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Cancer, Autoimmunity and Transplant Immunology > Introduction to Autoimmunity > Flashcards

Introduction to Autoimmunity Flashcards

1
Q

what is autoimmunity?

A

Defined as breakdown of mechanisms responsible for self tolerance and induction of an immune response against components of the self
- misdirected immune response against self
- interplay between immune system and autoantigens drive autoimmune disease

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2
Q

what are autoimmune diseases?

A

Conditions characterized by chronic immune response against self
- can be systemic or organ-specific
- a common issue - 5-7% adults effected
- 2/3s of patients are women

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3
Q

how do autoimmune diseases arise?

A

Autoimmune diseases arise due to a the presence of a combination of both environmental and genetic risk factors, in particular MHC genotype, which cause a breakdown in tolerance

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4
Q

what are the 4 criteria for autoimmunity?

A

Demonstration of circulating antibodies – autoantibodies

Recognition of specific autoantigen which autoantibodies bind

Production of autoantibodies against the same antigen in an experimental animal model

Animal model demonstrates equivalent pathology to the human disease

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5
Q

how are autoimmune diseases classified?

A

Organ specific - Organ specific means the auto-immunity is directed against a component of one particular organ.

Systemic - the auto-immunity is directed against an antigen that is present at many different sites and can include involvement of several organs

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6
Q

how is the body affected by a systemic autoimmune disease?

A

Systemic autoimmune diseases affect skin, joints, kidney & muscle. - Individual organs are more affected in some diseases than others

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7
Q

what are the most polar examples of organ-specific and systemic autoimmunity?

A

Hashimoto’s thyroiditis – autoimmune disease focused at thyroid

SLE – autoimmunity prevalent across body

this is due to differential distribution of the targeted autoantigen

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8
Q

why is SLE systemic?

A
  • Autoantigen for SLE is very diffuse – nuclear antigens e.g. dsDNA, which can be released in failure of apoptotic cell clearance – release of autoantigen into microenvironment where immune system can mount response
  • causes systemic distribution and autoimmunity
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9
Q

what are examples of organ-specific autoimmune diseases?

A

Antigens and autoimmunity restricted to specific organs in the body:
- Type I diabetes – destruction of pancreatic beta cells that produce insulin
- Goodpasture’s syndrome – affects kidneys basement membrane of glomeruli
- Multiple sclerosis
- Grave’s disease – hyperthyroidism – production of autoantibodies which bind and activate TSHR = over-production of thyroid hormone
- Hashimoto’s thyroiditis – hypothyroidism – autoimmune damage of thyroid due to reduction in thyroid hormone production
- Myasthenia gravis

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10
Q

what are examples of systemic autoimmune diseases?

A

Antigens and autoimmunity are distributed in many tissues (systemic):
- Rheumatoid arthritis – autoimmune inflammatory response against synovium which lines joints
- Systemic lupus erythematosus
- Scleroderma
- Primary Sjögren’s syndrome – targets exocrine glands – loss of function of salivary glands, dryness in mouth – can affect renal and neurological processes
- polymyositis

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11
Q

why does autoimmunity occur?

A

Failure of central tolerance.
Failure in peripheral tolerance.
= Polyclonal lymphocyte activation

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12
Q

what may cause immune regulation to go wrong?

A

Could be direct genetic defect in immune regulation mechanisms

Direct issue with immune cell populations – uncontrolled

Issue with environment in which immune cell is found so that it is hard to regulate

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13
Q

what is the key function of immune cells?

A

Immune cells need to have ability to mount response to pathogen, whilst being tolerant and unresponsive to self

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14
Q

what are central and peripheral tolerance?

A

Central tolerance during lymphocyte development in primary lymphoid organs

Peripheral tolerance to control mature autoreactive lymphocytes that are released into periphery following development

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15
Q

what is the current model for how the immune system is activated?

A

Danger model:
- The immune system is concerned by what is dangerous or not, i.e. damage
- Tissue damage in response to infection – release of IC molecules e.g. DNA, heat-shock proteins, is recognised by PRRs
- this drives inflammatory responses and second signal to adaptive immune system

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16
Q

what is the two-signal requirement for lymphocyte activation?

