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Immune Tolerance Flashcards

1
Q

What is immune regulation

A

The control of the immune response to inappropriate reactions

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2
Q

What is immune regulation required for

A

Avoid excessive lymphocyte activation and tissue damage during normal protective responses against infections
Prevent inappropriate reactions against self antigens ( tolerance )

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3
Q

Examples of autoimmune diseases

A 
• Graves' Disease (thyrotoxicosis)
	• Hashimoto's Thyroiditis 
	• Pernicious Anaemia
	• Addison's Disease
	• Insulin-dependant Diabetes Mellitus
	• Goodpasture's Syndrome
	• Myasthenia Gravis
	• Multiple Sclerosis(?)
	• Autoimmune Haemolytic Anaemia
	• Idiopathic Thrombocytopenic Purpura
	• Rheumatoid Arthritis
	• Scleroderma
	• Systemic Lupus Erythematosis (SLE)
Psoriasis
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4
Q

Causative factors of autoimmune diseases

A
  • Underlying causative factors: susceptibility genes + environmental influences
    • Immune response is inappropriately directed or controlled; effector mechanisms of injury are the same as in normal responses to microbes

Basically the fundamental problems is the imbalance between immune activation and control .

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5
Q

Immune mediated inflammatory diseases

A

Chronic diseases with prominent inflammation often causes by failure of tolerance or regulation

May be caused by T cells and antibodies and may be systemic or organ specific

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6
Q

Autoimmune diseases and cancer

A

Autoimmune diseases are more prevalent in women and so women may be less susceptible to infectious diseases as they are more disposed to excessive immune response ( cancer may be caused by decreased immune response )

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7
Q

Immune mechanisms of autoimmunity

A

May result from immune responses against self antigens or microbial antigens
Immune response is inappropriately directed or controlled, effector mechanisms of injury are the same as in normal responses to microbes
May be caused by T cells and antibodies
Many immunological diseases are chronic and self perpetuation : because it is attacking self antigen there is always more antigen to attack

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8
Q

Allergy

A
  • Harmful immune responses to non-infectious antigens that cause tissue damage and disease
  • Can be mediated by antibody (IgE) and mast cells – acute anaphylactic shock
  • Or by T cells – delayed type hypersensitivity
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9
Q

Hypercytokinemia and Sepsis

A
  • Too much immune response
  • Often in a positive feedback loop- perpetuates it
  • Triggered by pathogens entering the wrong compartment (sepsis) or failure to regulate response to correct level
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10
Q

3 phases of cell mediated immunity

A

Induction:

  1. Cell infected DC collects material - dendritic cell picks up on MHC molecule and moves into lymph node
  2. MHC: peptide TCR interaction

Effector:

  1. naive T becomes effector and moves back to the site of infection

Memory;

  1. effector cell sees MHC;Peptide on infected cells . Performs function.

Memory;
Effector pool contracts to memory

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11
Q

3 signals required for a response

A
  1. Antigen Recognition
    1. Co-stimulation
    2. Cytokine Release
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12
Q

Self limiting responses

A
  • Cardinal feature of all immune responses: SELF-LIMITATION
  • Manifested by decline of immune responses
  • Principal mechanism: immune response eliminates antigen that initiated the response
  • => First signal for lymphocyte activation is eliminated
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13
Q

Three possible outcomes of immune response

A

Resolution – no tissue damage, returns to normal. Phagocytosis of debris by macrophages.

Repair - healing with scar tissue and regeneration. Fibroblasts and collagen synthesis

Chronic inflammation – active inflammation and attempts to repair damage ongoing

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14
Q

Definition of tolerance

A

Specific unresponsiveness to an antigen that is induced by exposure of lymphocytes to that antigen ( tolerogen vs immunogen )

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15
Q

Significance ofimmunological tolerance

A
  • All individuals are tolerant of their own antigens (self-tolerance); breakdown of self-tolerance results in autoimmunity
    • Therapeutic potential: Inducing tolerance may be exploited to prevent graft rejection, treat autoimmune and allergic diseases
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16
Q

The two types of tolerance

A

1) before the T cell or B cell ever enter the circulation (central)

Or once in the circulation ( peripheral)

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17
Q

Central tolerance

A

Lymphocytes that recognise self antigens before maturation in the generative organs are eliminated (deletion) or made harmless.

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18
Q

Peripheral tolerance

A

destroy or control any self reactive T or B cells which do enter the circulation
Some B cells may change their specificity and some T cells develop into regulatory (suppressive) T lymphocytes

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19
Q

Central tolerance B cell selection

A

• If immature B cells in bone marrow encounter antigen in a form which can crosslink their IgM, apoptosis is triggered

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20
Q

Central tolerance T cell selection

A

T cell selection occurs in the thymus .
Includes MHC:TCR interactions
Need to select for T cell receptors which are capable of binding self MHC/self peptide

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21
Q

3 questions for T cell selection in terms of immune tolerance

A 
Is T cell useless? 
Doesn’t bind to any self-MHC at all
Death by neglect (apoptosis)
Is T cell dangerous?
Binds self MHC too strongly
Apoptosis triggered – negative selection
Is T cell useful?
Binds self MHC weakly
Signal to survive – positive selection
22
Q

Autoimmune REgulator (AIRE) - how T cells developing in the thymus encounter MHC bearing peptides expressed in other parts of the body .

