel hypersensitivity?
parallels Hypersensitivity types II, III and IV
no autoimmune diseases are IgE mediated like type 1 hypersensitivity
What is the autoantibody mediating Graves’ disease
anti-TSH receptor antibody
How does the antibody against the TSH receptor differ from TSH itself
antibody is not subject to the negative feedback on TSH, results in hyperthyroidism
why is Graves’ disease considered a Th2 type response
there is little inflammation or lymphocyte infiltration
What type of autoimmune response is Hashimoto’s thyroiditis
Th1 - lymphocytes invade the organ
How does Hashimoto’s thyroiditis affect the thyroid
lymphocytes infiltrate the
organ. Nevertheless, antibodies are generated
which block hormone production, causing
hypothyroidism
Which of the following result in a goiter
Graves’ disease
Hashimoto’s Thyroiditis
both
What happens in myasthenia gravis
autoantibodies to the AChR diminish neuromuscular transmission from cholinergic neurons by blocking the binding of ACh and by causing downregulation (degradation) of its receptor
Name an autoimmune disease caused by direct tissue pathology following antibody binding
rheumatic fever
How can immune complexes be cleared
complement binding on the complex to the complement receptor on RBCs
RBCs carry bound complex to liver and spleen where they are phagocytosed
Name 2 diseases that are caused by autoantibody-antigen complexes
SLE
Vasculitis
Which organ is particularly sensitive to immune complex deposition
kidney
What happens in SLE
systemic lupus erythematosus
patients have a wide variety of anti-cytoplasmic and anti-nuclear
auto-antibodies
Visible sign of SLE
butterfly/ wolf rash on face
Who is SLE more common in
African and Asian women
What is a predisposing factor for LSE
, complement deficiencies that impair immune
clearance, such as C1, C2, C4
there is often a complement depletion in SLE patients
What is the autoimmune mechanism behind T1D and MS
T cell mediated
T cell mediated damage leads to tissue destruction without requiring the production of
autoantibody
What are the different mechanisms of T cell mediated autoimmunity
cytotoxicity by CD8 T cells;
direct destruction by TNF;
recruitment of
macrophages and subsequent bystander killing;
induction of apoptosis by Fas Ligand.
What % of the population suffer RA
How is this changing
3%
decreasing as more people give up smoking
What is EAE
a model of MS
How can we show that MS can be transferred with T cells using EAE
The rat is immunised with myelin basic protein (MBP) in complete Freund’s adjuvant.
CD4+ T cells specific to MBP are isolated and can subsequently cause disease if injected into another animal.
What are most autoimmune diseases associated with genetically
one or more HLA allotype
Are the HLA allotypes associated with autoimmune diseases ‘mutant alleles’
no they are polymorphic variants in the normal populations
Give a good way to express the way allotypes influence disease
Relative Risk
in comparison with HLADQ6-ve people, HLA-DQ6+ves are 12 times more likely to develop multiple sclerosis. But HLA-DQ6 is
common in normal healthy individuals. Conversely, not all patients who develop the disease have this
allotype and only a fraction of DQ6+ves will succumb
What is a common haplotype in caucasian populations that is associated with T1D, SLE, Graves’ disease and myasthenia gravis
A1-B8-DR3-
DQ2.
What position on the MHC molecule plays a major role in T1D
position 57 in the HLA-DQβ
What does the different HLA types being associated with different autoimmune diseases reflect
binding of different peptides to the grooves of HLA
For example, a residue at position 57 of the beta chain of HLA-DQ is protective if charged
(aspartate) but not if hydrophobic, reflecting binding of different diabetogenic peptides
True or false:
T1D only involves 1 genetic locus
What is this referred to
What other disease can be placed in this categry
false
multiple loci are involved
multigenic disorders
rheumatoid arthritis
How does incidence of autoimmunity differ between sexes? Give specific examples (4)
e Grave’s
and Hashimoto’s are 4-5 times, and SLE 10 times, more common in females.
Ankylosing Spondylitis is 3-4
more frequent in males.
What is the twin concordance rate for common autoimmune diseases eg T1D and RA
20-40%
Give examples of autoimmune diseases being directly caused by infection
rheumatic fever can follow Streptococcal
infection;
reactive arthritis after Yersinia, Shigella or
Chlamydia.
Non-specific infection is known to cause a flare-up of MS
How much are environmental factors thought to contribute to T1D
Break this down
50%
The MHC contributes about 25% and the other
25% comprises a variety of other genes.
