Autoimmune Disease and Hypersensitivity Reactions Flashcards Preview

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Flashcards in Autoimmune Disease and Hypersensitivity Reactions Deck (176)
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1
Q

What is autoimmunity?

A

A state that is present when an individual has made an immune response to self-antigens

2
Q

What provides evidence for autoimmunity in many cases?

A

The presence of autoantibodies in serum

3
Q

What can autoantibodies in serum be helpful in?

A

Diagonsing and monitoring autoimmune diseases

4
Q

What is meant by autoimmune disease?

A

The term applied to a disease in which autoimmunity is thought to play a significant pathological role, i.e. when the tissue damage results from the autoimmune response

5
Q

What are the types of autoimmune disease?

A
  • Organ specific
  • Non-organ specific
6
Q

What is meant by organ specific autoimmunity?

A

The target antigen is located in one organ

7
Q

What is meant by non-organ specific autoimmune disease?

A

The target antigen is located on many different tissues/organs

8
Q

Give 10 examples of organ-specific autoimmune diseases

A
  • Hashimoto’s
  • Thyrotoxicosis
  • Primary myxoedema
  • Chronic atrophic gastritis
  • Pernicious anaemia
  • Addisons’s disease
  • Myasthenia gravis
  • Type 1 diabetes mellitus
  • Premature ovarian failure
  • Male infertility
9
Q

Give 4 examples of intermediate/mixed autoimmune diseases

A
  • Goodpasture’s syndrome
  • Primary biliary cirrhosis
  • Autoimmune haemolytic disease
  • Ulcerative colitis
10
Q

Give 4 examples of non-organ specific autoimmune diseases

A
  • Systemic Lupus Erythematosus
  • Rheumatoid arthritis
  • Sjogren’s syndrome
  • Progressive systemic sclerosis
11
Q

What does the existence of autoimmune disesae show?

A

Central tolerance is not fool proof

12
Q

What is central tolerance?

A

The mechanism by which auto-reactive B and T cells are deleted

13
Q

What is peripheral tolerance?

A

Collective term for further immunological processes that act to avoid the activation of auto-active T and B lymphocytes

14
Q

What happens when peripheral tolerance breaks down?

A

Autoimmunity can ensue

15
Q

What are the potential mechaniams of immunologically mediated tissue injury?

A
  • Defective immunoregulation
  • Cytokine dysregulation
  • Molecular mimicry
  • T cell bypass
  • ‘Hidden’ self antigens
16
Q

What is the mechanism of injury in defective immunoregulation?

A

Reduction in supressor/regulatory T cell number and/or function

17
Q

What diseases result from defective immunoregulation?

A

Thyroid, liver, GI, and other autoimmune diseases

18
Q

What is the mechanism of injury in cytokine dysregulation?

A

Cytokines provide additional signals to activate resting or tolerised autoreactive cells

19
Q

What disease results from cytokine dysregulation?

A

Autoimmune thyroid disease following IL-2 therapy

20
Q

What is the mechanism of injury in molecular mimicry?

A

Pathogen has cross-reactive epitopes with autoantigen; anti-pathogen immune response leads to anti-self response

21
Q

What diseases result from molecular mimicry?

A
  • Coxsackie virus and glutamic acid decarboxylase in type 1 diabetes.
  • Adenovirus 12 and gliadin in coeliac disease
22
Q

What is the mechanism of injury in T cell bypass?

A

Novel T cell carrier supplied for an associated T or B cell epitope for which tolerance exists, so T cell help via new carrier activates tolerised cell

23
Q

What disease result from T cell bypass?

A

Drug and virus induced auto-immune cytopenias

24
Q

What is the mechanism of injury of ‘hidden’ self antigens?

A

Tolerance exists to cryptic antigens (‘immunological ignorence’), and release or presentation of these breaks the tolerance

25
Q

What diseases result from ‘hidden’ self antigens?