A

Signal 1: specific recognition of antigen
- TCR-Peptide-MHC
- BCR-Native antigen
- Discriminates self and non-self

Signal 2: Non-specific
- Microbial-induced molecules on/from APC
- Microbial molecule (LPS, CpG etc)
- Upregulated in response to infection – leads to T cell co-stimulation via APC

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17
Q

why is signal 2 necessary for lymphocyte activation?

A

Signal 1 alone leads of unresponsiveness = anergy, deletion, apoptosis
Signal 2 is needed to avoid T cell anergy

Both signals needed for robust lymphocyte proliferation and differentiation
- Both signals must be properly regulated to prevent autoimmunity via central and peripheral tolerance

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18
Q

what is central tolerance?

A

Central Tolerance – Primary Lymphoid organs during development
- Negative selection
- Development of regulatory T cells
- Receptor editing (B cells)

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19
Q

what is peripheral tolerance?

A

Peripheral Tolerance – Periphery – control autoreactive escaped lymphocytes
- Regulatory cells and suppression
- Anergy/Ignorance
- Exclusion from lymphoid follicles (B cells)

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20
Q

what is signal 1?

A

Signal 1 = antigen receptor signal
- This is regulated during central tolerance in lymphocyte development in primary lymphoid organs

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21
Q

how is signal 1 regulated in central tolerance?

A

T cells migrate into thymus:
- Positive selection in cortex – random rearrangement of TCR – tested against MHC to check that TCR is functional
- As this is random, can likely result in autoreactive T cell clones
- Autoreactive T cells removed during negative selection
- T cells that respond to autoantigens are deleted via apoptosis or diverted to become Tregs

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22
Q

what factors can impact antigen-receptor signalling in the periphery?

A
  1. antigens released from cells which are usually hidden
  2. antigen generated by post-translational modifications
  3. molecular mimicry
  4. altered antigen presentation - The level of auto-antigenic peptide presented is determined by polymorphic residues in MHC molecules that govern the affinity of peptide binding.
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23
Q

how can normally hidden antigens be presented?

A

Antigen can be presented in periphery that isn’t usually visible to immune system e.g. intracellular proteins exposed by failed apoptotic clearance – autoantigen becomes accessible e.g. dsDNA in SLE

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24
Q

how can antigens be generated by molecular changes?

A

Changes to shape of antigen via post-translational modifications – can change immunogenicity or presentation of autoantigens

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25
Q

what is molecular mimicy?

A

Molecular mimicry – similarities in self and non-self peptides – stimulation of autoreactive lymphocyte by pathogen-derived peptides

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26
Q

is central tolerance perfect?

A

no - central tolerance is an imperfect process and autoreactive T cells are inevitably released into the periphery, particularly T cells that fall close to the negative selection affinity threshold

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27
Q

what are the 3 peripheral tolerance mechanisms?

A
  • immunological ignorance
  • Tregs - actively suppress autoreactive T cells
  • requirement for co-stimulatory molecules - additional scope for regulation
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28
Q

what is immunological ignorance?

A

Very few self proteins contain peptides that are presented by a given MHC molecule at a level sufficient for T cell activation.
- Autoreactive T cells are present but not normally activated
- Passive consequence – autoreactive lymphocytes may not get activated if autoantigen is not presented – IC antigen may not be released or may be adequately mopped up

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29
Q

what are the functions of co-stimulation?

A

Co-stimulation drives cell cycle progression and clonal proliferation for T cells by driving IL-2 expression – autocrine growth factor for T cells
- Also drives expression of CD25 (high affinity IL-2R) to respond to IL-2
- Also drives cell survival
- Prevents T cell anergy
- drives T cell differentiation

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30
Q

what happens in presence of TCR stimulation but lack of co-stimulation?

A

T cell anergy and clonal unresponsiveness
- In absence of inflammation, there is no danger, so lack of co-stimulation but TCR binding indicates that this is an autoantigen
- Both signals induce T cell activation.
Just TCR stimulation = anergy and unresponsiveness to autoantigen

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31
Q

what are the important co-stimulatory molecules?

A

CD28 – prominent co-stimulatory pathway - Expressed by resting/activated T cells
ICOS: Expressed following T cell activation

These are structurally related molecules that use similar signalling mechanisms
- These molecules upregulate T cell responses, so need to be regulated properly

also TNF

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32
Q

how are co-stimulatory molecules regulated?

A

Can be controlled by CTLA-4 and PD-1

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33
Q

what do signal 1 and signal 2 induce?

