Mechanisms of Auto-immunity and Hypersensitivity

Question 1

What is autoimmune disease?

Answer 1

Loss of immunological tolerance to self, associated with pathology

Disease may involve self-reactive T cells and/or self-reactive B cells

Question 2

What cannot be cleared in autoimmune disease?

Answer 2

Self antigen

Question 3

What factors predispose to autoimmune disease?

Answer 3

Background: incidence, gender bias

B or T lymphocytes that can react with self antigens

Genetics

Question 4

What can autoimmune disease be categorised into?

Answer 4

Organ specific:
-Psoriasis (skin)
-Hashimoto’s thyroiditis (thyroid)
-Graves disease (thyroid)
-Diabetes mellitus type 1 (pancreas)
-Multiple sclerosis (MS) (brain, spinal cord)

Systemic:
-Rheumatoid arthritis (RA)
-Ankylosing spondylitis
-Systemic lupus Erythematosus (SLE)

Question 5

Is there gender bias in autoimmune disease?

Answer 5

Yes, females tend to be more susceptible due to :

• Incomplete X chromosome inactivation
• Hormones - Oestrogen stimulation of innate immune receptor expression - TLR 3,7, 8, 9

Question 6

Where does the potential for self-reactive B- & T-cells come from?

Answer 6

-Generation of cell surface antigen receptors for B cells (sIgM, sIgD), Th and Tc cells is a random process

-so the mechanisms that drive diversity also produce large numbers of auto-reactive lymphocytes

Question 7

Where does the negative selection of B- and T-cells occur?

Answer 7

B-cells: bone marrow
T-cells: thymus medulla

Question 8

How is central tolerance achieved?

Answer 8

By negative selection of auto reactive cells

Question 9

What is positive selection?

Answer 9

Where cells that recognise the body’s own tissues are allowed to mature.

Cells that cannot recognise self-antigens are eliminated

Question 10

What is negative selection?

Answer 10

• After positive selection
• Cells that strongly react to self-antigens are eliminated.
• This prevents the immune system from attacking it’s own tissues.

Question 11

Why would it actually be disadvantageous if all cells with autoimmune potential were removed from lymphocyte repertoire?

Answer 11

Because it would provide a space for pathogens to mimic human structures & evade immune response

By maintaining some auto-reactive lymphocytes together with tight control of immune responses, the immune system has reached a balance between auto-reactivity & resistance to infection

Question 12

What 2 transcription factors in the medulla promote promiscuous expression of proteins?

Answer 12

Aire - helps developing developing T cells to recognise self-antigens. Regulates the expression of self-antigens in the thymus to prevent auto-immune disease

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Question 13

What happens to the some auto-reactive T cells that are not deleted in the thymus?

Answer 13

They develop into Treg cells & migrate to the periphery

Their function is to suppress the activity of potentially pathogenic, auto-reactive T cells

Question 14

How do Treg cells suppress the activity of potentially pathogenic, auto-reactive T cells?

Answer 14

1. Removal of 2 costimulatory activating receptors CD80, CD86 via Treg CTLA-4
2. Cytokine interleukin-2 required for activation, function and Maintence. High affinity IL-2 receptor depletes II-2. ??
3. Treg Fas ligand (death receptor) binds to Th Fas - apoptosis
4. Treg secretes inhibitory cytokines (IL-10, TGFB)

Question 15

What do genome-wide association studies (GWAS) show about genetic predisposition?

Answer 15

It shows association with MHC/HLA types e.g.

Ankylosing spondylitis: 90% patients HLA-B27 (~5% of those with HLA-B27)

Rheumatoid arthritis: HLA-DRB1 (80% patients)

Psoriasis: HLA-Cw6 (60%)

Answer 16

1. Autoimmune disease ~5% population, higher incidence in females v males.
2. Potential for autoimmune recognition results from need for diversity in B and T cell antigen recognition.
3. Central tolerance eliminates majority of autoreactive lymphocytes but not all.
4. Genome wide association studies (GWAS) implicate multiple genes (many with small effect): immune activation, antigen presentation etc.
5. Large contribution from environmental factors - infections, microbiome

Question 17

What is molecular mimicry?

Answer 17

Antigens of infectious agent may resemble self antigens & stimulate cross-reactive B- & T-cells

(Cross-react = immune system might mistakenly target and attack hosts tissues that share similarities with the microbial molecules)

Question 18

How else might the effects of regulatory T cells be bypassed?