Describe how release of a sequestered antigen can result in autoimmunity, using an example to demonstrate
In the case of autoimmune sympathetic ophthalmia, damage to one eye leads to subsequent
autoimmune attack of the contralateral eye.
How can T cell tolerance be bypassed
modification - generation of neoantigens recognized by T cells
this results in breaking of tolerance to a self antigen
Give an example of modification allowing bypassing of T cell tolerance
e.g. by modification of proteins, such as
citrullination, by environmental factors, such as smoking
Why is coeliac not strictly an autoimmune disease
it is dependent on eating gluten
What does coeliac disease involve presentation of
deamidated gliadin peptides by specific HLA-DQ molecules
True or false
Rheumatoid arthritis may involve protein modification
true
protein citrullination by peptidylarginine deiminase.
Initially, occurs in the lung (there is a strong link between RA and smoking). Antibodies to the modified proteins: ACPA (anti-citrullinated protein antibodies) are present in most patients with RA.
How can gum infection lead to autoimmunity
periodontitis
Infection of teeth and gums with P. gingivalis can result in citrullination of epitopes which again result in ACPA
What do both periodontitis and RA have in common
both involve bone erosion
both have risk factors involving smoking and ageing
periodontitis often precedes RA
What are the 2 distinct types of animal models
spontaneous
induced
Describe spontaneous autoimmune disease models
They exist as a result of deliberate inbreeding of strains of animals
for particular characteristics including the incidence of autoimmune disease.
Such inbred strains are therefore
genetically susceptible and spontaneously develop disease
Give an example of spontaneous autoimmune disease models
the non-obese diabetic
(NOD) mouse
Describe induced autoimmune disease models
require some treatment of the animal to trigger the disease. They also generally require the presence of some genetic susceptibility factors
How can you induce MS in mice
inject mouse with spinal chord extract and powerful adjuvants will trigger an autoimmune encephalomyelitis (EAE) but only
in a few inbred strains. This disease resembles multiple sclerosis, as introduced above in the T cell transfer
experiment in rats.
Describe the non obese diabetic mouse
a spontaneous T1D model,
The islets of these mice are infiltrated
with T cells and macrophages, with associated cytokine release and production of autoantibodies that could kill cells by ADCC
What do the immune mechanisms in NOD mice lead to
abnormalities in glucose metabolism and
ketoacidosis, a breakdown product of fat
What happens if you switch bone marrow cells between NOD and normal mice
induces T1D in normal mouse
How were Tregs implicated in protection against T1D
n using the NOD model as it was
demonstrated, using GFP-tagged FoxP3, that this transcription factor was key in
controlling the development of regulatory T cells and thus the disease.
Can the immune system return to a tolerised state
yes a number of induced autoimmune diseases resolve themselves
Treatment against autoimmune conditions is usually ineffective except in which case?
organ specific cases s where specific
agents can be used to exert metabolic control, such as thyroxine for hypothyroidism
What is the blunt tool to use to treat autoimmunity
immunosuppressive drugs
Describe a promising new treatment for RA
Blocking reagents such as anti-TNF antibodies or soluble receptor
Why is the Th1/Th2 paradigm useful for thinking about autoimmunity?
in some cases a predominantly cytotoxic response
is required and in others emphasis is more on antibody production.
Other than Th1/2 what other Th is involved in autoimmunity
Th17
What is a useful method to identify different subsets of T cells
staining for the associated transcription factors
What does Th2 make
Whhat does this drive
IL-4
M2 macrophages production
When do Th17 cells function primarily
What do they do
used in anti microbial immunity at epithelial barriers
promote recruitment of neutrophils to sites of bacterial and fungal infection
What do Tfh cells do
localise in
B cell follicles and activate B cells.
responsible for Ab development, isotype switching and affinity maturation
What is the issue with immunosuppressants?
Name some immunosuppressive agents
long term use has unwanted side effects
cyclosporin and rapamycin
What are cyclosporin and rapamycin
potent inhibitors of T cell activation
Why is blocking TNF alpha considered anti-inflammatory
TNFα is generally produced by innate
immune cells
What is CTLA4-Ig?
What does it do?
What is it approved for treatment for?
a fusion protein which binds CD80 and CD86 with high affinity,
prevents co-stimulation of
T cells via CD28
RA
What is hypersensitivity
to immune responses that are damaging rather than helpful to the host. In
other words, these are over-reactions of the immune system.
