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Year 2 - MCD - Immunology > 4 - Tolerance and Autoimmunity (19.02.2020) > Flashcards

4 - Tolerance and Autoimmunity (19.02.2020) Flashcards

1
Q

Autoimmunity

A
  • Autoimmunity: adaptive immune responses with

specificity for self “antigens” (autoantigens)

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2
Q

What can cause autoimmunity?

A
  • genetic and environmental factors

- e.g. diet, infections

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3
Q

Criteria for a disease to be AI

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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4
Q

Can we eliminate the AI response in AI disease?

A
  • generally unfortunately not

- we can only try to make things better

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5
Q

Genetic and environmental factors

A
  • Genes: twin and family studies, GWAS (e.g. 40 key loci in SLE); also FH; also if you have one AI disease you are more likely to get another one.
  • Sex: women more susceptible (hormones!) - (e.g. 9:1 in SLE); 80& of AI disease patients are female
  • Infections: inflammatory environment -> can help promote self tolerance loss and AI disease
  • Diet: obesity, high fat, effects on gut microbiome!!!: diet modification may relieve autoimmune symptoms; microbiome is important in regulating immune response.
  • Stress: physical and psychological, stress-related hormones
  • Microbiome: gut/oral microbiome helps shape immunity, perturbation (dysbiosis) may help trigger autoimmune disease (sex differences in microbiome now establishes)
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6
Q

Mechanisms in autoimmunity

A
  • Adaptive immune reactions against self use the same mechanisms as immune reactions against pathogens (and environmental antigens)
  • Autoimmune diseases involve BREAKING T-CELL TOLERANCE
  • nearly always IgG (which requires class switching so there has to be t-cell tolerance break)
  • Because self tissue is always present, autoimmune diseases are chronic conditions (often relapsing)
  • Effector mechanisms resemble those of hypersensitivity reactions, types II, III, and IV
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7
Q

Impact of AI disease

A
  • Approx. 100 chronic disorders have been identified which relate to aberrant immune responses causing the body to attack it’s own tissues
  • Approx. 8% of individuals are affected by autoimmune disease
  • Approx. 80% of affected individuals are women
  • The incidence of AI disease (and hypersensitivity) is increasing (hygiene hypothesis)
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8
Q

Hygiene hypothesis

A
  • the environment we live in now is very different from the environment we used to live in when the immune system evolved
  • less pathogen exposure
  • now responds to things it is not supposed to respond to
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9
Q

Sex different in AI disease

A
  • large difference in SLE and sjorgens
  • DI is more common in males
  • UC is about equal in males and females
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10
Q

AI disease and pregnancy

A
  • some AI diseases get better in pregnancy
  • some AI diseases get worse in pregnancy
  • switch in immune response in pregnancy (Th1-> Th2)
  • > cell mediated to AB mediated
  • SLE gets worse
  • RA gets better
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11
Q

List examples of important autoimmune diseases

A
  • RA (also affects children and young people)
  • MS
  • T1DM
  • SLE
  • ATD (AI thyroid disease)

=> AI disease is a massive health problem

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12
Q

How are AI responses in humans described?

A
  • Organs affected
  • Involvement of specific autoantigens
  • Types of immune responses
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13
Q

Organs specificity in AI diseasae

A
  • there is a spectrum (Organ-specific autoimmune diseases -> Multi-systemic autoimmune diseases)
  • some are very organ specific (e.g. Graves disease)
  • some are very systemic (e.g. SLE - immune complex mediated)
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14
Q

Which antibodies can cross the placenta?

A

IgG

  • e.g. women that are pregnant and have graves disease can transfer their AG to their children in utero and the babies show symptoms for some time and then when ABs are gone they don’t anymore.
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15
Q

Immune reactions known to play a direct role in the pathology of human AI disease

A

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

Immune complex formed by antibody against soluble antigen (Type III)

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

-> no type I AI disease

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16
Q

Name some examples of T2 AI disease

A
  • Graves’ Disesase
  • Goodpastures syndrome -> glomerulonephritis, pulm. haemorrhage
  • AIHA
  • Mysathenia Graves
  • pemphigus vulgaris

=> ABs to something insoluble (e.g. cell surface to matrix antigens)

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17
Q

Name some examples of T3 AI disease

A
  • SLE (immune complexes, IgG ABs to nuclear molecules eg. DNA, ribosomes) -> glomerulonephritis, arthritis, vasculitis
  • > immune complex (soluble in circulation) mediated AI disease
  • > damage much more widespread and systemic
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18
Q

