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Immuno > Immuno 2: Tolerance & autoimmunity > Flashcards

Immuno 2: Tolerance & autoimmunity Flashcards

1
Q

Define autoimmunity

A

adaptive (i.e. b and t cell) immune responses with

specificity for self “antigens” (autoantigens)

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2
Q

What leads to autoimmue disease

A

Normal autoimmunity –>autoimmune after

BREAKDOWN OF SELF TOLERANCE (affected by genetic and environmenta factors)

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3
Q

T/f health people have no autoimmunity

A

F..

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4
Q

What are the criteria for the disease to be autommune

A

Evidence of disease-specific adaptive immune response in the affected target tissue, organ or blood

Passive transfer of autoreactive cells or antibodies replicates the disease

Elimination of the autoimmune response modifies disease

History of autoimmune disease (personal or family), and/or MHC associations

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5
Q

Why might a baby experience graves at the beginning of life but not after

A

At first, maternal IgG can cross the placenta

This can be auto-IgG

But after a while then the baby will make their own antibodies (which might not include a graves autoantibody)

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6
Q

What are the genetic evidence relating to AI disease

A

twin and family studies, GWAS (e.g. 40 key loci in SLE)

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7
Q

What environmental factors can affect chances of AI disease

A

Sex

Infections

Diet

Stress

Microbiome

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8
Q

T/F men are more likely to get SLE than females

A

F (e.g. F:M is 9:1 in SLE)

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9
Q

Why do infections predispose to AI

A

inflammatory environment

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10
Q

How does sex affect chances of AI disease

A

women more susceptible

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11
Q

How can diet affect chances of AI disease

A

obesity, high fat, effects on gut microbiome: diet modification may relieve autoimmune symptoms

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12
Q

How can stress affect chances of AI disease

A

physical and psychological, stress-related hormones

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13
Q

How can microbiome effect AI isease

A

gut/oral microbiome helps shape immunity, perturbation (dysbiosis) may help trigger autoimmune disease (sex differences?)

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14
Q

What are the mechanisms of autoimmunity

A

Autoimmune diseases involve breaking T-cell tolerance (even in antibody mediated, IgG antibodies are present, so class switching must take place)

Effector mechanisms resemble those of hypersensitivity reactions, types II, III, and IV

Chronic conditions

Adaptive immune reaction

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15
Q

How is body’s response to autoantigens different to pathogen

A

Adaptive immune reactions against self use the same mechanisms as immune reactions against pathogens (and environmental antigens)

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16
Q

Why are autoimmue disease chronic conditions

A

Because self tissue is always present, autoimmune diseases are chronic conditions (often relapsing)

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17
Q

How many autoimmune diseases

How many affected by AI disease

What proportion of AI are in women

A

100

8%

80% in women

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18
Q

T/F there is a higher number of males with Diabetes mellitus than female

A

T (so not always the case that more common in female)

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19
Q

What happens to rheumatoid and SLE in pregnancy and why

A

Rheumatoid can get better (due to less inflammatory responses in pregnancy)

SLE worse as antibody mediated

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20
Q

List examples of important AI disease

A 
Multiple Sclerosis
Rheumatoid Arthritis
Type I diabetes
SLE 
Autoimmune thyroid disease
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21
Q

How have autoimmue reactions between described

A

Organs affected

Involvement of specific autoantigens

Types of immune responses

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22
Q

Which diseases are mostly organ-specific, which are systemc and which are both

A

Graves’ disease Thyroid

Hashimoto’s thyroiditis Thyroid

Type I diabetes Pancreas

Goodpasture’s syndrome Kidney

Pernicious anaemia Stomach

Primary biliary cirrhosis Liver, Bile

Myasthenia gravis
Muscles

Dermatomyositis/Polymyositis Skin/ Muscles

Vasculitis
Blood vessels

Rheumatoid Arthritis Joints

SLE
Multiple targets

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23
Q

How was it shown that autoantibodies play a role in autoimmune disease

A

Early experiments showed that autoantibodies against red blood cells were responsible for autoimmune haemolytic anaemia in humans

  • Result in the clearance or complement-mediated lysis of autologous erythrocytes
  • Direct link between autoantibodies and disease (also antibody transfer experiments)
24
Q

What are the immune reactions involved in autoimmunity

A

Antibody response to cellular or extracellular matrix antigen (Type II)

Immune complex formed by antibody against soluble antigen (Type III) (go into circulation i.e immune complex)

T-cell mediated disease (Delayed type hypersensitivity reaction, Type IV)