Answer 18

-In SLE,

-for example, innate immune receptors such as Toll like receptors can provide an alternative means of activating B cells

-This mechanism removes the need for T cell help & therefore bypasses the effects of Treg cells

Question 19

What is SLE characterised by?

Answer 19

Production of antibodies that recognise nucleic acid.

Question 20

What is the role of innate immune receptors (TLRs) in B cell activation in SLE?

Answer 20

1. Binding to slg (signal lymphocyte activation) induces 1st signal

2.slg traffics to endosome

3.Nucleic acid complex binds to TLR7, 9

4.TLR signal via nucleus triggers production of type 1 interferon

5.IFN binding to receptor provides second signal

6.B cell proliferates - plasma cells producing autoantibody + memory cells

Question 21

How do activated B cells act as antigen presenting cells to T cells in SLE?

Answer 21

1. Activated B cell takes up nucleic acid/protein complex
2. Protein component undergoes antigen processing and peptides are displayed on MHC class II
3. CD4 Th cell recognises MHC II/peptide – 1st signal from B cell

4.B cell delivers 2nd signal via CD40;CD40L

5.B cell secretes cytokines (IL-2,4,6)

6. Activated T cell stimulates other B cells, dendritic cells – spread of disease.

Question 22

What are hypersensitivity reactions?

Answer 22

Exaggerated immune mechanisms that damage host tissue

Requires previous exposure to antigens

Question 23

What are the 4 types of hypersensitivity reactions?

Answer 23

Types I-III (antibody-mediated) & produce relatively fast responses & they’re known as immediate hypersensitivity reactions

Type IV is a slower, T-cell mediated response & is known as delayed type hypersensitivity

Question 24

Describe a Type I hypersensitivity reaction.

Answer 24

mediated by IgE bound to high affinity Fc receptors on mast cells, basophils and activated eosinophils

cross-linking of IgE/Fc receptor complex by antigen causes degranulation – release of histamine, serotonin, leukotrienes, proteases, (minutes). Later phase – cytokine release (hours)

leukotrienes, histamine induce vascular permeability, smooth muscle contraction, bronchoconstriction

activates and attracts eosinophils, neutrophils, macrophages

extreme reaction – anaphylactic shock

peanut allergens – proteins involved in storage or defence against pathogens/environmental stress; intrinsic properties of activating antigen presenting cells

Question 25

Have Type I reactions been considered likely to contribute to autoimmune damage?

Answer 25

No, not really

Question 26

Describe a Type II hypersensitivity reaction.

Answer 26

-mediated by IgG (IgG1, IgG2, IgG3) binding to antigen on cell or tissue surface

-IgG Fc binds to Fcγ receptors of macrophages, NK cells

-IgG Fc also activates complement – opsonisation and activation of phagocytic cells

-degranulation or phagocytosis induces tissue damage

-mechanism in organ-specific disease (self-antigen on tissue)

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Question 27

Describe a Type III hypersensitivity reaction.

Answer 27

-mediated by IgG forming immune complex with soluble antigen

-immune complexes deposit in blood vessels, synovial fluid and other tissues

-activates complement and attract neutrophils, macrophages (via Fc receptors)

-extra-vascular sites bind to Fcγ receptors of mast cell, local inflammatory response, increases vascular permeability, fluid + neutrophils, macrophages

-action of complement and degranulation – tissue damage

-mechanism in non organ-specific autoimmune disease

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Question 28

Describe a Type IV hypersensitivity reaction.

Answer 28

Multiple granulomas = excessive tissue damage

-mediated by T cells (Th1, Th17, Tc)

-activated T cells secrete chemokines, cytokines (IFN-γ, TNF) to recruit and activate macrophages

-activated macrophages secrete further proinflammatory cytokines (IL-12, TNF), tissue damage from degranulation

-formulation of granuloma: macrophages/multi-nucleated giant cells, eosinophils, T cells, fibroblasts

-mechanism in organ-specific autoimmune disease

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Question 29

What are the key points to take away from this lecture?

Answer 29

Molecular mimicry whereby antibodies produced in response to pathogen-derived antigens that partially resemble host components may overcome self-tolerance and mediate autoimmune tissue damage

Innate immune receptors (TLRs) may contribute to initiation of autoimmune response

Tissue damage in autoimmune disease is mediated by hypersensitivity reactions