A
  • Sympathetic ophthalmia
  • Post myocardial complications
    • Dressler’s syndrome
  • MS (myelin antigens)
26
Q

What are hypersensitivity reactions?

A

Excessive or over zealous immune responses that can lead to tissue damage

27
Q

What are hypersensitivity reactions the basis of?

A

Autoimmune disease

28
Q

What can hypersensitivity reactions occur in response to?

A
  • Infectious agents
  • Environmental agents
  • Self antigens
29
Q

Give an example of a disease caused by hypersensitivity to infectious agents

A

Fulminant hepatitis

30
Q

Give an example of a disease caused by hypersensitivity to environmental substances?

A

Hayfever

31
Q

What are the types of hypersensitivity reactions?

A
  1. Immediate hypersensitivity
  2. Antibody mediated hypersensitivity
  3. Immune complex mediated hypersensitivity
  4. Delayed hypersensitivity
32
Q

What happens in immediate hypersensitivity?

A

Cross-linking of Antigen-specific IgE molecules on surface of mast cells or basophils

33
Q

What does the cross-linking lead to in immediate hypersensitivity?

A

Degranulation of the cells and the release of vasoactive substances

34
Q

Over what time scale to immediate hypersensitivity reactions typically occur?

A

In minutes

35
Q

What do immediate hypersensitivity reactions form the basis of?

A

Most common types of allergies

36
Q

What does immediate hypersensitivity represent a component of?

A

Childhood asthma

37
Q

What is anaphylaxis?

A

A severe form of type I hypersensitivity reaction

38
Q

What triggers anaphylaxis?

A

The exposure of a pre-sensitised individual to an allergen, causing mast cell degranulation

39
Q

What does systemic mast cell degranulation lead to?

A
  • Vasodilation
  • Tissue oedema
  • Airways obstruction
  • Fall in blood pressure
  • Shock
40
Q

How should acute anaphylaxis be treated?

A

Intramuscular adrenaline

41
Q

What is the purpose of intramuscular adrenaline in acute anaphylaxis?

A

It promptly reverses the symptoms and signs with an increase in blood pressure and reversal of airways obstruction

42
Q

What happens in antibody mediated hypersensitivity?

A

IgG antibodies reacting with antigen present on tissues or on the surfaces of cells

43
Q

What happens once the antibodies have bound with the antigens in antibody mediated hypersensitivity?

A

They interact with complement or the FC receptor on phagocytic cells, activating these innate mechanisms leading to the induction of localised inflammatory response and tissue damage

44
Q

What is the timescale for antibody mediated hypersensitivity?

A

The reactions may occur very quickly, but may also lead to prolonged activation

45
Q

Give 4 examples of antibody mediated hypersensitivity reactions

A
  • Goodpasture’s syndrome
  • Haemolytic anaemias / Rhesus disease
  • Stimulating Ab’s
  • Blocking Ab’s
46
Q

What happens in Goodpastures syndrome?

A

There are autoantibodies to the basement membrane in the lung and kidney

47
Q

What disease is caused by the stimulation of antibodies?

A

Grave’s disease (stimulates TSH)

48
Q

What diseases are caused by blocking antibodies?

A
  • Myasthenia gravis (Blocks AchR)
  • Diabetes (blocks insulin receptor)
49
Q

What happens in immune complex mediated hypersensitivity?

A

Deposition of immune complexes, usually IgG antibodies

50
Q

What happens when immune complexes are deposited in various tissues in immune complex mediated hypersensitivity?

A

They set up inflammatory reactions similar to Type II reactions (complement activation, phagocyte Fc receptor)

51
Q

What are the most common sites of Type III reactions?

A
  • Skin
  • Joints
  • Kidney
52
Q

How does type III hypersensitivity in the skin present?

A

Rash

53
Q

How does type III hypersensitivity in the joints present?

A

Arthritis

54
Q

How does type III hypersensitivity in the kidney present?

A

Nephritis

55
Q

Give 3 examples of diseases caused by type III hypersensitivity

A
  • Systemic Lupus Erythematosus
  • Farmer’s lung
56
Q

What happens in delayed hypersensitivity?