A

TCR and CD28-mediated signals contribute towards a combined activation threshold and promote T cell activation, proliferation and effector function.

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34
Q

how are signals 1 and 2 provided?

A

T cell activated via TCR engaging antigen, in addition to CD28 signal
CD28 signal delivered via binding to CD80/CD86 expressed on APCs
- CD80/86 only expressed in response to damage-induced inflammation

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35
Q

what is CTLA-4?

A

CTLA-4 is expressed by activated T cells and Tregs
- it regulates CD28 co-stimulation

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36
Q

how does CTLA-4 function?

A

CTLA-4 has a higher affinity for CD80 and CD86 than CD28 so it can outcompete for ligand binding and therefore inhibit CD28 costimulation.
- In addition it removes CD80 and CD86 from APCs by transendocytosis so that there are less CD28 ligands available
- This is all about controlling the activation thresholds

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37
Q

what is PD-1?

A

PD-1 functions via Shp2. - This is a phosphatase that is recruited to the PD-1 cytoplasmic tail upon ligand binding
- Same family as CD28 and CTLA-4

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38
Q

how does PD-1 function?

A

Negatively regulates TCR signal and CD28 co-stimulatory signal following PDL1/2 ligand binding expressed by APCs and fibroblasts
- causes dephosphorylation of CD28 in particular but also shows capacity to inhibit TCR driven activation

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39
Q

why is co-stimulation balance important?

A
  • in autoimmunity, there is too much TCR/CD28/ICOS signalling, and too little CTLA-4/PD-1 inhibitory signals
  • a strategy could be to rebalance this
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40
Q

what is abatacept?

A

Abatacept blocks CD28 signalling to treat RA
- balances co-stim and inhibitory signals

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41
Q

how should co-stimulatory molecules be balanced in cancer?

A

In cancer, we want costimulatory pathways to drive antitumour response
- But this doesn’t happen, as PD1 and CTLA-4 are highly expressed by cancer to inhibit T cells
– opposite therapeutic response to block these T cell inhibitory signals provided by cancer with checkpoint blockade, but can lead to autoimmunity due to loss of T cell regulation

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42
Q

what are the types of Tregs?

A

CD4+CD25+Foxp3+

Thymus-derived (natural Treg)
Peripheral lymphoid tissue-derived (induced Treg)

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43
Q

how are induced Tregs generated?

A
  • when a naïve T cell receives TCR signal in absence of inflammation, there is risk that this is an autoantigen:
  • Environment rich in anti-inflammatory cytokines such as IL-10 and TGFb favours Treg differentiation
  • Effector T cell response is inhibited, and becomes biased to Treg differentiation – induced Tregs
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44
Q

what are the key features of Tregs?

A
  • Define Tregs via CD25 positivity in combination with low IL-7R
  • Tregs depend on IL-2 for homeostasis and survival – can bind CD25 (IL-2R)
  • FOXP3 expression also defines Tregs – master TF for Treg differentiation
  • CTLA-4 expression is required for suppressive function of Tregs
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45
Q

what do Tregs do?

A

Tregs suppress immune cell activation, mainly T cells – can affect B and NK cells by modulating their environment and signals

46
Q

how do Tregs mediate their function?

A

soluble factors (IL-10, TGFb) inhibition of effector phase

direct interaction: inhibition of activation and differentiation of naïve T cells
- e.g. CTLA-4

47
Q

what happens when CTLA-4 is deleted in Foxp3+ cells?

A

Genetic deletion of CTLA-4 in Foxp3+ cells results in severe systemic autoimmunity and lymphoproliferation

48
Q

how does CTLA-4 prevent autoimmunity?

A

CTLA-4 has higher affinity for CD80/86 than CD28, so can outcompete CD28 for ligand binding:
- CTLA-4 cycles between cytosol and cell surface
- When CTLA-4 is at surface, it captures CD80/86 from APC surface
– can internalise CD80/86 into the Treg to be degraded in lysosomes – rips co-stim from APC
– limits APC ability to drive T cell response – limits autoreactivity by suppressing activation signals

49
Q

how can Tregs suppress effector responses via IL-2?

A

Tregs can control consumption of local IL-2 levels:
- Tregs express CD25 highly – this is a component of high affinity IL-2R
- Tregs can use up IL-2 in microenvironment to deprive effector autoimmune T cells present in that local environment from essential IL-2 growth factor

50
Q

what is B cell central tolerance?

