Immunology of autoimmune diseases Flashcards

1
Q

What are the two types of immune cells haematopoetic stem cells can differentiate into?

A

Myeloid progenitor cells or Lymphoid progenitor cells

(Remember as the two classifications of leukemia)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
2
Q

What are the differences in maturation sites of myeloid and lymphoid progenitor cells?

A

Myeloid cells can mature within the bone marrow whereas lymphoid cells require maturation outside of the bone marrow.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
3
Q

What are the three cells types lymphoid progenitor cells are capable of differentiating into?

A

Natural killer cells
T lymphocytes
B lymphocytes

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
4
Q

Where do T and B lymphocytes undergo maturation?

A

T lymphocytes: T for thymus

B lymphocytes: B for bone marrow

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
5
Q

What are the four cell types myeloid progenitor cells are capable of maturing into?

A

Megakaryocyte
Erythrocyte
Mast cells
Myeloblast

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
6
Q

What are the source of platelets?

A

Platelets also known as thrombocytes are made from large progenitor cells known as Megakaryocytes which release platelets once having undergone a series of complex maturation processes in the bone marrow.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
7
Q

What can myeloblasts further differentiate into?

A

Basophil
Neutrophil
Eosinophil
Monocyte (can further differentiate into macrophages)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
8
Q

Explain what is meant by immunological self-tolerance in the prevention of autoimmunity?

A

Immunological self-tolerance is the ability of white blood cells to distinguish between the self antigens presented on our healthy cells and foreign antigens and hence only initiate an appropriate immune response to foreign antigens.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
9
Q

In application to immunological self-tolerance, when does autoimmunity occur?

A

When an immune system loses it natural immunological tolerance meaning that our lymphocytes can no longer distinguish between self (autologous) and non-self antigens and begins to attack our healthy cells leading to tissue damage and loss of organ function (Type 1 DM).

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
10
Q

Compare and contrast immunogen and a tolerogen?

A

Whilst both are foreign antigens;
Immunogens are antigens that induce the immune response whereas tolerogens are antigens that suppress the immune response (evokes tolerance).

Crucially an antigen can be both an immunogen and a tolerogen but its effects are dependent on how and where it is presented to the immune system.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
11
Q

What are the 3 methods of achieving self tolerance?

A

Immune privileged sites such as the eyes where B and T cells are unable to enter and hence respond to any antigen
Central tolerance
Peripheral tolerance

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
12
Q

Define central tolerance.

A

Central tolerance is the selection process in the maturation of lymphocytes in which strongly reacting cells to self antigens are instructed to undergo apoptosis.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
13
Q

Define peripheral tolerance.

A

Peripheral tolerance is the monitoring of mature B and T cells in the periphery to ensure they are not initiating an immune response to self antigens in the periphery, either anergic or undergo deletion.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
14
Q

How is central tolerance incorporated into T cell maturation?

A

During maturation in the thymus, T cells undergo positive and negative selection. Positive and negative selection is a crucial aspect of achieving central tolerance.
Immature T lymphocytes during maturation are exposed to antigen presenting cells which present a self-antigen via their MHC-11 complex. Depending on how strongly the immature T lymphocyte reacts with the APC decides whether it undergoes positive or negative selection.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
15
Q

Explain the possible outcomes of an immature T lymphocyte having undergone positive or negative selection.

A

Strong reaction:
Negative selection, apoptosis

Intermediate reaction:
Becomes a T regulatory cell and enters the peripheral tissue

Weak reaction:
Positive selection

No reaction:
Apoptosis

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
16
Q

How is central tolerance incorporated into B cell maturation?

A

An immature B lymphocyte is exposed to an APC presenting with an self antigen on its MHC-11 complex within the bone marrow. Similarly to T cells the dependence on the avidity IgG (the BCR) of the B lymphocyte reacting to an APC with the self antigen present decides whether the fate of the cell.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
17
Q

Explain the possible outcomes of an immature B lymphocyte having been exposed to a self antigen on an APC.