A

T cells activate macrophages or cytotoxic T cells

57
Q

What do activated macrophages/cytotoxic T cells cause?

A

Tissue damage

58
Q
A
59
Q

What time scale do delayed hypersensitivity reactions typically occur over?

A

Two to three days after exposure to antigen

60
Q

What can cause delayed hypersensitivity reactions?

A
  • External agents
  • Autoimmune reactions
61
Q

Give two examples of diseases that are caused by a delayed hypersensitivity reaction to external agents

A
  • Tuberculoid leprosy
  • Contact dermatitis
62
Q

Give two examples of autoimmune diseases caused by delayed hypersensitivity

A
  • Coeliac disease
  • Multiple sclerosis
63
Q

What causes coeliac disease?

A

A delayed type hypersensitivity reaction taking place in the intestinal wall

64
Q

What facilitates the reaction taking place in coeliac disease?

A

The allele HLA-DQ2

65
Q

What is the mechanism of disease in coeliac disease?

A

Gluten is digested to gliadin, which is recognised as an antigen by HLA-DQ2 and presented to T cells. B cells then make autoantibodies to the transglutamase that is attached to the gliadin. The T cells interact with macrophages, activating them and causing the hypersensitivity, damaging the intestinal villi

66
Q

What is the appearance of the damaged intestinal villi in coaelic disease?

A

Flattened

67
Q

What happens if gluten is withdrawn from the diet in coeliac disease?

A

It reverses the process and the villi return to normal architecture

68
Q

What is immunotherapy?

A

The manipulation of the immune response to treat disease

69
Q

What can immunotherapy involve?

A
  • Enhancing immunity
  • Suppressing immunity
70
Q

What immunotherapy enhances immunity?

A

Vaccination

71
Q

When is it required to suppress immunity?

A

To treat allergies and autoimmune conditions

72
Q

What is the treatment for allergies?

A
  • Anti-histamines
  • Allergen desensitisation
73
Q

What are the major therapeutic effects of anti-histamines via?

A

Blocking H1 histamine receptors, leading to inhibition of histamine mediated;

  • Vascular permeability
  • Smooth muscle contraction
  • Reduction in exocrine secretions
  • Reduction in sensory nerve stimulation
74
Q

What is sensory nerve stimulation in allergies responsible for?

A

Itching, sneezing etc.

75
Q

Give 3 examples of anti-histamines

A
  • Cetirizine
  • Terfanidine
  • Loratidine
76
Q

When are allergies treated with allergen desensitisation?

A

When they are severe

77
Q

What happens in allergen desensitisation?

A

Regular, subcutaneous injections of the relevant antigen are given ovr a period of weeks or months

78
Q

What is the mechanism of antigen desensitisation?

A

Not fully understood

May be due to shifting T cell response towards Th1 / inducing IgG blocking antibodies

79
Q

How is asthma treated?

A
  • ß2 adrenoagonists
  • Corticosteroids
  • Leukotriene receptor antagonists
  • Sodium cromglicate
80
Q

What do ß2-adrenoagonists do?

A

Bronchodilate

81
Q

Give an example of a ß2-adrenoagonist?

A

Salbutamol

82
Q

Give an example of a corticosteroid?

A

Budesonide

83
Q

What do leukotriene receptor antagonists do?

A

Blocks smooth muscle contraction, production of mucous, recruitment of inflammatory cells, promotion of inflammation and modulation of cytokine production

84
Q

Give an example of a leukotriene receptor antagonist

A

Montelukast

85
Q

What does sodium cromglicate do?

A

Helps stabilise the mast cell membrane, preventing degranulation

86
Q

How do anti-inflammatory drugs work?

A

Largely by blocking or suppressing functions of non-specific inflammatory cells, or pro-inflammatory mediators produced by these cells

87
Q

What inflammatory cells to anti-inflammatory drugs block/suppress?