A

specialised transcription factor allows thymic expression of genes that are expressed in peripheral tissues
• Promotes self tolerance by allowing the thymic expression of genes from other tissues
• Mutations in AIRE result in multi-organ autoimmunity (Autoimmune Polyendocrinopathy Syndrome type 1)

23
Q

Peripheral tolerance

A

Destroy or control any self reactive T or B cells which do enter the circulation . Picks up on any escapees and also things that change

24
Q

3 key B cell decisions after antigen exposure e

A
  1. Antibody production
  2. Memory
  3. Affinity maturation
25
Q

Can B cells change specificity after leaving the bone marrow

A

Yes ( somatic hypermjtation) unlike T cells . This improves antibody quality

26
Q

Mechanisms of peripheral tolerance

A

RAID

Regulation : block in activation
Anergy ; +antigen - co-stimulation
Ignorance ; - antigen - co stimulation
Deletion/AICD: + antigen + Fasl

27
Q

Anergy

A
  • Naive T cells need costimulatory signals in order to become activated
  • Most cells lack costimulatory proteins and MHC class II
  • If a naive T cell sees it’s MHC/peptide ligand without appropriate costimulatory protein it becomes anergic – i.e. Less likely to be stimulated in future even if co-stimulation is then present

If the antigens presented on self cells do not give co stimulators signals then the T cells become apoptosed

28
Q

Ignorance

A

• Antigen may be present in too low a concentration to reach the threshold for T cell receptor triggering
• Immunologically privileged sites e.g. eye, (brain)
Compartmentalisation of cells and antigen controls interactions

29
Q

Regulation

A

T reg cells produce Il10 cytokines which downeegulate other self reactive T cells. This regulation is done by Fox P3 transcription factor ( needed for T reg development)

30
Q

Deletion

A

T cells that bind to self cells die in circulation due to Fas-Fas linkages . Here T cells are activated to be killed

31
Q

Antigen Induced Cell Death ( AICD)

A

Activation through the T-cell receptor can result in apoptosis
• Influenced by the nature of the initial T-cell activation events
• In peripheral T cells is often caused by the induction of expression of the death ligand, Fas ligand (CD95 ligand, FasL)

32
Q

T helper cell subset

A

T helper 1 cells (Th1):
Produce Interferon gamma
Boost intracellular immune response
T helper 2 cells (Th2):
Produce IL4, IL-5, IL-13
Boost anti-multicellular organism response
Follicular helper T cells (Tfh):
Produce IL-21, reside in B cell follicles
essential for generation of isotype-switched antibodies
Th17 cells:
secrete IL-17 in autoimmune diseases such as arthritis
Important for control of bacteria
NB other Th cells defined by cytokines e.g. Th9 (IL-9) and Th22 (IL-22)
Treg:
T cells that regulate the activation or effector functions of other T cells
natural and induced regulatory T cells
necessary to maintain tolerance to self antigens

33
Q

How are T helper cells defined

A

By the cytokines they produce and the transcription factors they use

34
Q

Reg T cells ( CD4)

A
  • Phenotype: CD4, high IL-2 receptor (CD25), low IL-7 receptor, Foxp3 transcription factor; other markers
  • Mechanisms of action: multiple
    • secretion of immune-suppressive cytokines (TGFb, IL-10, IL-35),
    • inactivation of dendritic cells or responding lymphocytes
35
Q

F oxP3

A

• Mutation in FoxP3 leads to severe and fatal autoimmune disorder -
Immune dysregulation, Polyendocrinopathy, Enteropathy X-linked (IPEX) syndrome.
• Mice had similar condition called scurfy – was associated with mutations in FoxP3 (Forkhead box Protein 3)

36
Q

Il10

A
  • Key anti-inflammatory cytokine
  • Multi-functional (pleiotropic)
  • Acts on a range of cells
  • Blocks pro-inflammatory cytokine synthesis including TNF, IL-6, IL-8, IFNγ
  • Downregulates Macrophages
  • Viral mimics
37
Q

Regulation and Pregnancy

A
  • Pregnancy as a parasitic infection
  • Exposure to new antigen
  • Expressed in the context of foreign MHCI
  • Tregs only exist in mammals
38
Q

Natural T ref cells .

A
  • Development (in thymus) requires recognition of self antigen during T cell maturation
    • Reside in peripheral tissues to prevent harmful reactions against self
39
Q

Inducible T reg cells ( iTreg)

A
  • Develop from mature CD4 T cells that are exposed to antigen in the periphery; no role for thymus
    • May be generated in all immune responses, to limit collateral damage
40
Q

Th17

A

Control bacterial and fungal infections

41
Q

TfH

A

Pro antibody

42
Q

Th1

A

Boost cellular immune response

43
Q

Th2

A

Anti- multicellular organism

44
Q

Treg( Th0)

A

Anti inflammatory

45
Q

Cytokines

A

Cytokines program the immune response
They can focus it for the right kind of response
They can be inflammatory ( increase the response)
Or anti inflammatory ( decrease response )

46
Q

What kind of cytokines is Interferon gamma

A

Inflammatory

47
Q

What kind of cytokines is Il 10

A

Anti inflammatory

48
Q

Chenokines

A

Chemokines drive movement across the body

49
Q

T cells boost antibody response / B cell response

A

Antigen ;MHC: Peptide (on the DC or B cell)

Co stimulation ; Expresses CD40L to activate B
Expresses CD28 to be activated

Cytokines; IL-4, IFNγ, IL-21

50
Q

T cells cytokines drive IgG class switch

A

T cell cytokines drive IgG class switch

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