A

High avidity:
There is an opportunity for the B cell to undergo receptor chain editing where there can be alteration in the light chain sequence resulting in a new expression of the light chain which can affect the binding affinity of the BCR (IgG) to the self antigen.

If the B lymphocyte now demonstrates avidity below the threshold or has a low avidity to the self antigen initially, receptor expression can be reduced and the B cells becomes anergic meaning that it will be functionally unresponsive to the self antigen again.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
18
Q

Explain how peripheral tolerance of T cells is achieved?

A

When a mature T cell is exposed to a self antigen in the periphery it will either be:

Functionally unresponsive (anergic); the T cell will not become activated due to lack of co-stimulatory signals

Suppressed by T regs: Co-stimulatory signals is present but the activation of the T cell is prevented by T regulatory cells

Apoptosis: if the T cell does become activated it is then instructed to undergo apoptosis to prevent it becoming activated/reacting again with another self antigen

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
19
Q

Explain the immunological response of a B cell reacting with a non-self antigen.

A

Foreign antigen binds to the BCR, the cell recognises it as a foreign complex presents it on the cell surface via an MHC-11 complex. B cell activation is not achieved until the cell presents the antigen to a Th2 cell to the TCR and then this T cell release cytokines which initiates differentiation of plasma cells producing antibodies in response to the foreign antigen.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
20
Q

Describe what happens when a B cell is exposed to a self antigen in the periphery?

A

Similar to the B cell response to a foreign antigen, the BCR binds to the self antigen and either distinguishes it as a self antigen itself or inhibited by the lack of T cell activation. This can be categorised as one of three outcomes as a result of exposure to a self antigen:

Anergy the B cell becomes functionally unresponsive to the self antigen without assistance from T cell inhibition

Regulated by inhibitory receptors

Apopotosis: instructed to undergo controlled cell death to prevent initiating an immune response to a cell antigen again in the future.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
21
Q

Discuss whether lack of T or B cell tolerance would be less impactful in the development of autoimmunity?

A

Lack of B cell tolerance- even if B cells were to loose immunological tolerance and their ability to distinguish between self and non-self antigen, their activation and synthesis of antibodies would be inhibited by lack of T cell activation which B cell activation is dependent upon.

Therefore maintaining T cell tolerance enforces B cell tolerance to the same antigens.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
22
Q

What are the six ‘layers’ of tolerance?

A

Central tolerance
Antigen segregation
Peripheral anergy
Regulatory cells
Cytokine deviation
Clonal deletion

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
23
Q

How do regulatory T cells achieve self tolerance?

A

Regulatory T cells act in the secondary lymphoid tissue (Peyer’s patch for example)

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
24
Q

What is the transcription factor that is expressed highly in T reg cells but not in other T cells?

A

FOXP3

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
25
Q

What are the two types of T regs and what are their differences in roles?

A

Natural T regs are responsible for maintaining peripheral tolerance

Induced T regs which are derived from naive T cells are responsible for controlling inflammation

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
26
Q

How are T regs able to maintain peripheral tolerance?

A

Produce anti-inflammatory cytokines such as IL-10 and TGF-B which prevent activation of other immune cells

Instruct cytolysis of self-reactive T cells in the periphery

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
27
Q

How do T regs cause metabolic regulation and how does that help control inflammation?

A

T regs can consume large quanties of glucose and amino acids which are crucial for the proliferation of pro-inflammatory cells which drive inflammation.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
28
Q

What are the five processes in which T cells can help achieve immune tolerance and control inflammation?

A
  1. Anti-inflammatory cytokine production (IL-10 and TNF-B)
  2. Metabolic regulation
  3. Prevent activation of dendritic cells
  4. Direct killing of self reactive T cells
  5. Limiting an immune response to cancer cells
How well did you know this?
1
Not at all
2
3
4
5
Perfectly
29
Q

How does antigen segregation help to induce immune tolerance?

A

This is the physical barrier separation which prevents the exposure of self-antigens to the lymphoid system- preventing over exposure to possible self-reactive lymphocytes.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
30
Q

What is peripheral anergy?