A
  • B cell tolerance controlled centrally during Ig gene rearrangement in bone marrow
  • Recognition of self-antigen in bone marrow leads to apoptosis or receptor editing
  • Elimination of lymphocytes with high affinity receptors for abundant, widely expressed, cell membrane or soluble self antigens.
51
Q

what is B cell peripheral tolerance?

A

Autoreactive mature B cells controlled by requirement for T cell help:
- If autoreactive T cells are inhibited, they cannot activate autoreactive B cells

Exclusion of autoreactive B cells from GC response
- Autoreactive B cells arising from somatic hypermutation in GC response will undergo apoptosis

52
Q

why are both central and peripheral tolerance needed?

A

Central tolerance mechanisms shapes the lymphocyte receptor repertoire to one that is effective in mediating protective immunity but is inherently limited in its capacity to respond to self.

Central tolerance is an imperfect process so autoimmune T cells are released to the periphery. Peripheral tolerance mechanisms exist to reduce the possibility for these cells to drive autoimmunity

53
Q

what causes clinical symptoms in autoimmune disease?

A

Clinical symptoms are grouped into a disease
- In autoimmunity, symptoms created by altered biological process or tissue damage created by autoimmune response

54
Q

how can autoimmune damage mechanisms be classified?

A

Specific components: adaptive immune system
- Antibodies (majority of autoimmune diseases )
- T cells

Nonspecific components: innate immune system
- Complement
- Phagocytes (PMN and macrophages)
- NK and other cells

autoantibodies may enhance self-damage via innate immune system

55
Q

what is hypersensitivity?

A

excessive immune response causing undesirable consequences

56
Q

what is type 1 hypersensitivity?

A

allergic – driven by histamine production by mast cells caused by IgE

57
Q

what is type 2 hypersensitivity?

A

Type 2 – autoantibodies binding cell or matrix-associated antigen e.g. autoantibodies binding to platelet antigens, causing their clearance, leading to issues with clotting

58
Q

what is type 3 hypersensitivity?

A

Type 3 – autoantibodies bind soluble antigen to form immune complex – these trigger local inflammation when deposited in small blood vessels e.g. in kidneys – glomerulonephritis, associated with SLE

59
Q

what is type 4 hypersensitivity?

A

Type 4 classified by T cell involvement
- Subclassified by T cell subset involved

60
Q

what T cell subsets are implicated in autoimmunity?

A

Th17: pro-inflammatory via IL-17 release that drive local immune responses and recruit neutrophils

Th1: produce TNFa and IFNy which are proinflammatory – activate macrophages

Th2 and TFH to produce B cell GC responses

61
Q

how are Th1 cells implicated in autoimmunity?

A

Th1 also implicated – produce TNFa and IFNy which are proinflammatory – activate macrophages

62
Q

how are autoimmune lymphocytes activated to cause damage?

A

Autoimmune lymphocytes receive activation signals in secondary lymphoids
- They then traffic to inflammatory sites impacted by autoimmunity
- Effector function of lymphocytes in target organs leads to disease autoimmune phenotype

63
Q

how do effector lymphocytes drive autoimmune damage?

A

In synovial inflammation during RA:
- Cellular interactions between infiltrating immune cells with resident cells e.g. fibroblasts and macrophages
- These interactions cause reciprocal feedback loop – modulation of both populations
- Stromal cells supply growth and survival factors to promote lymphocyte activation and function
- Persisting lymphocytes produce inflammatory mediators to drive inflammation along side resident cells – synchronous tissue damage between infiltrating populations and resident population

64
Q

what is Sjorgen’s syndrome?

A

damage to exocrine glands – salivary glands – reduced saliva production

65
Q

how are salivary glands damaged in Sjorgen’s syndrome?

A

In syndrome – inflammatory infiltrate of lymphocytes – drives tissue damage and loss of function of acini
- T and B cells mostly infiltrate to drive tissue damage and loss of function of salivary glands
- Lymphocytes organise into aggregates – tertiary lymphoid structures where there activation status is maintained

66
Q

what are the features of tertiary lymphoid structures in Sjorgen’s syndrome and how do stromal cells drive the disease?