25
Q

Examples of type II immune reactions in AI

A

ANTIBODY TO INSOLUBLE ANTIGEN

E.g. Goodpasture’s, leads to Ab binding to type 4 collagen e.g. in BM of kidney –> neutrophil and complement recruitment. IgG (needs T cell breakdown of tolerance to allow this class switching from IgM)

E.g in Grave’s, AB binds to TSH receptor, stimulates it so that it doesn’t have negative feedback (i.e. it is constitutively on, ignoring the fact that TSH would be low)

26
Q

Outline type 3 immune reactions example

A

SLE…. immune compexes with DNA, histones, ribosomes, snRNP and scRNP

Immune complex deposition in glomerulus

Glomerulonephritis

27
Q

Differentiate type II and type III disease

A

Basically the same mechanism
-Inflammatory cells (neutrophils and macrophages) are activated by Fc receptor of Ab bound to auto-antigen, and also activated by complement

-The difference is that the type II is happening against EC matrix./membrane bound insoluble antigen, and antibody binding causes cell destruction, whereas type III involves soluble antigen, which are not bound to cell surface. Only when the immune complex gets deposited, will it recruit the immune cells.

28
Q

Give examples of type IV disease.

Name the autoantigen and the pathologyin each case

A

Mostly T cell mediated , both CD8+ and CD4+

Initial triggers are mostly T cell, but then can have antibody too

Insulin-dependent diabetes mellitus (NOTE, YOU MIGHT THINK THIS WOULD BE TYPE II BUT IT’S NOT!):
Autoantigen: Pancreatic b-cell antigen
Pathology: b cell desturction

RA:
AA:Unknown synovial joint antigen
Pathology: Joint inflammation and destruction

MS
AA: Myelin Basic Protein,
Proteolipid protein
Pathology: Brain degeneration (demyelination), weakness/paralysis

29
Q

Ho are antigens presented in normal T cell response

A

MHC II- CD4 receptor

MHC I- CD8 receptor

30
Q

Which genes are associated with AI disease

A

Human MHC (HLA) CLASS 2!!!! Is the dominant genetic factor affecting susceptibility to autoimmune disease

especially on the DR

(remmeber that these genes are highly polymorphic, and some variations are associated with increased risk of AI disease)

31
Q

What do HLA associations imply

A

HLA associations strongly imply a role for T cells in initiating autoimmune disease

32
Q

Define immunological tolerance

A

Defined as the acquired inability to respond to an antigenic stimulus

33
Q

What is immunological tolerance based on

A

3 As:

Acquired -involves cells of the acquired immune system and is ‘learned’

Antigen specific

Active process in neonates, the effects of which are maintained throughout life

34
Q

How does self tolerance work

How can it lead to autoimmune disease

A

Central tolerance
-deletion of auoreactive cells in primary lymphoid organ

Peripheral tolerance

  • Anergy
  • Active suppression using regulatory T cells
  • immune privilege, ignorance of antigen (note that this is difference to B cell ignorance in the bone marrow, where the bone marrow does not contain high enough amounts of the autoantigen, so the b cell is released into periphery and can cause autoimmune disease)

Failure in one or more of these mechanisms may result
in autoimmune disease

35
Q

Outline T cell maturation with regard to tolerance

A

Central tolerance

T cell precurosrs go from bone marrow to thymus

Selection process after generation of the TCR

Based on the peptides presented by the thymic epithelium cells and dendritic cells (enabled by AIRE)

CD4+ selected on MHC II presenting peptides

CD8+ selected on MHC I presenting peptides.

95% of developing lymphocytes do not survive! Those that remain will see self-MHC and bind it weakly and not cause autoimune disease

36
Q

Outline B cell maturation

A

If there is no self reaction, they become mature B cell and express IgG and IgM, and migrate to periphery

Crosslinking of surface immunoglobulin by polyvalent antigens expressed on bone marrow stromal cells facilitates deletion (or receptor editing

If cells react with soluble self antigen with fairly low affinity, they are released into the circulation but they are ANERGIC and express IgD (non-functional). Reside in 2o lymphoid tissue

IMPORTANT: Finally, they can react weakly or not at all with self antigen, but have receptors that would recognise autoantigen, if it was presented in the bone marrow in high enough amounts, and thus migrate to periphery and have potential to cause autoimmune disease. I.e. they are ignorant in the bone marrow, but could then see their antigen in the periphery

37
Q

Outline T cell selection in the thymus

A

Useless (can’t see MHC): die by apoptosis

Useful (see MHC weakly): receive signal to survive. “Positive selection”

Dangerous (see self strongly): receive signal to die by apoptosis. “Negative selection”

38
Q

Which types of B cells can cause the autoimmue disease

A

The B cells which bind with low affinity, and don’t cross link when exposed to self molecule in the bone marrow, can migrate to the periphery as a mature B cell.