A

It is when mature T and B cells are exposed to a self-antigen in the secondary lymphoid tissue and are functionally unresponsive (anergic) by weak signalling without co-stimulus

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
31
Q

When do autoimmune conditions tend to occur?

A

When there is a breakdown of multiple layers of immunological tolerance, underlying genetic conditions which increase susceptibility to an auto-immune disease in addition to an environmental trigger (illness, infection, injury etc).

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
32
Q

What would you expect to appear in a blood test for a patient that has an auto-immune condition?

A

High circulating levels of auto-antibodies

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
33
Q

True or false.
When somebody has an auto-immune disease this increases their potential to develop additional auto-immune diseases.

A

True

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
34
Q

Is it more common for males or females to have an auto-immune condition?

A

Females, it is believed to link to the estrogen levels which increases susceptibility

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
35
Q

What are the UK statistics for auto-immunity prevalence?

A

Approximately one in ten have an auto-immune condition.

Roughly 13% of women and 7% of men

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
36
Q

Describe the pathophysiology of how genetic susceptibility in addition to environmental factors leads to the development of auto-immune diseases.

A

A patient has underlying susceptible genes which leads to layers of self tolerance. When a patient has an intercurrent infection, illness or injury this leads to inflammation. As you would expect with any other inflammatory response there is an increase of antigen presenting cells, this leads to an increase in the recruitment of lymphocytes. However because of the underlying susceptible genes it results in self-reactive lymphocytes which become activated evoking an immune response not only to the foreign pathogens but the self-antigens leading to chronic inflammation, tissue injury and development of auto-immune conditions.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
37
Q

Why would developing gene therapy to target a faulty gene known to cause an auto-immune disease be ineffective?

A

Auto-immune diseases are polygenic meaning that there are multiple genes known to increase the susceptibility of/ development of auto-immune diseases. Individuals multiple genetic polymorphism that contribute to disease susceptibility. Therefore it would be ineffective to target one gene when the disease is known to be polygenic.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
38
Q

Which gene is particularly associated with auto-immune diseases?

A

MHC class 2

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
39
Q

What is the relationship between infection and auto-immunity?

A

Infection can prevent some auto-immune diseases but often auto-immunity can occur as a result of infection which triggers an acute inflammatory response. Continuous underlying inflammation (chronic inflammation) can then precipitate into an autoimmune disease.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
40
Q

What are some examples of systemic auto-immune diseases?

A

Rheumatoid arthritis
Systemic lupus erythematosus
Systemic sclerosis

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
41
Q

What are some examples of organ specific auto-immune diseases?

A

Myasthenia gravis
Grave’s disease
Autoimmune diabetes

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
42
Q

What are the 5 immunologically privileged sites?

A

Eyes
Testes
Uterus
Brain
Hamster cheek pouch

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
43
Q

Is the increased incidence of auto-immune diseases higher in monozygotic or dizygotic twins?

A

Monozygotic (identical) twins

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
44
Q

What is the difference between induction of co-stimulators and molecular mimicry as mechanisms of causing auto-immune disease?

A

Induction of co-stimulators is simply the process of a microbe infecting a healthy cell that normally expresses self antigens. By the microbe infecting the cell this activates the antigen presenting cell leading to recruitment of T cells, but those with underlying auto-immunity result in the recruitment of self-reactive T cells leading to tissue damage.
Molecular mimicry is when a microbe infects a cell and instead of a self-antigen being presented a microbial antigen is presented which looks identical. A self-reactive lymphocyte is recruited and again initiates an immune response causing tissue damage.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
45
Q

What are some of the roles of auto-circulating antibodies?

A

Complement lysis
Interaction with the cell receptor
Formation of toxic immune complexes
Antibody dependent cytotoxicity
Penetration into living cells

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
46
Q

How do T lymphocytes play a role in auto-immunity?

A

Cytokines cause the polarisation of CD4 cells toward Th1 responses
CD8 cells become activated inducing cytotoxic damage and cause cytolysis.