How many types of hypersensitivity are there
4:
3 Ab mediated
1 T cell mediated
Which hypersensitivity uderlie rapid allergic reactions
type 1
Name 3 kinds of type 1 hypersensitivity
hayfever
eczema
asthma
what is allergic rhinitis
hay fever - a type 1 hypersensitive reaction to pollen
What is the cause of a type 1 hypersensitive reaction
contact with antigen to which the host has pre-existing IgE and a Th2 type response is elicited
What happens after an allergen is detected in type 1 sensitivity
Give 3 stages
mast cells are activated by cross linking of FcεRI via antigen binding to the bound IgE molecule
mast cells release serotonin and histamine
six hours later, secondary inflammatory mediators are released in the later response
What are the different categories of allergens in involved in Type 1 hypersensitivity
Give examples of each
Pollens: birch tree/ragweed/oil seed rape
Foods: nuts/eggs/seafood
Drugs: penicillin/aspirin
Insect products: bee venom/house dust mite
Animal hair: cat hair and dander.
What distinguishes allergens which stimulate strong IgE responses from other antigens? (4)
no single common factor
often proteases
low MW
highly soluble (so diffuse readily into mucus)
generally stable and can survive as a desiccated particle
Can allergens which stimulate a type 1 hypersensitive response activate T cells
yes - they contain peptides that bind MHC Class II to prime t cells
the low dose encountered favours IL-4 producing, Th2 response
BUT REMEBER TPE 1 IS IgE MEDIATED (NOT T CELL MEDIATED)
How can you diagnose a type 1 hypersensitivity to an allergen
wheal and flare test
prick patient’s skin with the allergen and wait for a reaction
Describe the wheal and flare test
prick patient’s skin with suspected allergen
if they’re allergic, ‘wheal and flare’ reaction appears at the site of infection within a few minutes.
wheal= swelling (edema)
subsequent redness (flare or erythema) = from increased blood flow.
After 6 hours there may be a late-phase reaction where the swelling spreads to involve the surrounding tissue.
How common is type 1 hypersensitivity
30% of some populations
is there a genetic component to type 1 hypersensitivity
Having two susceptible
parents doubles the risk of an affected child, indicating a genetic component
How can you recognise a child who atopic to type 1 hypersensitivity
have serum IgE raised 10-100 times the usual level
Is there a selective advantage to having type 1 hypersensitivity
increased protection against parasites (common in tropical countries)
When can extreme type 1 hypersensitive reactions occur
What can result
if the antigen is directly injected into the blood
stream.
In systemic anaphylaxis the increased permeability of blood vessels results in extreme drop in blood
pressure and anaphylactic shock, which can be fatal
What is the difference between systemic anaphylaxis and anaphylactic shock
In systemic anaphylaxis the increased permeability of blood vessels results in extreme drop in blood
pressure and anaphylactic shock, which can be fatal
How can you treat type 1 hypersensitivity
identification and avoidance of the
antigen;
antihistamine and corticosteroids, which suppress leukocyte function.
In some cases,
desensitisation may be achieved by gradual exposure to increased dose of antigen, to convert Th2 to Th1
and/or iTreg responses.
Which immune cells are involved in asthma (5)
increased TH2
lymphocytes, eosinophils, neutrophils and basophils, which amplify inflammation and airway remodeling.
Name some genetic susceptibility loci implicated in asthma (5)
HLA class II,
TCR
genes which affect the TH1/TH2 balance
genes which affect IgE receptor and cytokines eg IL-4
effects of non-immune genes such as those influencing smooth muscle cell behavior, bronchial
physiology and tissue repair
How can you induce asthma in mice genetically
. Mice lacking the T-Bet transcription factor, which drives T cells to differentiate into TH1 cells, and suppresses the TH2 pathway, have increased levels of IL-4, IL-5 and IL-13 cytokines and have a disease similar to human asthma
True or false
the skin prick test cannot be used to test if an asthmatic person is allergic to a certain allergen because asthma is not a type 1 hypersensitivity
false
asthma IS type 1 hypersensitivity
skin prick test is unsuitable so a breathing exhalation rate is tested after exposure to inhaled antigen
Describe the reaction an asthmatic person would have after inhaling an allergen
acute constriction of bronchial smooth muscle in an attempt to expel the antigen (lasts an hour)
late response after 6 hours - more damaging and if the antigen persists, asthma becomes chronic and re-exposure to antigen can trigger further attacks
Describe the cell mediators underlying each stage of the asthmatic reaction following inhalation of the allergen
a) immediate bronchial constriction: due to degranulation of mast cells in the respiratory tract, armed with allergen-specific IgE. Ends after an hour
b) late response follows after
about 6 hours, due to leukotrienes and
other inflammatory mediators. This phase is most damaging and leads to recruitment of eosinophils and TH2
lymphocytes.