Grave’s disease

A
  • anti-TSHR AB
  • no negative feedback
  • a lot of thyroid hormone production
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19
Q

Name some examples of Type 4 AI disease

A
  • RA
  • MS
  • T1DM
  • > T-cells are involved (CD8+ and CD4+ responses can be involved)
  • > you can also get AB responses as well(e.g. CCABs in RA)
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20
Q

The normal T-cell response to antigens

A

Antigen is presented to T-cells by MHC expressed on
the surface of antigen-presenting cells

CD4 + Response:
Proliferation
Function

21
Q

What is the most important genetic factor in AI disease?

A
  • Human MHC (HLA) class II is the dominant genetic factor affecting susceptibility to autoimmune disease
  • MHC class 2 is recognised by CD4+ T-cells
  • this shows us that CD4+ T-cells are important in specific AI diseases because otherwise there would not be this correlation
22
Q

Summary of human AI reactions

A
  • Mechanisms in autoimmunity are the same as in normal responses against foreign antigens
  • Immune responses to autoantigens (self) have a direct role in the pathology of autoimmune diseases
  • Both B cells (antibody) and T cells can be involved
  • HLA associations strongly imply a role for T cells in initiating autoimmune disease
23
Q

What are the mechanisms which normally prevent our

immune system from attacking our own tissues?

A
  • TOLERANCE!
24
Q

Evidence for the concept of tolerance against self

A
  • Freemartin cattle have fused placentas and exchange cells and antigen in utero.
  • Non-identical twins have different sets of blood group antigens.
  • As these twins are non-identical, as adult cattle they would normally be expected to react to each others cells and tissues

However:

  • Adult cattle tolerate blood transfusions from a non-identical twin
  • They also accept skin grafts from each other
25
Q

Evidence for the concept of tolerance against self

A

Evidence 1:
- Freemartin cattle have fused placentas and exchange cells and antigen in utero.

  • Non-identical twins have different sets of blood group antigens.
  • As these twins are non-identical, as adult cattle they would normally be expected to react to each others cells and tissues

However:

  • Adult cattle tolerate blood transfusions from a non-identical twin
  • They also accept skin grafts from each other

Evidence 2: timing is important
as a neonate ability to tolerate more

Evidence 3: tolerance has specificity

26
Q

What is tolerance?

A

Defined as the acquired inability to respond to an antigenic stimulus

‘The 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
27
Q

How does self tolerance work and how does it fail?

A

Central Tolerance
- induced during lymphocyte development

Peripheral Tolerance
- mechanisms that help control self reactive lymohocytes
- anergy
- active suppression (by regulatory T-cells)
(- immune priviledge, ignorance of AG, you don’t come across that AG)

=> failure in one or more of these mechanisms may cause AI disease

28
Q

Selection in the Thymus gives rise to 3 groups

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”

=> only 5% of thymocytes survive selection

29
Q

Central tolerance

A

T cell selection in the thymus

  • Dependent on MHC: peptide: T-cell receptor (TCR) interaction
  • Most cells die by neglect: no or very weak recognition
  • Negative selection occurs for cells with high affinity TCRs, which die by apoptosis
  • Surviving cells are MHC-restricted, with low/intermediate affinity for self-peptide

B-cell selection in the bone marrow
- Crosslinking of surface immunoglobulin by polyvalent antigens expressed on bone marrow stromal cells facilitates deletion

=> Failure in central tolerance can lead to autoimmunity. In most diseases, a complex interaction of multiple factors is usually involved.

30
Q

Anergic B-cells

A
  • don’t mature in BM properly
  • short half life once out of BM
  • weak responses
31
Q

Does central tolerance fail in AI disease?

A

sometimes

e.g. APECED (rare genetic disease)
Autoimmune
PolyEndocrinopathy-
Candidiasis-
Ectodermal 
Dystrophy
Rare autoimmune disease which affects the endocrine glands
 Thyroid
 Kidneys
 Chronic mucocutaneous candidiasis
 Gonadal failure
 Diabetes mellitus
 Pernicious anaemia

This shows that central tolerance is important in preventing AI disease.

32
Q

AIRE

A
  • AIRE is important for the expression of “tissue-specific” genes in the thymus
  • Involved in the negative selection of self reactive T-cells in the thymus
  • causes APECED (results from a failure to delete T-cells in the thymus)

=> evidence that central tolerance is important at removing aautoreactive T-cells so we don’t get AI disease.