A

Structures form distinct B and T cell zones, similar to in secondary lymphoid organs
- Organisation driven by chemokines released by resident stromal cell populations to promote T and B cell organisation
- CCL19 for T cells, CXCL13 for B cells
- stromal cells also produce survival factors e.g. BAF for B cells, IL-7 for T cells
- These factors drive persistence of autoimmune responses and chronic inflammaton, leading to tissue destruction

67
Q

what do tertiary lymphoid structures induce for B cells in Sjorgens?

A

B cells can further evolve to form GC structures, supported by FDCs normally found in secondary lymphoid organs but differentiated from resident fibroblasts
- also further production of survival factors
- These promote autoreactive B cell survival and production of autoantibody

Immune structures are hallmarks of autoimmune responses in inflamed tissues

68
Q

what is the overall incidence of autoimmune (AI) diseases?

A

many AI diseases are rare, but RA, type 1 diabetes and Graves are more common
- AI is a common problem: 5-7% population
- women 2.7x more likely to develop AI diseases
- SLE and Sjorgen’s syndrome have a sex bias of 9:1 for females

69
Q

what are the key risk factors for autoimmune diseases?

A
  • age
  • sex
  • Infection
  • Pollutants – cigarette smoke
  • Dietary risk factors – vitamin D3, omega 3 fatty acid levels – involved in dev of AI
  • genetics
70
Q

what is the biological basis of sex bias in autoimmune diseases?

A

Males and females have different immune responses
- females have higher antibody titier and more vigorous immune responses than men
- females have higher levels of CD4 T cells and serum IgM
- difference due to sex hormones which influence gene expression
- oestrogen can trigger B cell-driven autoimmunity whilst testosterone is immunosuppressive

71
Q

how does autoimmune disease correlate with age?

A

Many autoimmune diseases are more prevalent with increasing age
- e.g. increased incidence of RA with increased age

72
Q

why is age implicated in autoimmunity?

A
  1. sex hormones
    - Increased RA incidence post menopause – increased production of IL-6 and IL-1 pro-inflammatory mediators
  2. AI can take several decades from initial breakdown of tolerance to symptom presentation
    - In RA, autoantibodies can be detected years prior to symptoms
  3. age-related immunodeficiency
    - shrinking T and B cell populations and loss of receptor diversity
    - T cells become less responsive
  4. excess production of inflammatory cytokines - inflammaging
73
Q

what is the paradoxical relationship between age and autoimmunity?

A

in very elderly populations, RA incidence decreases
- Increased prevalence of autoantibodies – evidence of breakdown of tolerance
- But there is contraction of lymphocyte populations due to thymic atrophy with increasing age
- Breakdown of immune system – less effective immune response, but also less regulated to not recognise self

74
Q

why do autoimmune diseases develop?

A

Accumulation of genetic and environmental risk factors
- Genetic risk factors make lymphocyte populations more prone to AI or more difficult to regulate
- These combine with environmental risk factors e.g. age, infection

These risk factors combined lead to tolerance breakdown – characterised by autoreactive lymphocyte activation and expansion, with autoantibody production
- Causes tissue damage

75
Q

what evidence is there for different genetic and environmental risk factors contributing to autoimmune diseases?

A

Concordance rates in monozygotic and dizygotic twin pairs
- Monozygotic, identical twins have higher concordance than dizygotic twins – indicates genetic component
- Monozygotic twins don’t show 100% concordance – some environmental factors are involved

Discordance between monozygotic twins suggests that environmental factors play a significant role in the pathogenesis of autoimmune disease

76
Q

what is concordance?

A

Concordance – where both twins develop the disease

77
Q

are genetic and environmental risk factors varied across autoimmune diseases?

A

yes:
- Celiac disease has strong genetic bias
- RA has strong environmental bias – low concordance in monozygotic twins

78
Q

what are the key genetic risk factors for rheumatoid arthritis (RA)?

A
  1. variant peptide sequence in HLA-DRb1 - risk factor for presentation of citrullinated peptides
    - genetic polymorphism
  2. PTPN22 encodes LIP - tyrosine phosphatase that negatively regulates TCR signalling
    - genetic polymorphism
  3. CTLA-4 and PD-1 variants – negative regulators of T cell responses
  4. IL-2R – T cell growth factor receptor – regulates Treg homeostasis
79
Q

what is the key environmental risk factors for RA and how does this increase incidence?

A

cigarette smoke
- cigarette smoke upregulates peptidylarginine deaminase 2 (PAD2) enzyme
- this converts peptidylarginine to peptidylcitrulline in a post-translational modification in the lungs
- enhances protein citrullination

80
Q

what happens when tolerance is broken in RA?