A
  • Monocytes
  • Macrophages
  • Granulocytes
88
Q

What properties do anti-inflammatory drugs sometimes also have?

A

Immunosuppressive properties

89
Q

What anti-inflammatory drugs also have immunosuppressive properties?

A

Steroids

90
Q

What is meant by immunsuppressive?

A

Inhibition of specific immune cells and their mediators

91
Q

What is the result of some types of anti-inflammatory drugs also having immunosuppressive properties?

A

The distinction between the two is not always clear

92
Q

What do corticosteroids represent?

A

A major class of anti-inflammatory and immunosuppressive drugs in clinical use

93
Q

What are corticosteroids structurally related to?

A

The glucocorticoid steroid hormone cortisol

94
Q

How can corticosteroids be administered?

A
  • Topically
    • Creams
    • Inhalers
    • Drops
  • Systemically
    • Oral
    • Parenteral
95
Q

What are the immunomodulatory effects of corticosteroids?

A
  • Leukocyte trafficking
  • Functional effects
96
Q

What is the effect of leukocyte trafficking?

A
  • Increased neutrophils
  • Reduced lymphocytes (especially T cells) and monocytes
97
Q

What are the functional immunomodulatory effects of corticosteroids?

A
  • Inhibition of NFkB intracellular signalling pathway
  • Reduced cytokine release (IL-1, IL-2, and TNF-α)
  • Impaired leukocyte proliferation
  • Suppressed phagocytosis and bacteriocidal activity
  • Impaired antigen presentation
  • Reduced arachidonic acid metabolism
98
Q

What are the types of corticosteroid drugs?

A
  • Glucocorticoids
  • Mineralocorticoids
99
Q

What are the side effects of glucocorticoids?

A
  • Diabetes
  • Cushing’s
  • Adrenal suppression / acute adrenal insufficiency in abrupt withdrawal
  • Osteoporosis
    • Avascular necrosis of head of femur
  • Mental disturbances
100
Q

What are the side effects of mineralocorticoids?

A
  • Hypertension
  • Sodium and water retention
  • Potassium loss
101
Q

What are the immunosuppressive side effects of corticosteroids?

A
  • Increased susceptibility to infections
  • Impaired wound healing
102
Q

What are the other side effects of corticosteroids?

A
  • Obesity and muscle wasting
  • Growth arrest in children
103
Q

What do non-steroidal anti-inflammatory drugs (NSAIDs) represent?

A

A wide group of drugs that is one of the most frequently prescribed worldwide

104
Q

What properties do NSAIDs have?

A

Both analgesic and anti-inflammatory properties

105
Q

Give 4 types of NSAID

A
  • Salicyclic acid
  • Propionic acid derivatives
  • Non-Propionic acid derivatives
  • Selective COX-2 inhibitors
106
Q

What is the best known and most common type of NSAID?

A

Salicyclic acid

107
Q

Give an example of a salicyclic acid

A

Aspirin

108
Q

Give two examples of propionic acid derivatives?

A
  • Ibuprofen
  • Naproxen
109
Q

Give two examples of non-propionic acid derivatives

A
  • Indomethacin
  • Diclofenac
110
Q

Give two examples of selective COX-2 inhibitors

A
  • Celocoxib
  • Etoricoxib
111
Q

What are the main anti-inflammatory properties of NSAIDs due to?

A

The inhibition of cyclooxygenase in the production of prostaglandins

112
Q

What is the major side effect of older NSAIDs?

A

GI toxicity

113
Q

What is the major side effect of newer NSAIDs?

A

CVS effects

114
Q

What kind of molecule is TNF-α?

A

A pro-inflammatory cytokine

115
Q

What does TNF-α play a central role in?

A

The pathogenesis of a number of autoimmune diseases

116
Q

Give two examples of diseases where TNF-α plays a crucial role in the pathogenesis

A
  • Rheumatoid arthritis
  • Crohn’s disease
117
Q

Give two drugs used against TNF-α related diseases

A
  • Infliximab
  • Etanercept
118
Q

What is infliximab?