How well did you know this?
1
Not at all
2
3
4
5
Perfectly
47
Q

Describe the non-specific mechanism of auto-immune damage.

A

Recruitment of auto-immune leucocytes into auto-immune lesions.

48
Q

List some of the conventional therapies for auto-immune disease.

A

NSAIDS

Immunosupressant drugs (DMARDS)
Methotrexate
Ciclosporin
Sulfasalazine

Non-specific control of autoantibodies
Plasmapheresis
Infusion of intravenous immunogloblin

Organ specific:
Insulin for diabetes
Acetylcholine inhibitors for MG

49
Q

What are the main symptoms of inflammation?

A

Heat
Pain
Redness
Swelling
Loss of function

50
Q

What causes fever?

A

Either infection or a non-infectious agent such as inflammation, malignancy or an auto-immune disease.

51
Q

What is a pyrogen?

A

A pyrogen is an infectious substance that induces a fever.

52
Q

What are some examples of pyrogens? What is the most common?

A

Bacteria, viruses, fungi.

The most common pyrogen are endotoxins which are lipopolysaccrides produced by gram negative bacterium such as E coli.

53
Q

Explain the pathophysiology of a fever.

A

Macrophages engulfs gram negative bacterium.
The bacterium is then degraded in the vacuole causing the release of endotoxins. This triggers the macrophage to produce IL-1 and TNF-a which then travels in the blood vessels to the hypothalamus.
IL-1 and TNF-a then causes the hypothalamus to produce prostaglandins specifically prostaglandin E2 act via the specific EP3 receptor to affect hypothalamic neurons that regulate thermoregulation. This initiates fever.

54
Q

What does inflammation occur due to?

A
  • Infectious agents
  • Toxins
  • Physical stresses
55
Q

What is the main goal of inflammation?

A

To remove injurious stimuli and initiating the healing process

56
Q

Explain the first stage of inflammation beginning with mast cells.

A

Bacteria begins to release endotoxins and activates mast cell either by directly damaging the mast cell or by endotoxin binding to the mast cell receptors which initiates the release of many cytokines.

57
Q

What are the molecules released by mast cells?

A

Histamines
Leukotrienes
Prostaglandins

58
Q

How does the secretion of endotoxins link to the COX enzyme pathway?

A

When endotoxins damage any cell membrane this activates phospholipase A2 which breaksdown phospholipids within the cell membrane converting them to arachidonic acid.

59
Q

What enzyme converts kinninogen to bradykinins?

A

Kalikiren which is derived from Coagulation factor 12

60
Q

What are the two enzymes that act on arachidonic acid?

A

Lipo-oxygenase cleaves arachidonic acid to leukotrienes

COX-1 or COX-2 cleaves arachidonic acid to prostaglandins

61
Q

Describe the process in which cell adhesion molecules become expressed on the cell surface and the consequence of their expression.

A

Stimuli such as histamines (released from mast cells) and thrombin cause endothelial cells mobilise the immediate release P-selectin to be expressed on endothelial cells followed shortly by E-selectin. Once these cells adhesion molecules become expressed on the cell surface they act as chemo-attractants, intercepting rapidly moving leukocytes in the blood vessel and causing them to migrate into the inflammatory tissue.

62
Q

What cytokine is responsible for initiating the transcription of E and P selectin?

A

TNF-alpha

63
Q

What are some of the effects of the initial cytokines that are released in the inflammatory response? (Effects on endothelial cells)

A

Act on endothelial cell receptors causing:

Expression of P selectin (cell adhesion molecules), phagocytes (neutrophils and monocytes) express sugars on their cell membrane bind to selectin receptors that recognise carbohydrates, hooks them to the site of inflammation and they undergo margination

Contraction of endothelial cells, increase in vascular permeability, plasma leaks from inter-cellular cleft, accumulation of fluid leading to oedema (swelling)

Fluid accumulation causes physical trauma and activation by bradykinin acts on nociceptor causing pain

Smooth muscle relaxation caused by leukotrienes and histamine binding, which induces vasodilation, causing heat and redness

64
Q

Which cytokines induce the synthesis and expression of P-selectin?

