IMI8: Autoimmunity and autoimmune inflammation Flashcards

1
Q

Define autoinflammatory diseases?

A

A group of rare disease characterised by seemingly unprovoked episodes of fever and inflammation. Because the inflammatory episodes occur regularly, the diseases are also known as periodic fever syndromes. Autoinflammatory diseases thus involve abnormal activation of the innate immune system.

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2
Q

Give a few examples of autoinflammatory diseases

A

Majeed syndrome
Blau syndrome
Familial Mediterranean fever (FMF)
Cryopyrin-associated periodic syndromes (CAPS), which include a variety of syndromes such as FCAS, MWS, NOMID
Deficiency of IL-1-Receptor Antagonist (DIRA)
Hyper IgD Syndrome (HIDS)

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3
Q

What is the body’s first line of defence?

A

The innate immune system: When microbes, such as bacteria or viruses, invade the body the innate immune system quickly responds by triggering fever and inflammation, which help the body fight infection

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4
Q

What happens to the innate immune system in autoinflammatory diseases?

A

the innate immune system is activated without an apparent cause and it remains so for some time.

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5
Q

Name the main difference between autoimmune diseases and autoinflammatory diseases

A

Patients with autoinflammatory diseases do not produce autoantibodies. It is the lack of autoantibodies in autoinflammatory diseases that makes them different from autoimmune diseases.

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6
Q

What are autoantibodies?

A

Antibodies produced by the immune system that are directed against a given individual’s one or more own proteins.

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7
Q

What is the most common symptom of autoinflammatory disease?

A

recurrent fever

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8
Q

What are the symptoms of an autoinflammatory disease?

A

recurrent fever
sores, inflammation of eyes, muscles, joints, skin, the gastrointestinal tract and internal organs. If not properly controlled, repeated inflammation can lead to amyloidosis.

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9
Q

What is amyloidosis?

A

A serious condition caused by a build-up of amyloid protein in organs and tissues throughout the body. Amyloid protein deposits can make it difficult for the organs and tissues to work properly. Without treatment, this can lead to organ (such as kidney and heart) failure.

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10
Q

What is the most common autoinflammatory disease?

A

Familial Mediterranean fever (FMF)

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11
Q

Discuss the details of FMF

A
  • most often seen in people of Middle Eastern ancestry. - both sexes equally
  • symptoms usually start in childhood
  • 1 in 250 to 1 in 500 in non-Ashkenazi Jews
  • 1 in 1,000 in the Turkish population

The cause of FMF has been ascribed to abnormalities in a gene called MEFV which encodes for a protein called Pyrin. FMF is a recessive disease, meaning that about 85% of patients with FMF have changes (a mutation) in both copies of their MEFV gene. Interestingly, most individuals with a single mutation are completely healthy. Up to 1 in 4 healthy people in some eastern Mediterranean populations carry an MEFV mutation. This has led to the suggestion that FMF carriers may have had an evolutionary advantage in the past, such as possibly a diminished vulnerability to infections prevalent in their environment.

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12
Q

What is Pyrin?

A

An intracellular pattern recognition receptor (PRR) found in macrophages. Unlike other PRRs, Pyrin does not directly recognise pathogens

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13
Q

Where is Pyrin produced?

A

Leukocytes

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14
Q

What is Pyrin believed to do?

A

Keep inflammation under control, this may have something to do with its ability to interact with the cytoskeleton, where it is located. There is evidence to suggest that pyrin carries out its functions by, at least in part, behaving as a monitor of certain cell processes such as the function of the Rho GTPases.

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15
Q

What are Rho GTPases?

A

Small G proteins and they represent a sub-family of the Ras family. They are small messengers that enable cells to communicate with each other and are involved in cytoskeletal rearrangements, cell shape and cellular transport pathways, as well as in the regulation of a number of transcription factors.

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16
Q

Why is Pyrin activated when Rho GTPase function is shut down?

A

Members of this family of GTPases are common targets of bacterial exotoxins and blocking Rho activity can interfere with macrophage migration and phagocytosis, therefore Pyrin can counter this.

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17
Q

After activation, what does Pyrin do?

A

It plays an important role in assembling the molecular complex called the inflammasome. Inflammasomes form in response to infection although, as you will recall, various other stimuli can also trigger inflammasome assembly.

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18
Q

What is the inflammasome?

A

An intracellular multiprotein oligomer that promotes the maturation and secretion of pro-inflammatory cytokines.

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19
Q

What is the mutated pyrin protein thought to do to the inflammasome?

A

The mutated pyrin protein is thought to cause inappropriate activation of the inflammasome, leading to release of the pro-inflammatory cytokine IL-1β.