33
Q

Genetic traits in AI disease

A

e.g. SLE: Genes affecting multiple biological pathways
may lead to a failure of tolerance
(40-50 genes have been implicated in genetic susceptibility)

  • 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
34
Q

Induction and maintenance of tolerance in the periphery

A

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

Mechanisms are required to prevent mature lymphocytes becoming auto-reactive and causing disease

  • Anergy
  • Suppression by regulatory T cells
  • (Ignorance of antigen)
35
Q

Anergy

A
  • cell don’t mature properly
  • the cells are eliminated eventually
  • don’t cause a proper immune response
  • Anergy: absence of costimulation
  • 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
  • Without costimulation then cell proliferation and/or factor production does not proceed
  • Subsequent stimulation leads to a refractory state termed ‘ANERGY’
36
Q

Immunological ignorance

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
  • molecules like interferon gamma can up regulate MHC expression on cells that don’t normally express MHC molecules so in inflammatory situations cellhtat don’t usually express MH II start expressing it and can activate T cells.
  • 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
37
Q

Failure of ignorance

A

e.g. sympathetic ophthalmia

  • trauma to one eye results in the release of sequestered intraocular protein antigens
  • released intraocular antigens are carried to lymph nodes and activate T-cells
  • effector T-cells return via bloodstream and attack antigen in both eyes.

= ignorance is broken and you have an immune reponse.

38
Q

Suppression/ Regulation

A
  • Autoreactive T-cells may be present but do not respond to autoantigen
  • Controlled by other cell types
    Regulatory T-cells…..CD4+CD25+CTLA-4+FOXP3+
    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
39
Q

FOXP3

A
  • Important it T-cell regulation

- (in Tregs)

40
Q

IPEX

A
  • mutation in FOXP3 gene
  • a failure in the regulation of peripheral tolerance
  • accumulation of auto reactive T-cells
  • 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-cells
Symptoms include: 
early onset insulin dependent diabetes mellitus
severe enteropathy
eczema
variable autoimmune phenomena
severe infections
41
Q

Does infection break peripheral tolerance?

A
  • there is evidence that some infections are involved int eh development of AI disease
  • EBV, HepC, CMV, Mumps….
42
Q

How can infections affect the tolerant state?

A
  • Molecular mimicry of self molecules (if the pathogen expresses something similar to a self antigen)
  • Induce changes in the expression and recognition of self proteins
- Induction of co-stimulatory molecules (e.g. IF) or inappropriate MHC class II expression: pro-inflammatory environment (if MHC is expressed more effectively, this can trigger AI disease)
If APCs are activated, they beco me better at co-stimulation.
  • Failure in regulation : effects on regulatory T-cells
  • Immune deviation: shift in type of immune response e.g. Th1->Th2 in pregancy (also infections can cause a shift)
  • Tissue damage at immunologically privileged sites
43
Q

Peripheral Tolerance Summary

A

Induction and maintenance of peripheral tolerance will depend on:

  • Site of antigen expression (MHC expression, immune privilege)
  • Timing of antigen expression
  • Amount of antigen expression
  • Costimulation
  • T cell help for B cell responses
  • Regulation

Infections may help break tolerance by a variety of mechanisms

44
Q

AIHA

A

= AI haemolytic anaemia

  • 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)
45
Q

B-cell central tolerance - what are the different outcomes?

A

a) cell does not respond to self antigens -> releases, matures in lymphoid organs
b) cell binds to multivalent self molecule -> deleted
c) cell binds to soluble self molecules -> cell migrates to the periphery, however it doe snot mature properly and is anergia, ineffective at generating immune responses, eliminated with time.
d) cells that bind to low affinity non-cross linking self molecule -> these cells migrate into the periphery, mature normally; these cells have the potential to cause AI disease however they are ignorant (don’t come across the antigen).

46
Q

CTL4

A

delivers inhibitory signals

47
Q

What is important in T-cell regulation?

A

FOXP3

-> if it is absent you can get IPEX (a failure in the regulation of peripheral tolerance, accumulation of auto reactive t-cells)

48
Q

What is molecular mimicry?

A

When a pathogen expresses a similar surface antigen to a self antigen -> this can lead to autoimmunity

Year 2 - MCD - Immunology (5 decks)

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