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BOD > T cell, autoimmune, hypersensitivity > Flashcards

T cell, autoimmune, hypersensitivity Flashcards

1
Q

T cells

A

CD8 cytotoxic
class I

Cd4 T helper
class II

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2
Q

TCR

A

no somatic hypermutation as can lose ability to recognise MHC otherwise
monovalent
membrane bound
antigen recognition
more variable than BCR

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3
Q

TCR diversity

A

2 chains Beta and alpha
VDJ rearrangement
Beta chain first
Dj then VJ
CD4, CD8 double negative expressed

Then alpha chain rearranged
CD4, CD8 double positive expressed

RAG 1/2 P and N nucleotide addition

As no somatic hypermutation needs more diversity as fixed

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4
Q

T cell selection

A

successful TCRβ chain rearrangement

Positive selection
double positive TCR against self peptide/MHC on cortical epithelial cells
Only cells with no affinity die as no positive survival signals
Depending on the MHC T cell becomes single positive

NEgative selection
Remove T cells with high affinity for self peptide/MHC by apoptosis

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5
Q

Thymus

A

cortical epithelial cells for positive selection

(dendritic cells and macrophages to trigger negative selection

Macrophages are important for removing
thymocytes that fail to mature

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6
Q

TCR signalling

A

TCR can only be expressed with CD3
Once bound to MHC Lck binds CD8/4
CD3 phosphorylated by Lck
recruits ZAP-70
ZAP-70 phoshporylates LAT
LAT gets PLCgamma and GRB2
GRB2 gets SOS, activates RAS and MAPK pathways RAF,MEK,ERK
Activates transcription factors including IL-2

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7
Q

Cytotoxic T cell

A

CD8 T cell recognise MHC class I
Proliferate with IL-2 and also make perforin and granzyme

Release IFN gamma to increases expression of MHC

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8
Q

Il-2

A

Master T cell regulator
Cause T cell survival and proliferation

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9
Q

Co stimulation

A

T cells need 2 signals

signal 1
TCR and MHC
with CD4/8

signal 2
CD28 with B7 on APC for signal and
CD40L with CD40 on APC to activate APC

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10
Q

Thymus dependent antigens

A

APC, dendrite takes up antigen and presents on MHC
Presents to T cell
MHC class II-TCR and CD4
B7-CD28
CD40-CD40L

T cell activates B cell
CD40L-CD40
CD28-B7
TCR,CD4-MHC

B cell can take up antigen and present on MHC, when T cell binds it recognises to help activate

CD28-B7
CD40L-CD40
signals needed for survial and proliferation-CD40

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11
Q

Germinal centres

A

follicular
dendritic cells hold antigens for a long time on immune complexes

Somatic hypermutation occurs so only B cell with highest affinity after muations survive

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12
Q

Thymus independent antigens

A

TI antigens are microbial products
composed of repetitive elements (polysaccharides and lipopolysaccharides) which crosslink membrane Ig and induce B cell proliferation.

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13
Q

T helper 1

A

Made by IL-12 and IFN-γ
Make IFN-γ, inflammation
activate phagocytes

T-BET
ILC1

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14
Q

Th2 cells

A

Made by IL-14
Make IL-4, IL-5 and IL-13
Help against parasites

Parasite too big for phagocytosis, mostly antibodies made

GATA3
ILC2

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15
Q

Th17 cells

A

Made by IL-6 and TGF-β
Make IL-17 and IL-22
extracellular bacteria and fungi

RORγT
ILC3

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16
Q

Follicular helper T (Tfh) cells

A

MAde by IL-6
MAke IL-21
promtoe antibody response

small amount so B cells compete and only highest affinity survive

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17
Q

Treg

A

made by TGF-β
supress the activity of other T cells

FOXP3.

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18
Q

Innate lymphocytes

A

Similar to T helper cells
act before T helper cells

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19
Q

Memoery cells

A

Some T/B cells develop long lived cells that cause a secondary response that is faster and greater in magnitude than the first

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20
Q

Tolerance

A

aquired
recognise infectious non-self

need adjuvant, PAMPs and DAMPS as well as antigen

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21
Q

Central tolerance

A

First make T cell receptors
positively selecting those clones with some
affinity for self MHC and negatively selecting clones that bind too strongly to self MHC
plus peptide

timing, dose of antigen,
amount of costimulation and location are important

A mouse A with bone marrow from B at borth accept a skin graft from B but not from C

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22
Q

How can all relevant self antigens be expressed in the thymus?