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20
Q

The inflammasome is thought to be responsible for the activation of which caspases? What does this lead to?

A

caspase 1 and 5: leading to the processing and secretion of the pro-inflammatory cytokines IL-1β

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21
Q

Which proteins of the inflammasome come together on activation to form active caspase 1 and 5?

A

Protein called NALP1 and a adaptor protein ASC

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22
Q

What are caspases 1 and 5 and what do they do?

A

Enzyme proteases that cleave inactive proIL-1β to the active pro-inflammatory cytokine IL-1β.

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23
Q

What is the long term treatment of FMF? How does this drug work?

A

Colchicine: it is thought to inhibit multiple proinflammatory mechanisms and thereby relieve symptoms.

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24
Q

What are newer therapeutic targets focusing on?

A

Given that IL-1β is often overexpressed in autoinflammatory diseases (see figure in the section on the mechanism of IL-1β production during inflammasome activation), it is hardly a surprise that newer therapeutic approaches tend to target IL-1β.

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25
Q

Name some monoclonal antibodies that target IL-1β

A

anakinra, rilonacept and canakinumab

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26
Q

Describe the breach in self-tolerance, which allowed autoimmune diseases to arise

A

A simple hypothesis is that polymorphisms in various genes result in the defective regulation or reduced threshold for lymphocyte activation, and environmental factors initiate or augment activation of self-reactive lymphocytes that have escaped control and are, therefore, poised to react against self-antigens.

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27
Q

Define self-tolerance

A

The ability of the immune system to recognise self-antigens as safe while remaining able to recognise and mount an appropriate immune response to foreign substances, which are perceived as a threat. Self-tolerance is thus absolutely critical to maintaining normal physiological function.

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28
Q

What are the two types of self-tolerance and what do they depend on?

A
  • Central tolerance

- Peripheral tolerance

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29
Q

What does the mechanism of self-tolerance involve?

A

the removal of self-reactive lymphocytes that have receptors that bind strongly to self-antigens. These autoreactive cells are removed by apoptosis (programmed cell death), termed clonal deletion, or by the induction of anergy, which is a state when cells can no longer respond to the antigen.

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30
Q

Where does central tolerance take place?

A
Thymus (T-cells)
Bone marrow (B-cells)
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31
Q

Where does peripheral tolerance take place?

A
Lymph gland
Lymph tissue
Circulation
Or other tissues
At the site of antigen recognition, where lymphocytes could begin to elicit an immune response
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32
Q

In the central tolerance system, what happens to immature lymphocytes that recognise/react to self-antigens?

A

They undergo modulation of their antigen receptors, become functionally inactive or apoptose via clonal deletion

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33
Q

In the peripheral tolerance system, what happens to mature B & T lymphocytes that recognise/react to self-antigens?

A

B-cells: anergy

T-cells: apoptosis via clonal deletion

34
Q

What is the mechanism of central tolerance

A

Central tolerance is the mechanisms that make new developing lymphocytes tolerant to self-antigens.

35
Q

What is the mechanism of peripheral tolerance?

A

The mechanisms that prevent lymphocytes from initiating immune responses against our own tissues, or against harmless material, like commensal organisms or food.

36
Q

What process/processes that create adaptive immune diversity is/are the one(s) that need to be scrutinised to establish central tolerance?

A

The central lymphoid organs are the sites of VDJ recombination, deleting T- and B-cells whose VDJ-rearranged genes recognise self proteins.

37
Q

What process/processes occur in peripheral lymphoid tissues that would need additional establishment of tolerance?

A

Affinity maturation or somatic hypermutation

Since B cells undergo affinity maturation in peripheral tissues, peripheral tolerance in B cells is about ensuring that these changes to the BCR do not produce self-reactive antibodies.

This is mainly mediated by needing to have T cells that recognise the MHC Class II-presented antigen that is internalised by the B cell. If a self-antigen is presented on MHC Class II by the B cell, there will be no T cells to detect it (due to central tolerance of T cells) so that B cell will not get the signals it needs to survive.

In contrast, T cells do not change their receptor in the periphery. However, T cells do need to be removed or shut down if they recognise common harmless environmental antigens

38
Q

Why do memory T cells not undergo any more tolerance to prevent anti-self recognition

A

As the TCR is unchanged. Therefore, the removal of self-reactive T cells must have happened in the thymus before they become memory cells.

39
Q

What will stop a T cell from helping a B cell to attack a harmless environmental antigen?

A

Lack of co-stimulation of the T cell by the antigen-presenting cell (APC)

40
Q

When does an autoimmune disease occur?