A

A humanised monoclonal antibody against TNF-α

119
Q

What is infliximab used to do?

A

Treat Crohn’s disease and rheumatoid arthritis

120
Q

What is etanercept?

A

Soluble, recombinant, human TNF-α receptor fusion protein

121
Q

What is etanercept used to do?

A

Treat rheumatoid arthritis

122
Q

What is a side effect of anti-TNF-α drugs?

A

Reactivation of latent tuberculosis

123
Q

What does the reactivation of latent TB with ant-TNF-α drugs show?

A

The important protective effect of TNF-α in this condition

124
Q

Why were cytotoxic and anti-proliferative drugs introduced into clinical practice?

A

For the treatment of cancer in the 1950’s

125
Q

What properties was it discovered that cytotoxic and anti-proliferative agents had?

A

Immunosuppressive

126
Q

What can the immunosuppressive properties of cytotoxic and anti-proliferative drugs be used to do?

A

Treat autoimmune disease and try and inhibit organ transplant rejection

127
Q

What are side effects of cytotoxic and anti-proliferative drugs due to?

A

The agents targeting all proliferating cell types

128
Q

What are the side effects of cytotoxic and anti-proliferative agents?

A
  • Cytopenias
  • GI toxicities
  • Reduced fertility
129
Q

Give 4 examples of cytotoxic and anti-proliferative agents

A
  • Azathioprine
  • Methotrexate
  • Cyclophosphamide
  • Mycophenolate Mofetil
130
Q

What do azathioprine and methotrexate act on?

A

Cells in the S phase

131
Q

At what cell stage is cyclophosphamide toxic?

A

All

132
Q

What does cyclophosphamide predominantly act on?

A

Active cells rather than resting

133
Q

What does Mycophenolate Mofetil do?

A

New anti-proliferative agent that blocks the synthesis of guanine nucleotides

134
Q

What is the advantage of Mycophenolate Mofetil?

A

It has a degree of selectivity for lymphocytes

135
Q

Why does Mycophenolate Mofetil have a degree of selectivity for lymphocytes?

A

As proliferating lymphocytes rely heavily on the de nova generation of guanine

136
Q

Give 8 immunological diseases in which cytotoxic drugs are used

A
  • Organ transplant rejection
  • Rheumatoid arthritis
  • Systemic lupus erythematosus
  • Systemic Vasculitis
  • Wegener’s Granulomatosis
  • Polymyositis
  • Membranous and membroproliferative glomerulonephritis
  • Inflammatory bowel disease
137
Q

Give 3 examples of T-cell selective immunosuppressants

A
  • Cyclosporine
  • Tacrolimus
  • Rapamycin
138
Q

What is the mechanism of action of cyclosporine and tacrolimus?

A

They are calcineurin inhibitors, blocking nuclear factor of activated T cells (NFAT).

They inhibit transcription of IL-2, and so inhibits unwanted T-helper responses

139
Q

What is the mechanism of action of rapamycin?

A

Blocks cellular protein called mTOR

Inhibits IL-2 production

Also has anti-proliferative effects

140
Q

What is a potential use for the anti-proliferative effects of rapamycin?

A

Cancer therapy

141
Q

What is the result of the cyclosporine and tacrolimus, and rapamycin working in different ways?

A

They can be used together for greater effect

142
Q

What are cyclosporine, tacrolimus and rapamycin widely used in?

A

The prevention of organ transplant rejection, and in certain T-cell driven autoimmune conditions

143
Q

What cytokines are biological immune response modifiers?

A
  • Interferon-α
  • Interferon-ß
  • IL-2
  • Granulocyte Colony Stimulating Factor (G-CSF)
144
Q

Give 5 conditions interferon-α can be used to treat

A
  • Chronic Myelogenous Leukaemia
  • Hairy cell Leukaemia
  • Follicular lymphoma
  • AIDS-related Kaposi’s Sarcoma
  • Chronic infections of hepatitis B and C
145
Q

What can interferon-ß be used to treat?