A

Thrombin
Leukotriene B4
Complement fragment 5a
Histamine
TNFa
LPS

65
Q

What ligand does the P selectin bind to and where is it expressed?

A

PSGL-1 (P-selectin glycoprotein ligand 1) which is expressed on all white blood cells. Once it interacts with the P selectin receptor* it results in the “rolling” of the white blood cell on the endothelial cell surface followed by stable adhesion and transmigration of the white blood cell through interacting with PCAMs through the capillary into the site of inflammation.

66
Q

Which cytokines induce the synthesis and expression of E-selectin?

A

IL-1 and TNF-alpha

67
Q

What ligand does the E selectin bind to and where is it expressed?

A

PSGL-1 (expressed on white blood cells) and ESL-1

68
Q

Explain the process of Diapedesis.

A

It the process of white blood cells squeezing through the capillaries to the site of inflammation

69
Q

Once the white blood cells (monocytes and neutrophils) have marginated what happens next?

A

Pro-inflammatory cytokines cause positive chemotaxis attracting the white blood cells to the bacteria.

70
Q

Once macrophages have detected the bacterium which cytokines are released from macrophages?

A

TNF-a, IL-1 and IL-8

71
Q

What are some of the roles of the pro-inflammatory cytokines IL-1 and TNF-a?

A

Act on endothelial cells causing the expression of E-selectins (this typically takes a bit longer, hence why for the first couple of hours of inflammation P-selectins predominates).

72
Q

What selectins are expressed first in the inflammatory response P selectin or E selectin?

A

P-selectin as there expression is induced by histamines and leukotrienes which are produced initially in the inflammatory response. However TNF-alpha and IL-1 which are responsible for E selectin expression are not synthesised until later on in the inflammatory response- once the macrophage has recognised the bacterium.

73
Q

What is the role of IL-8 produced by macrophages in the pro-inflammatory response?

A

IL-8 is produced alongside IL-1 and TNF-a. Whilst IL-1 and TNF-a cause the expression of E-selectins, IL-8 acts on a receptor on the endothelial cells causing it to synthesize and express VCAMs (vascular cell adhesion molecules) and ICAMs (intracellular cell adhesion molecules).
IL-8 then activates the neutrophil, the intergrins on their cell surface become activated and roll over from the E-selectin and interact with the VCAM or ICAM. White blood cell then undergoes diapedisis again entering the site of inflammation.

74
Q

What are the benefits of inducing a fever?

A

Harsher environment for micro-organisms to grow, denature their proteins- DNA

Speeds up our cyto-metabolism, speeds up the healing process

Sequestere iron and zinc in the spleen that the bacterium needs

Acts on the liver causing acute phase reactant proteins (CRP)

75
Q

Aside from TNF-a and IL-1, what other cytokine can induce the liver to produce acute phase proteins?

A

Il-6 which is also produced by macrophages

76
Q

What is leukocytosis?

A

Leukocytosis is the process of TNF-alpha and IL-1 alongside IL-3, IL-5 stimulating the bone marrow to produce and release more white blood cells in response to inflammation.

77
Q

When bacterium first enters the skin what is it recognised by?

A

Either mast cells or macrophages and an appropriate inflammatory response is initiated.

78
Q

What are the lipid mediators that are released from mast cells/macrophages in the acute inflammatory response?

A

This includes:
Leukotrienes
Prostaglandins
Platlet activating factor

79
Q

Briefly outline the inflammation process.

A

Trauma or pathogen causes an acute phase reaction
There is platelet adhesion, transient vasoconstriction of the efferent vessels (fluid accumulation, oedema)
Vasodilation of afferent vessels causing (redness and swelling)
Activation of the complement system, coagulation, kinin and fibrinolytic system
Leukocyte adhesion cascade due to increased vascular permeability resulting in extravstation
Phagocytosis
Resultant healing and remodelling

80
Q

List the pro-inflammatory mediators.