These can cause autoimmune disease

39
Q

What can cause APECED

A 
Autoimmune
PolyEndocrinopathy-
Candidiasis-
Ectodermal 
Dystrophy

Caused by mutations in AIRE (autoimmune regulation)

AIRE is important for the expression of “tissue-specific” genes in the thymus, contained in medullary thymic epithelial cell (mTEC)

Involved in the negative selection of self reactive T-cells in the thymus

You get persistence of autoreactive cells, and this shows central tolerance is necessary

40
Q

What is AIRE

A

A transcription factor

41
Q

…..

A

……

42
Q

t/f like APECED, most AI disease are monogenic

A

F

Most autoimmune diseases are associated
with multiple defects and genetic traits

In SLE genes affecting multiple biological pathways may lead to failure of tolerance

40-50 genes implicated in genetic susceptibility

43
Q

What gene defects might lead to SLE

A

induction of tolerance (B lymphocyte activation: CD22, SHP-1): autoantibody production

apoptosis (Fas, Fas-ligand): failure in cell death

clearance of antigen (Complement proteins C1q, C1r and C1s): abundance/persistence of autoantigen

44
Q

When might peripheral tolerance be needed

A

Some antigens may not be expressed in the thymus or bone marrow, and may be expressed only after the immune system has matured

45
Q

Why would you not get T reaction when it is presented with a self antigen

A

Naïve T-cells require costimulation for full activation: CD80, CD86 and CD40 are examples of costimulatory molecules expressed on APC

These are absent on most cells of the body

So not likely to activate T cells, and the cells then become anergic

46
Q

Give an example of costimulation

A

CD80/86 (APC) and CD28 (T cell)

APCs upregulate costimulation due to PRRs

47
Q

When does immunological ignorance occur

A

Occurs when antigen concentration is too low in the periphery

Occurs when relevant antigen presenting molecule is absent: most cells in the periphery are MHC class II negative (remember, you need MHC II for T cells to mount a response)

Occurs at immunologically privileged sites where immune cells cannot normally penetrate: for example in the eye, (central and peripheral nervous system) and testes. In this case, cells have never been tolerised against the auto-antigens

48
Q

Give an example of breakage of ignorance

A

Sympathetic opthalmia
Trauma to one eye result in release of sequestered intraocular protein antigens

Released intraocular antigens are carried to lymph odes and activate T cells

Effector T cells return via blood stream vand attack antigens in both eyes

49
Q

What are Tregs?

A

Autoreactive T-cells may be present but do not respond to autoantigen

DUE TO PRESENCE OF:

Regulatory T-cells…..CD4+CD25+CTLA-4+FOXP3+

50
Q

How does Treg work

A

CD25 is the Interleukin-2 Receptor

CTLA-4 binds to B7 and sends a negative signal

FOX P3 is a transcription factor required for regulatory T-cell development

CONTROL BOTH CD4+ AND CD8+ T CELLS

51
Q

What happens when FOXP3 is mutated

A

IPEX (not that this is a failure in regulation of PERIPHERAL tolerance, whereas AIRE and the APECED associated with it, are failures of CENTRAL tolerance)

IPEX:
Immune dysregulation, Polyendocrinopathy, Enteropathy and X-linked inheritance syndrome

Fatal recessive disorder presenting early in childhood

Mutation in the FOXP3 gene which encodes a transcription factor critical for the DEVELOPMENT of regulatory T-cel

52
Q

What are the symtpoms of IPEX

A 
early onset insulin dependent diabetes mellitus
severe enteropathy
eczema
variable autoimmune phenomena
severe infections
53
Q

Give example of infeciton associated with developing an AI disease

A

Rheumatic fever/myocarditis: streptococci

54
Q

How could tolerance deplete self tolerance?

A

Molecular mimicry of self molecules (if pathogen has similar molecule to self molecules)

Induce changes in the expression and recognition of self proteins

Induction of co-stimulatory molecules or inappropriate MHC class II expression: pro-inflammatory environment

Failure in regulation : effects on regulatory T-cells

Immune deviation: shift in type of immune response e.g. Th1-Th2

Tissue damage at immunologically privileged sites

55
Q

What is anergy

A

Costimulation is required to mature a naive T cell.

Costimulatory molecules include CD80/CD86/CD40. They are expressed on APC.

But absent on most cells in the human body.

Without costimulation, the T cell will not proliferate, nor will factors be produced.

Subsequent stimulation of the T cell leads to a refractory state= ANERGY

Immuno (5 decks)

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