If the antigen persists the condition may become chronic, whereby allergen-specific TH2 cells
promote further IgE production and recruitment of eosinophils and neutrophils.
The condition may deteriorate and the airways become occluded by mucus plugs. Re-exposure to antigen can trigger further attacks
How can asthma be exacerbated
by bacterial and viral infections, dominated by TH2 cells and a type IV
hypersensitivity response
What is type 2 hypersensitivity
IgM / IgG mediated
tends to lead to destruction of RBCs (hemolytic anemia) or platelets
(thrombocytopenia)
Give an example of type 2 hypersensitivity
uncommon side effect of penicillin
drug binds to self cell surface and is a target for Igs
cell-bound antibody triggers clearance of the cell by tissue macrophages in the spleen, which
bear Fcγ receptors, or by complement lysis.
What hypersensitivity is blood grouping related to
type 2
Why is the ABO blood group special
it is the only histocompatibility alloantigen for which pre-existing antibody is present in naïve, previously untransplanted (untransfused) recipients.
Explain the ABO blood grouping
RBC surface molecules consist of a core H antigen The O (null) allele is unmodified H antigen
Sugars may be attached to this core:
The A allele adds a terminal N-acetylgalactosamine
The B allele adds a terminal galactose
AB indicates both modifications
What are the ABO phenotype frequencies in European Caucasoid populations
O - 45%
A - 40 %
B - 11 %
AB - 4 %
What kind of hypersensitivity is Rhesus reaction
type 2
What is hemolytic disease of the newborn
Rhesus reaction
How does the hemolytic disease of the newborn come about
If the mother is Rhesus negative and the child
is Rhesus positive the mother can produce antibodies to the Rhesus antigen. This happens because some Rh+ cells leak into the maternal circulation at birth. The IgG can cross the placenta and compromise the
subsequent Rh+ baby.
How can the rhesus reaction be circumvented
by giving anti-Rh antibody (RhoGam) to the mother before she reacts to her child’s red blood cells. The antibody crosslinking to FcgRIIB receptor prevents activation of naïve B cells
What is type III hypersensitivity
inability to clear immune complexes
IgG mediated
What differentiates a hypersensitive response from IgE to IgG mediated
IgG hypersensitivity reactions occur when the antigen is soluble and in high quantities
low levels
tend to produce IgE responses
Describe the process involved in type 3 hypersensitivity
individual exposed to soluble allergen in high quantity
IgG produced
Immune complexes formed and deposited in tissue
mast cells triggered via FcgRIII receptor
activation of complement and polymorphs -> local tissue damage and inflammation
What are common examples of type III hypersensitivity reactions
post-infection complications such as arthritis and glomerulonephritis
What is the Arthus reaction
a local type III
hypersensitivity reaction. This can be triggered in the skin of sensitized individuals who have IgG against the sensitising antigen
Name 2 examples of type III hypersensitivity reaction where the allergen is inhaled
pigeon fancier’s lung or farmer’s lung
What is serum sickness
a transient immune complex mediated syndrome caused by injecting horse serum (passive immunisation)
Why could serum sickness result after being treated for pneumonia
horse serum which was immune to pneumonia is injected to treat the patient’s pneumonia
this leads to type III hypersensitivity
What is delayed type hypersensitivity
type IV sensitivity
t cell mediated
memory t cells release cytokines that recruit and activate macrophages
When is the maximal type IV hypersensitivity reaction
48-72 hours after exposure
How much antigen is required for t celll mediated hypersensitivity compared to the other types
Requires MUCH more antigen (10-100x) than for Ab mediated hypersensitivity
What kind of reaction is poison ivy implicated in
hapten=Urushiol – passes through endothelial layers ad taken up by a dendritic cell which uses MHCII to expose the antigen to a naïve T cell
Naïve T cell’s CD28 binds to the dendritic B7, promoting IL-12 release which makes T cell mature. Mature T cell produces. Mature T cells encourage a pro-inflammatory response, leading to dermatitis
What is a hapten
a small molecule which, when combined with a larger carrier such as a protein, can elicit the production of antibodies which bind specifically to it (in the free or combined state).