A

When tolerance breaks down and tissues in the body are attacked by their own immune system

41
Q

Give examples of autoimmune diseases

A
Type 1 diabetes (T1D) 
Crohn’s disease (CD)
Multiple scleriosis
Asthma
Celiac disease
Eczema
Psoriasis
Rheumatoid arthritis
42
Q

What does incidence rate mean?

A

What the risk of developing a disease is

43
Q

What does prevalence rate mean?

A

They provide you with an indication of how common a disease is at any one time within a given population

44
Q

What are the incidence rates for autoimmune diseases

A

1-20 per 100,000 of individuals/year depending on the disease

45
Q

What are the prevalence rates for autoimmune diseases

A

hey range from less than 5 per 100,000 (e.g. chronic active hepatitis, uveitis) to more than 500 per 100,000 (e.g. Grave’s disease; thyroiditis; rheumatoid arthritis, RA).

46
Q

Do autoimmune diseases affect males or females more?

A

Females: at least 85% of thyroiditis, multiple sclerosis (MS), SLE, and Sjögren disease (which often is found in patients that also suffer from RA or SLE) patients are female

47
Q

Give examples of different autoimmune diseases that occur at different times of life

A

Children/adolescence: Type 1 diabetes
mid-adult: myasthenia gravis
older adults: rheumatoid athritis

48
Q

Who were the two founders of immunology who defined the theories of cellular and humoral immunity?

A

Paul Ehrlich and Élie Metchnikoff

49
Q

What environmental modulations can lead to autoimmune disease?

A
  • Western diet
  • molecular mimicry
  • epitope modification
  • epitope modification
  • epitope spreading/drift
  • idiotype cross-reaction
  • cytokine deregulation
  • T-cell bypass
50
Q

How could a western diet have an impact on autoimmune disease predisposition?

A

It is rich in saturated fat and salt that can have a profound impact on local and systemic immune responses

51
Q

What is the molecular mimicry mechanism of autoimmune disease?

A

There may be structural similarities of exogenous antigen to host antigens. Therefore, antibodies produced against antigen that mimics self-antigen can bind to the host and initiate the immune response.

52
Q

What is the epitope modification mechanism of autoimmune disease?

A

self-reaction can result from the exposure of otherwise unseen carbohydrate motifs of glycoproteins on non-haematopoietic cells (e.g. stromal cells). This exposure of glycoprotein motifs activates one or more innate immune cell receptors to induce a chronic sterile inflammatory state.

53
Q

What is the epitope spreading or epitope drift mechanism of autoimmune disease?

A

when the immune reaction changes from targeting the primary epitope to also targeting other epitopes with similar structure.

54
Q

What is the idiotype cross-reaction mechanism of autoimmune disease?

A

idiotypes are groups of antibodies with similar sequences around the antigen-binding site (Fab region) of the immunoglobulin molecule. Autoimmunity can arise as a result of binding between the idiotype of an antibody (usually a part of the variable region that is not the CDR) and a host protein.

55
Q

What is the cytokine deregulation mechanism of autoimmune disease?

A

many cytokines are overexpressed (or underexpressed) in autoimmune diseases, therefore propagating the pathogenesis of the disease.

56
Q

What is the T-cell bypass mechanism of autoimmune disease?

A

B cells usually require activation by T cells to survive affinity maturation and undergo differentiation into plasma B cells and produce antibodies. In some instances, infection can initiate polyclonal activation of B cells in a non-specific fashion. For instance, superantigen (IMI5) can crosslink a TCR to MHC, allowing T cell signalling without antigen specificity. This can potentially over-produce autoreactive antibody propagates autoimmune responses

57
Q

Name the process, or processes, involved in recruiting leukocytes from the blood into tissues?

A

Adhesion cascade and transmigration
-> This is followed by activation of negative‐feedback mechanisms that serve to attenuate inflammation to limit tissue damage and initiate repair.

58
Q

Which monocytes are thought to play a crucial in rheumatoid arthritis?

A

Macrophages

59
Q

How do macrophages promote inflammation in the synovium fluid during RA?

A

They produce cytokines which recruit additional immune cells, T-cell polarisation and fibroblast activation

60
Q

What is the response to RA modulated cytokine secretion in the synovium include?

A

• activated synovial fibroblasts- that secrete receptor activator of nuclear factor κB ligand (RANKL)
• macrophage colony-stimulating factor 1 (M-CSF)
-> Together they can induce osteoclast differentiation, which is enhanced by macrophage-derived TNF⍺ and other cytokines

61
Q

What do immune complexes formed by autoantibodies and antigens do?

A

activate macrophages kick start this whole process. Finally, macrophages are influenced by cell–cell contact or by cytokines produced by T-cells, fibroblasts and other innate immune cells, such as neutrophils .