A

Acute phase proteins
Complement system (C3a and C5a)
Kinins (bradykinin causing pain)
Cytokines –
Pro-inflammatory TNF, IL-1, IL6 etc
Chemokines – CXCL-8, CCL2, CCL5 etc
Growth factors – M-CSF, GM-CSF etc
Adhesion molecules – VCAM-1, ICAM-1
Matrix metalloproteinases – MMP-1, 2, 9 etc
Clotting factors
Prostaglandins

81
Q

What are the five main pro-inflammatory cytokines?

A

IL-1B
TNF-a
IL-6
IL-12
Interferon a/b

82
Q

What are the main roles of IL-1B in inflammation?

A

Expression of E-selectin- contributes to leukocyte extravastation

Acts on the hypothylamus to produce prostaglandin E2 causing reset of the thermostat generating fever

Acts on the liver causing the release of acute phase proteins

83
Q

What are the main roles of TNF-a in inflammation?

A

Expression of E-selectin- contributes to leukocyte extravastation

Cause the inductioon of apoptosis (cell death)

Acts on the liver causing the release of acute phase proteins

Causes neutrophil activation

Cachexia

84
Q

What are the main roles of IL-6 in inflammation?

A

Acts on the liver causing the release of acute phase proteins

Influences the adaptive immunity (proliferation and antibody secretion by B cells

85
Q

What are the main roles of IL-12 in inflammation?

A

Induces cytokine production, primarily of IFN-gamma, from NK and T cells

Acts as a growth factor for activated NK and T cells

Enhances the cytotoxic activity of NK cells, and favors cytotoxic T lymphocyte generation

86
Q

What are the main roles of INF a/b in inflammation?

A

Induces an anti-viral state

Activates natural killer cells

87
Q

What are the five main acute phase proteins that are produced in response to pro-inflammatory cytokine production?

A

C reactive protein
Fibrinogen
Serum Amyloid A
Complement factors
Haptoglobin and ferritin

88
Q

Briefly describe the role of C reactive protein in inflammation.

A

Activates the C1q molecule in the complement system leading to opsonisation of pathogens

89
Q

Briefly describe the role of fibrinogen in inflammation.

A

Coagulation factors

90
Q

Briefly describe the role of serum amyloid A in inflammation.

A

Recruits inflammatory cells to the site of inflammation

Induces enzymes that degrade the ECM

91
Q

Briefly describe the role of complement factors in inflammation.

A

C3a and C5a drive inflammation
C3b attaches to the microbe inducing opsonisation
C5b, C6, C7, C8 and C9 cause lysis of microbes by forming a pore (membrane attack complex) - granzyme can eneter?

92
Q

Briefly describe the role of haptoglobin and ferritin in inflammation.

A

Attaches to haemoglobin preventing its oxidative activity. Ferritin binds to iron

93
Q

Define chemokines.

A

A family of small cytokines or signaling proteins secreted by cells that induce directional movement of leukocytes, essentially cytokines that have chemotactic properties.

94
Q

What receptors do chemokines act on?

A

GPCR

95
Q

What are the four families of chemokines?

A

CC, CXC, C, CXXXC

96
Q

Give three examples of chemokines and list the cell types they attract.

A

IL-8 (CXCL8) attracts neutrophils

Monocyte chemotactic protein 1 (MCP1/CCL2) attracts monocytes

Eotaxin (CCL11) attracts eosinophils

97
Q

What are the main role of cell adhesion molecules?

A

Allows for cells to interact with each other as well as the extracellular matrix as they can be expressed on the endothelial cell layer

98
Q

What are the four main classes of cell adhesion molecules and give examples.

A

Ig superfamily -VCAM-1, ICAM-1

Cadherins - E, P, N (cell-cell adhesion)

Selectins – E, P, L – recognise carbohydrates

Integrins – 8 subfamilies causing ECM and cell to cell adhesion

99
Q

What are the three main subtypes of MMPs involved in inflammation?