Which Th cells are involved in type IV hypersensitivity
Often TH1 – IV orchestrated by cytokines from TH1 CD4 cells (including TNFα IFNγ and IL-3) the recruited macrophages present antigen to T cells to amplify response
What are contact sensitivities
Give examples
Cutaneous responses to haptens, which form stable complexes with host proteins.
type IV hypersensitvity
For example, poison ivy, metal salts and small reactive chemicals.
What is Abacavir sensitivity syndrome
a T cell mediated drug hypersensitivity that occurs in individuals possessing the HLA class I allele HLA-B*57
In humans, the situations when allogeneic cells come into contact are either:
Iatrogenic (effects of medical treatment), such as blood transfusion, or
Natural, such as pregnancy in placental mammals
What is the main problem with transplantation
most cells express polymorphic surface
antigens encoded by the MHC.
What are the 4 possible relationships between transplanted donor material and the recipient
autologous
syngeneic
allogenic
xenogenic
What is the most common type of transplant
What does it display
allogenic
immunological memory
How is the immune system primed in transplantation
by the allograft upon first encounter with the antigen
What happens if a recipient that has previously rejected a
skin graft is regrafted with skin from the same donor
What happens if a graft from a third party is added
the graft is rejected more rapidly in a second set reaction
3rd party graft will be rejected the same as for the 1st set reaction
How do we know second set reactions in transplantation is caused by a memory immune response from clonally expanded and primed T cells specific for the donor skin?
The rapid second set rejection course can be transferred to normal or irradiated recipients by T cells from the
original recipient
Why is the second set reaction in transplant rejection faster?
Memory T cells are produced alongside
effector T cells in a primary immune response.
Upon a second exposure to the same antigens memory T cells promote a more rapid, more effective response.
This is because memory T cells to a specific antigen are
more numerous than naïve T cells and they are more readily activated.
Which cells are important in recognition of transplants
A central role for recognition of transplanted tissue is played by T cells but other cells may be involved
in rejection, including NK. However, in some cases antibodies are important, although their production may be
initiated by T cells.
How can T cells recognize antigens on transplanted tissue
through direct recognition of the donor MHC or indirect recognition, of
an antigen presented by self MHC molecules.
What are the 3 types of rejection following an allotransplant
- Hyperacute rejection
- Acute rejection
- Chronic rejection
What are hyperacute rejections
occurs very rapidly, within minutes or a few hours. It results from pre-existing
antibody, such as in ABO incompatible transplants
Give 3 examples of hyperacute rejection occurring
What type of Ab is involved in all of these
y:
1. From previous organ transplants (e.g. children who have multiple transplants)
2. From pregnancy – at childbirth fetal cells enter maternal circulation and stimulate adaptive
response to paternal HLA
3. From blood transfusion (matched for ABO but not HLA)
anti-HLA
Why are tissues rejected rapidly in hyperacute rejection
ABO and HLA antigens are expressed on the endothelial cells lining blood vessels
How is the tissue damaged in hyperacute rejection
by complement activation, coagulation and leakage of fluids, as well as
by aggregation of platelets that block the microvasculature
What is the issue facing companies who hope to use pig organs to transplant into humans
What are the problems that need to be overcome
Hyperacute rejection also takes place in Xenotransplants
First, we make
natural IgM and IgG antibody to modified sugars on pig tissue. These transplants are said to be discordant.
Second, complement does not function well across species. Normally complement is disabled on self tissues by the action of regulatory proteins such as decay accelerating factor (DAF). This does not work on pig
tissue and the graft is attacked by the human complement.
What is the main immunological barrier to allotransplantation
acute graft rejection
What is acute graft rejection caused by
What can it be compared to
T cell recognition of the transplanted tissue.
Acute rejection can be thought of as a type of Type IV hypersensitivity reaction as it involves the response of CD8 T cells to HLA class I differences and CD4 T cells to HLA class II differences.
Why does blood transfusion not result in acute graft rejection
RBCs do not carry MHC antigens
Why does the polymorphic nature of the MHC genetic region make transplants problematic
and it is highly polymorphic. In
spite of attempts at matching, most organ transplants are
performed across some HLA class I and/or class II
differences. The recipient’s naïve T cell population contains
clones of so-called alloreactive T cells that recognise HLA
allotypes that are not shared with the recipient. Some of
these clones are of the memory type and were initially
stimulated and expanded in response to pathogens but
cross-react with allogeneic HLA