A

joint damage and abnormal inflammatory response in synovial lining

81
Q

what is the shared epitope?

A

HLA-DRb1
- The shared epitope is a risk factor for the presentation of citrullinated peptides
- genetic polymorphism

82
Q

why is PTPN22 a risk factor for RA?

A

it undergoes an arginine to tryptophan mutation - LOF
- can no longer encode LIP, so can’t control TCR signalling
- genetic polymorphism

83
Q

how does the interaction between the shared epitope and cigarette smoke increase incidence of RA?

A

High odds ratio for RA development when shared epitope is present in association with cigarette smoke
– leads to increased presentation of citrullinated peptides autoantigens, generated by smoke inducing PAD2 enzyme

co-operation between genetic risk factor and environmental risk factor

84
Q

how are infections implicated in autoimmune diseases?

A

Different infections can increase risk of AI
- e.g. Indirect association in inflammatory bowel disease – antibiotics affect balance of microflora of gut – tips balance from regulatory to inflammatory responses in gut
- Microorganism interactions can alter regulation of immune system and drive AI

85
Q

what are the key processes in which infection can induce autoimmunity?

A
  1. bystander activation
  2. epitope spreading
  3. molecular mimicry
  4. generation of neo-epitopes
86
Q

what is bystander activation?

A
  • Immune responses against a pathogen lead to the generation of an environment that is rich in pro-inflammatory cytokines/mediators
  • Activated APCs accumulate at sites of infection/inflammation and sense PAMPs, leading to upregulation of CD80/86
  • Any autoreactive ‘bystander’ T cells near APCs could access signal 2 and become activated and expand – leads to AI response
87
Q

what is epitope spreading?

A

Infections can lead to tissue damage and the release/exposure of autoantigens – supplies signal 1 to autoreactive T cells
- Release of autoantigens from cells into the tissue microenvironment, in association with tissue damage = signal 1 and 2 are provided

88
Q

how can epitope spreading lead to autoimmunity?

A
  • T cell activated in lymph node and traffics to site of infection
  • differentiates to Th1 which activates TRMs
  • TRMs release pro-inflammatory cytokines, which may cause collateral tissue damage
  • release of autoantigens from apoptotic cells which have not been cleared
  • autoantigens are then internalised and presented to autoreacitve T cells by APCs in the lymph nodes
89
Q

why do infections enhance autoimmune risk?

A

Infection can enhance delivery of signals 1 and 2 to autoreactive T cells, leading to AI response
- Immunoregulation is important at peripheral sites

90
Q

what is molecular mimicry?

A

sequence overlap between pathogen epitopes and autoantigen epitopes – cross-reactivity between pathogen and host antigen

91
Q

what is an example of molecular mimicry in autoimmune disease?

A

Guillain-Barré syndrome – comparable to MS but autoimmunity is targeted towards the peripheral nervous system
- ~30% cases are associated with Campylobacter jejuni
- Bacterial cross-reactive antigen is recognised by the immune system resulting in the production of anti-ganglioside antibodies
- Inflammatory responses result in damaged myelin, causes axonal degeneration and blocks nerve conduction

92
Q

how can neo-epitopes be generated during infection?

A

post-translational modifcations e.g. Peptide citrullination following Porphyromonas gingivalis infection (periodontitis) in Rheumatoid arthritis

93
Q

how can P. gingivalis induce RA?

A

P. gingivalis expresses an enzyme with peptidylarginine deiminase (PAD) activity
- PAD mediates the conversion of peptidylarginine to peptidylcitrulline in the infected gums
- citrullinated neoantigens are presented by APCs to T cells which can activate B cells
- Immune response generated against citrullinated peptides including the generation of anti-citrullinated peptide antibodies (ACPA) and targeted joint inflammation
- Association with periodontitis and RA

94
Q

how can P. gingivalis infection have enhanced risk of RA?

A

it may act in conjunction with the shared epitope if the patient has this genetic polymorphism
- generation and then presentation of citrullinated neoantigens

95
Q

how does incidence of infection and autoimmunity differ across the world?

A
  • Some degree of protection against AI in areas of high infection incidence – paradoxical
  • Incidence of MS and type 1 diabetes more common in economically developed countries, where incidence of infectious disease is less common
96
Q

how can infections and microflora support regulation of the immune system?