A

MMPs
ADAMS
ADAMTS

100
Q

What is the specific role of MMPs in inflammation?

A

Degrade and remodel extracellular matrix
Create chemokine gradients

101
Q

What is the specific role of ADAMs in inflammation?

A

Cleave cytokine and adhesion molecule receptors from cell surface

102
Q

What is the specific role of ADAMTS in inflammation?

A

Cleave receptors also
Degrade proteoglycans

103
Q

What does the extracellular matrix usually contain?

A

Collagen fibres -
Collagen type 1, 2 and 3 are found in the fibrillar of the bone, skin and cartilage

In addition to Laminin, Elastin, Proteoglycans, Aggrecan, Fibronectin, Matrilin, Nidogen

104
Q

How is the activation of NFKB involved in the inflammatory response?

A

Under normal physiological circumstances NF-kB is bound to IkB and therefore the transcription factor which controls the expression level of many pro-inflammatory cytokines is inactive. When DNA damage has occurred as a result of trauma, infection or illness, IkB kinase is recruited, phosphorylating IkB and targeting it for degradation meaning that NF-kB is released and able to migrate to the nucleus and bind to promoter regions that code for pro-inflammatory mediators.

105
Q

What are some of the pro-inflammatory mediators that are dependent upon NF-kB for their transcription?

A

Cytokines - TNFa, IL-1 and IL-6
Chemokines and their receptors - IL8, MCP-1, MIP-1s
Adhesion molecules - VCAM-1, ICAM-1, E-and P-selectin
MMPs - MMP-3, MMP-9
Growth factors - GM-CSF, M-CSF
Acute phase proteins - Serum amyloid A

106
Q

What can the two phases of inflammation be categorized as?

A

Phase 1- pro-inflammatory phase, driven by pro-inflammatory mediators aiming to attract many immune cells to the site of inflammation for phagocytosis

Phase 2- anti-inflammatory phase also known as resolution driven by anti-inflammatory mediators which aims to restore normal physiological conditions.
Phagocytosis and apoptosis occurs in this stage

107
Q

What are the anti-inflammatory mediators that are present in phase 2 of the inflammatory response?

A

Anti-inflammatory cytokines – IL10 etc
Soluble adhesion molecules
TIMPs
Plasmin activation system
Opioid peptides
Resolvins/Protectins

108
Q

Explain briefly the role of IL-10 in driving an anti-inflammatory response.

A

Inhibits macrophage activation by blocking the co-stimulatory molecules present

It downregulates the expression of Th1 cytokines, MHC class II antigens

It enhances B cell survival, proliferation, and antibody production.

IL-10 can block NF-κB activity, and is involved in the regulation of the JAK-STAT signaling pathway.

109
Q

Briefly describe the role of soluble adhesion molecules in driving the anti-inflammatory response.

A

Soluble adhesion molecules bind to the cell adhesion molecules such as selectins which are expressed on the endothelial cell surface as a result of inflammation. By these soluble adhesion molecules binding this prevents these selectins from binding to leukocytes enabling their transmigration through to the site of inflammation.

110
Q

Briefly describe the role of TIMPS in driving the anti-inflammatory response.

A

Inhibit matrix metalloproteinases

111
Q

Briefly describe the role of plasmin activation system in driving the anti-inflammatory response.

A

Plasminogen is transferred to wound sites by inflammatory cells early during healing and it helps to clear fibrin and neutrophils and forming new connective tissue and blood vessels during wound healing

112
Q

Briefly describe the role of opioid peptides in driving the anti-inflammatory response.

A

Counteracts pain

113
Q

Briefly describe the role of resolvins and protectins in driving the anti-inflammatory response.

A

Block the lipid mediated pathways that drive inflammation

114
Q

What happens if there is no resolution phase of inflammation?

A

Results in ongoing acute pro-inflammatory phase leading to inappropriate chronic inflammation resulting in abscess formation, excess scarring and auto-immunity.

115
Q

What happens when there is excessive acute inflammation?

A

Leads to organ failure and death (sepsis)