A

transcription factor called AIRE
Turns on pheripheral genes in the thymus so T cell see all genes

Without AIRE
Autoimmune Polyglandular Syndrome Type
1 (APS-1)
or APECED

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23
Q

B cell tolerance

A

B cells that react to abundant antigens on self cells are
eliminated as they develop

Self-reactive cells have an opportunity to avoid apoptosis by
replacing the light chain in a process called receptor editing, recombination

HIgh doses of self antigen cause anergy induction in spleen
non resposnsive

24
Q

T cell tolerance
Ignorance

A

Ignorance
immunologically privileged sites include the brain,
eye, placenta and testis cant be reaced by cells, can be damaged

blood brain barrier

Testes sperm are halpoid so T cells have never seen them before so need to be protected

25
Q

T cell tolerance
Pregnancy

A

foetus and placenta share the child’s genotype

Physical barrier to the mother’s T cells
Lack of MHC class I expression on outer placenta

Production of immunosuppressive factors such as α-fetoprotein and IDO
(indoleamine 2,3-dioxygenase, a tryptophan catabolising enzyme

26
Q

T cell tolerance
Split tolerance

A

T cell tolerance has been established but autoreactive B cells are still present.
Without T cell help the B cells are ‘helpless.

27
Q

T cell tolerance
Anergy

A

If T cell only binds MHC and no costimulatory B7 and CD40

No longer responds to anything

PAMPs cause dendritic cells to express B7 and go to the lymph node
dendritic cells not activated anergise T cells

28
Q

T cell tolerance
Treg supression

A

On contacting self antigen presented by MHC class II molecules Tregs suppress the proliferation of naive T
cells responding to autoantigens

Use IL-10 and TGF-β
Produce IDO
decrease B7 expression on APCs using CTLA4 which has higher affinity than CD28

Kill T cells by perforin and granzymes

Take up all availabe IL-2

29
Q

T cell tolerance
T cell exhaustion

A

Exhausted T cells express the co-receptor PD1 and CTLA4

PD! binds PD-L1 and PD-L2 which causes suppression of T cell signalling

Anti PD1 and CTLA4 are cancer treatment

30
Q

Experimental tolerance

A

Abetacept is an engineered
soluble form of CTLA4
removes CD28, T cell cant get costim so dont function

31
Q

Cancer decreasing toleracnce

A

Tumours have lost MHC

Ipilimumab is an antibody against CTLA4, block CTLA4 and so allows more T cells to be activated

CAncer can make PD-L1 which deactivated T cells so anti PD1 or PD-L1 can be used

32
Q

Autoimmunity

A

Autoimmunity is an excessive adverse immune response against self-antigens

33
Q

Autoimmunity disease

A

Organ specific- Graves diseas

Systemic- Systemic Lupus erythematosis
affects every organ

34
Q

Hypersensitivity

A

Hypersensitivity
types II (antibody)

Type III (immune complex)

IV (cell-mediated)

35
Q

Graves disease
Antiobody

A

TSH binds TSH receptors stops thyroxine production

Antobody binds TSH,
overproduction of thyroxine
hyperthyroidism

Hashimoto thyroditis- antibody binds thyroid peroxidases, TSH receptor, decreased production of thyroxine

36
Q

Myasthenia Gravis
Antiobody

A

Antibodies block acetylcholine receptor
Receptor internalise and degraded and less responsive
Can’t perform long muscle contraction

37
Q

Immune complex mediated effects.

A

Complement binds immune complex
Then binds to complement receptor 1 on erythrocytes

Taken to liver and spleen, phagocytosed
If not removed deposition occurs, can damage

38
Q

SLE (systemic lupus erythematosus),

Immune complex

A

wolf rash on face

Have a wide variety of anticytoplasmic and anti-nuclear auto-antibodies

Lots of immune complexes made and deposited everywhere, recruits lots of complement

In kidney complexes get stuck in glomerulus, damage

complement deficiencies that impair immune clearance, such as C1, C2, C4 are predisposing factors

39
Q

T cell-mediated (cellular autoimmune) diseases

A

Multiple Sclerosis (MS)
T cells cross the blood-brain barrier
damage myelin sheath
Central nervous system demyelinated
Impaired nerve transduction and
hence impaired mobility

In mice transmitted by transferring T cells

Type 1 Diabetes (T1D)
insulin-producing β cells
destroyed by T cells

blood glucose levels can become dangerously
high, causing neurological and vascular damage.