A

Multiple infections can enhance healthy, diverse population of gut microflora:
- Normally, gut bacteria will coexist in gut and will not drive tissue damage
- commensal bacteria maintain systemic immune regulation

97
Q

how do commensal bacteria maintain systemic immune regulation?

A

Presentation of commensal antigens to T cells in the absence of tissue damage results in the generation and maintenance of regulatory T cells
- crucial for tolerance and regulation

98
Q

why can imbalances in the microflora occur in the developed world, leading to autoimmunity?

A

Imbalances in the gut microflora resulting from antibiotics, poor diet etc. promote a switch towards inflammatory responses
- loss of regulatory responses
- Leads to AI due to damage

99
Q

how are microorganisms paradoxical in autoimmunity?

A

Infection can create conditions for A

but bacteria can also maintain healthy gut microflora and promote peripheral tolerance

Balance between pro- and anti-inflammatory responses via interactions between microbes and immune system

100
Q

how is vitamin D implicated in the risk of autoimmune disease?

A

Reduced vitamin D intake or reduced sunlight exposure can increase risk of AI
- Incidence of AI increases in countries distant from the equator – low sunlight exposure, less vitamin D in populations
- Vitamin D deficiency is common in the UK – an estimated 60-70% population display insufficient levels

101
Q

what is the process of vitamin D biosynthesis?

A

Major source of vitamin D is exposure to sunlight
- UVB radiation converts cholesterol to vitamin D3 in the skin
- Vitamin D3 is metabolised in liver via hydroxylation
- Another hydroxylation step in kidneys by 1-a-hydroxylase to produce bioactive form of di-hydroxy-vitamin D3
- 1-a-hydroxylase also expressed in APCs and other immune cells – these also produce bioactive vitamin D3 for T cells

102
Q

what are the functions of vitamin D3?

A

Maintains bone health
- Calcium absorption
- Bone mineralization

Plays role in immune regulation
- Enhances protective immunity by the innate immune system
- Dampens adaptive immune responses by enhancing its regulation

103
Q

in what autoimmune diseases is poor vitamin D status involved?

A

Multiple sclerosis
Type I diabetes
Systemic lupus erythematosus (SLE)
Rheumatoid arthritis
Vasculitis

104
Q

how does vitamin D impact disease severity of MS?

A

Highest risk of emergency admission of MS patients is during the times of the year where the average previous 4 months of serum Vitamin D levels were at the lowest
- e.g. in spring, where previous 4 months were during winter when sunlight exposure is lowest
- Correlation between MS emergency admission and vitamin D deficiency

105
Q

how does vitamin D signal?

A

Vitamin D signals via vitamin D receptor – an intracellular steroid receptor that complexes with retinoid X receptor
- When vitamin D binds, the complex is translocated into nucleus and binds vitamin D responsive elements throughout genome

106
Q

how does vitamin D signalling impact T cells?

A
  • Suppresses TH1 and TH17 proinflammatory T cells often involved in AI
  • Decreases inflammatory cytokine production
  • Increases Th2 – anti-inflammatory role
  • Increases Treg differentiation
107
Q

how does vitamin D signalling impact B cells?

A
  • Reduced proliferation upon activation
  • Inhibition of plasma cell differentiation
  • Reduced antibody production
108
Q

how does vitamin D signalling impact APCs?

A

Decreased capacity to stimulate T cell responses – reduced co-stimulatory ligand expression so cannot prime T cell responses

109
Q

what experiment can show vitamin D3 effects on T cell differentiation?

A
  • Purified T cells from whole blood
  • T cells stimulated with antibodies to CD3 and CD28 activation molecules
  • T cells will become activated and proliferate
  • Activated T cells left in culture for 5 days with or without vitamin D
110
Q

how does Vitamin D3 effect T cell differentiation?

A

Vitamin D3-treated T cells bias towards Treg differentiation – measured by flow cytometry
- Increased foxp3 and CTLA-4 expression under vitamin D3 treatment

111
Q

how does vitamin D3 effect Treg function?

A

Increased expression of CTLA-4 on Tregs:
- Removes CD80/86 from APC via transendocytosis – limits ability for APC to prime T cell responses
- More CTLA-4 due to vitamin D = more immunoregulation of T cell activation
- Helps resolve normal immune responses

Cancer, Autoimmunity and Transplant Immunology (15 decks)

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