A

Relapsing, remitting multiple sclerosis

146
Q

What can IL-2 be used to treat?

A

Metastatic renal cancer

147
Q

How can G-CSF be used clinically?

A
  • Mobilise granulocytes when neutropenia is a problem
  • Increase bone marrow progenitor cells in the blood for harvesting prior to stem cell transplantation
148
Q

What has systemic administration of a number of cytokines proven to be?

A

Highly toxic

149
Q

Give a potential toxic consequence of systemic administration of cytokines

A

Capillary leak syndrome in IL-2 therapy

150
Q

Give two examples of cytokine inhibitors

A
  • Infliximab
  • Etanercept
151
Q

What do infliximab and etanercept inhibit?

A

TNF-α

152
Q

What is given in replacement immunoglobulin therapy?

A

Intravenous immunoglobulin

153
Q

When is replacement immunoglobulin therapy used?

A

Primary and secondary antibody deficiencies

154
Q

Give 4 diseases where intravenous immunoglobulin has a therapeutic benefit?

A
  • Kawasaki disease
  • Idiopathic thrombocytopenia
  • Guillain-Barre syndrome
  • Chronic Inflammatory Demyelinating Polyneuropathy
155
Q

What are monoclonal antibodies?

A

Antibodies of a single specificity

156
Q

What produces monoclonal antibodies?

A

Fusion of an antigen specific B cell clone with an immortalised plasma cell line

157
Q

How are monoclonal antibodies produced?

A
  1. Hyper-immunise mice with an antigen
  2. Harvest splenic B-cells
  3. Fuse with immortalised plasma cell line
  4. Humanise antibodies
158
Q

What is meant by humanising antibodies?

A

Engineering a human antibody so it contains the antigen specificity of the mouse antibody

159
Q

What are the potential mechanisms of action of therapeutic monoclonal antibodies?

A
  • Neutralising the target antigen
  • Induce complement mediated cell lysis
  • Induce antibody dependant (NK-mediated) lysis of target cells
  • Block cellular interactions of receptor ligand binding
  • Induce apoptosis in target cells
  • Conugated to radioisotopes to deliver to target cell
  • Conjugated to cellular toxins to deliver to target cell
160
Q

Give 8 examples of monoclonal antibodies used therapeutically

A
  • Infliximab
  • Herceptin
  • Omalizumab
  • Alemtuzumab
  • Palivisumab
  • Basiliximab
  • Bevacizumab
  • Rituximab
161
Q

What is the target antigen for infliximab?

A

TNF-α

162
Q

What diseases is infliximab used to treat?

A
  • Rheumatoid arthritis
  • Crohn’s disease
163
Q

What is the target antigen for herceptin?

A

Her-2 (EGF receptor)

164
Q

What is herceptin used to treat?

A

Her-2+ Breast cancer

165
Q

What is the target antigen for omalizumab?

A

IgE

166
Q

What is omalizumab used to treat?

A

Severe allergic asthma

167
Q

What is the target antigen for alemtuzumab?

A

CD52 (most WBCs)

168
Q

What is alemtuzumab used to treat?

A

Chronic lymphocytic leukaemia

169
Q

What is the target antigen for palivisumab?

A

RSV F-protein

170
Q

What is palivisumab used for?

A

RSV prophylaxis in ‘at risk’ children

171
Q

What is the target antigen for basiliximab?

A

CD25 (IL-2 receptor)

172
Q

What is basiliximab used to treat?

A

Organ transplant rejection

173
Q

What is the target antigen for bevacizumab?

A

VEGF

174
Q

What is bevacizumab used to treat?

A

Tumour angiogenesis in colorectal cancer

175
Q

What is the target antigen for rituximab?

A

CD20 (B-cell)

176
Q

What is rituximab used to treat?

A
  • B-cell leukaemia/lymphoma
  • Some severe autoimmune diseases