Rheumatoid arthritis (RA)
CD4 T cells destroy joints

40
Q

GEnetic factors causing autoimmune disease

A

HLA allotype can predispose

HLA B27 causes 9/10 people to have ankylosing spondylitis, 150x risk

Due to binding different peptide in MHC

41
Q

Endocrine factors (sex differences)
causing autoimmune disease

A

Females more susceptible
due to hormone
pregnancy can make it better or worse

42
Q

Environment and microbes
causing autoimmune disease

A

Streptococcal infection
can cause rheumatic fever
as cell wall similar to heart valve protein so attacked
Molecular mimicry

Epstein Barr virus causes multiple sclerosis

Ethnicity also a factor

43
Q

Potential triggers and causes of autoimmunity

A

Proteins like gluten modified by enzyme so MHCII picks it up in Coeliac disease

protein citrullination by peptidylarginine deiminase
causes Rheumatoid arthritis (RA)
starts in lung due to smoking
ACPA (anti-citrullinated protein antibodies) are present in patients

44
Q

Treatments

A

thyroxine for hypothyroidism
and insulin for type-1 diabetes.

Immunosuppressive drugs like steroids

immunosuppressive agents include cyclosporin and
rapamycin. These are potent inhibitors of T cell activation.

Antibodies for TNF-α or its receptor have proved to be effective in RA as TNF-alpha inflammatory

CTLA4 to treat RA by removing B7 so no costim for T cells

45
Q

Type I hypersensitivity
IgE mediated

A

Hypersensitivity is extreme response to foreign agent
autoimmune to self

IgE mediated
Sensitivity when dendritic cell presents antigen to T cell, becomes TH2, activates B cell and makes antibodies

asthma pollen
anaphylaxis-peanuts

IgE binds antigen
binds to Fc receptor on mast cell
Cross links 2 receptos
degranulation
histamine release-inflammation

Test by skin prick, causes wheal (swelling), flare(redness) due to increased blood flow

Genetic inheritance, susceptible parents doubles risk for child

46
Q

Asthma

A

Increased TH2 lymphocytes

amplify inflammation and airway remodeling
constrict the
bronchial smooth muscle to attempt expulsion of the offending material by coughing

a late response follows after
about 6 hours, due to leukotrienes, most damaging

Breathing test after exposure

Desensitization therapy by giving small amounts of antigen

47
Q

Type II hypersensitivity
Antibody mediated

A

IgM or IgG antibody binding
destroying rbc or platelets

Blood transfusion
ABO
O-umnodified H antigen
A-adds a terminal N-acetylgalactosamine
B-adds a terminal galactose
AB both

You pre existing antibodies to the sugars you dont have

O can donate to all as no antigen on blood
A only to A or AB as O and B have anti B
Same for B

48
Q

Type II
Rhesus reaction

Rhesus antigen on RBC

A

RhD- mother makes anitbodies for Rhesus antigen

DUe to RhD+ cells from child leaking into mother, only happens during birth so problem for second child

IgG can cross placenta and harm child

anti-Rh antibody (RhoGam) usedto eliminate Rh anitgen in leaked child cells before mother responds
Mother B cell Fc receptors may be cross linked and tolerised

49
Q

Type III Hypersensitivity
Immune-complex
mediated

A

IgG hypersensitivity when antigen is soluble and in high
quantities so foms complex
trigger mast cells visa FcgammaRIII receptor

Complement C5a prime mast cells to respond to immune complexes of anitgen

MAst cells degranulate, histamine release, inflammation

Serum sickness when horse serum was used to treat pneumonia

50
Q

Type IV hypersensitivity
T cell mediated

A

Delayed type hypersensitivity
Needs high dose of antigen,10-100 times more

TH1 cells release cytokines, after 48-72hours and recruit macrophages causing damage

Due to haptens-antigens which forms complexes with host proteins
Activate TH1

metal, poison ivy

51
Q

The Mantoux test for Mycobacterium tuberculosis exposure

A

inject a small amount of tuberculin under the skin

T cells will recognise
the inoculum and mediate a type-I immune response leading to oedema(visible lesion)

Vaccinated people also respond

52
Q

Transplants

A

Mostly allogenic, from same species, second graft rejected faster due to memory T cells

53
Q

HYperacute rejection

A

results from
pre-existing antibody due to
previous transplant
pregnancy
blood transfusion
Complement and immune complexes form and clog blood vessels,

Fast

54
Q

Acute graft rejection

A

barrier to allotransplantation.

Direct recognition
T cells recognise allogenic MHC and respond
Cytotoxic T cell killing

Not an issue in blood transfer as rbc no MHC

Indirect recognition
APC take up allogenic protein, present to T cells which react

55
Q

Chronic Rejection

A

IgG antibodies against
allogeneic HLA class form immune complexes that block blood vessels

56
Q

Other transplants

A

In immuno privleged sites work well

Haemopoietic stem cell transplants
Host immune system destoryed by chemo,
donor stem cells added

graft versus host (GvH) as donor T cells react with host HLA

Autologous transplant, own cacnerous stem cells removed, tumour removed and put back in
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BOD (5 decks)

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