TH1 = type 1 T helper cells
TH17 = type 17 T helper cells
CCL2 = chemokine monocyte chemoattractant protein 1
62
Q

Which is the name of the cytokine expressed by macrophages, that plays a central role in pathogenesis of RA?

A

TNF-α

63
Q

What does TNF-α bind to during inflammation?

A

Two distinct TNF receptors, TNFR1 and TNFR2

64
Q

What does TNF-α binding to its receptors do?

A

1) increase vascular permeability;
2) enhance recruitment of other leukocytes;
3) generate immune complexes;
4) synergise with IL‐1β to induce synovitis by induction of other chemokines and cytokines, such as the pro-inflammatory cytokine IL‐6.

65
Q

Overall what does the molecular response to TNF-α cause? How?

A

Cartilage destruction:
by triggering synovial fibroblasts to produce metalloproteinases (MMPs), enzymes that can destroy tissue extracellular matrix and cause bone resorption. This unfortunately contributes to the bone destruction seen in RA by increasing the differentiation of osteoclasts, which are large multinucleated bone cells that can absorbs bone tissue.

66
Q

What are the three types of clinical treatment?

A

1) Steroids
2) Immunosuppressants
3) Biologics

67
Q

How have steroids helped in the treatment of systematic lupus erythematosus (SLE)?

A

Suppression of NF-kB signalling amongst other things:
This works by suppressing the activation of the NF-kB transcription factor leads to the activation of inflammatory response genes. The dosage naturally depends on the severity of the symptoms. The side-effects of steroids are, however, problematic and include weight gain, muscle weakness, and osteoporosis that weakens bones and can lead to fractures.

68
Q

When are immunosuppressants more likely to be used?

A

In the more severe stages of the disease

69
Q

What are the most commonly used immunosuppressants?

A

azathioprine, methotrexate and cyclophosphamide

70
Q

When is Azathioprine used?

A

Azathioprine is a milder drug and used for mild to moderate kidney disease in SLE, or where it is difficult to reduce steroid dosage.

71
Q

When is Cyclophosphamide?

A

It is widely used for lupus nephritis and is very effective.

72
Q

What is the general mechanism for immunosuppressants?

A

They can inhibit both CD4+ and CD8+ T cell activation and reduce expression of the adhesion molecules involved with recruitment of leukocytes during inflammatory responses.

73
Q

What is the major problem of immunosuppressants?

A

They cannot be given during pregnancy, which is very problematic given the prevalence of SLE in young females. Moreover, immunosuppressants will obviously increase risk from infections.

74
Q

What is a benefit of biologics?

A

hey are specific for a particular receptor, or molecule, and do not have as broad effects as the other two categories, thereby reducing potential off-target side effects.

75
Q

What is a biologic?

A

Any pharmaceutical drug product manufactured in, extracted from, or synthesised from biological sources. The biggest class of biologics is that of monoclonal antibodies.

76
Q

Give an example of a biologic

A

Rituximab for SLE

77
Q

How does Rituximab function?

A

It’s an antibody directed against CD20
CD20 is a transmembrane protein present on B cells, from the pre-B cells to naive to memory cells. It is not expressed on plasma cells and thus Rituximab will deplete (and thus kill) B cells, stopping autoantibody production and the activation of autoimmunity.

78
Q

What can biologics target?

A

either inflammatory mediators, or their critical signalling pathways, eg:

  • TNF-α soluble receptor or blocking antibodies;
  • IL‐6R blocking antibody ;
  • Janus kinases (JAKs) inhibitors- small molecule inhibitors that block intracellular signalling downstream of IL-6 as IL-6 signalling triggers activation of this class of kinases.
79
Q

Which cell types can be responsible for mis-identifying a self-protein as foreign and triggering an autoimmune response?

A

T helper cell
Cytotoxic T cell
B cell
Plasma Cell

80
Q

What is the underlying cause that result in macrophage-driven immune pathology in Rheumatoid arthritis disease?

A

Clusters of antibodies against self-antigens are bound by Fc receptors on the macrophage:
The first step in any autoimmune reaction is the inappropriate recognition of an antigen.

Antigen recognition is an adaptive process, so it must be either inappropriate T cell recognition of a peptide on MHC (Class I for CTL autoimmune response; Class II for T helper cells), or production of inappropriate antibodies that can bind self-protein (self-antigen).
If there are autoreactive TH cells, this can then allow an autoreactive B cell response to develop. Or a cross-reactive antibody response can get help from binding a pathogen, while making antibody that also does damage to a self-system.

Macrophages cannot bind directly to antigens and produce the proinflammatory cytokines as well as responding to them. Once the inflammation has started, this will bring in more and more macrophages.