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Z Old Infection IGNORE > Autoimmune Disease and Hypersensitivity Reactions > Flashcards

Autoimmune Disease and Hypersensitivity Reactions Flashcards

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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

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2
Q

What provides evidence for autoimmunity in many cases?

A

The presence of autoantibodies in serum

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3
Q

What can autoantibodies in serum be helpful in?

A

Diagonsing and monitoring autoimmune diseases

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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

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5
Q

What are the types of autoimmune disease?

A
  • Organ specific
  • Non-organ specific
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6
Q

What is meant by organ specific autoimmunity?

A

The target antigen is located in one organ

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7
Q

What is meant by non-organ specific autoimmune disease?

A

The target antigen is located on many different tissues/organs

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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
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9
Q

Give 4 examples of intermediate/mixed autoimmune diseases

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

Give 4 examples of non-organ specific autoimmune diseases

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

What does the existence of autoimmune disesae show?

A

Central tolerance is not fool proof

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12
Q

What is central tolerance?

A

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

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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

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14
Q

What happens when peripheral tolerance breaks down?

A

Autoimmunity can ensue

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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
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16
Q

What is the mechanism of injury in defective immunoregulation?

A

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

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17
Q

What diseases result from defective immunoregulation?

A

Thyroid, liver, GI, and other autoimmune diseases

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18
Q

What is the mechanism of injury in cytokine dysregulation?

A

Cytokines provide additional signals to activate resting or tolerised autoreactive cells

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19
Q

What disease results from cytokine dysregulation?

A

Autoimmune thyroid disease following IL-2 therapy

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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

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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
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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

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23
Q

What disease result from T cell bypass?

A

Drug and virus induced auto-immune cytopenias

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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

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25
What diseases result from 'hidden' self antigens?
* Sympathetic ophthalmia * Post myocardial complications * Dressler's syndrome * MS *(myelin antigens)*
26
What are hypersensitivity reactions?
Excessive or over zealous immune responses that can lead to tissue damage
27
What are hypersensitivity reactions the basis of?
Autoimmune disease
28
What can hypersensitivity reactions occur in response to?
* Infectious agents * Environmental agents * Self antigens
29
Give an example of a disease caused by hypersensitivity to infectious agents
Fulminant hepatitis
30
Give an example of a disease caused by hypersensitivity to environmental substances?
Hayfever
31
What are the types of hypersensitivity reactions?
1. Immediate hypersensitivity 2. Antibody mediated hypersensitivity 3. Immune complex mediated hypersensitivity 4. Delayed hypersensitivity
32
What happens in immediate hypersensitivity?
Cross-linking of Antigen-specific IgE molecules on surface of mast cells or basophils
33
What does the cross-linking lead to in immediate hypersensitivity?
Degranulation of the cells and the release of vasoactive substances
34
Over what time scale to immediate hypersensitivity reactions typically occur?
In minutes
35
What do immediate hypersensitivity reactions form the basis of?
Most common types of allergies
36
What does immediate hypersensitivity represent a component of?
Childhood asthma
37
What is anaphylaxis?
A severe form of type I hypersensitivity reaction
38
What triggers anaphylaxis?
The exposure of a pre-sensitised individual to an allergen, causing **mast cell degranulation**
39
What does systemic mast cell degranulation lead to?
* Vasodilation * Tissue oedema * Airways obstruction * Fall in blood pressure * Shock
40
How should acute anaphylaxis be treated?
Intramuscular adrenaline
41
What is the purpose of intramuscular adrenaline in acute anaphylaxis?
It promptly reverses the symptoms and signs with an increase in blood pressure and reversal of airways obstruction
42
What happens in antibody mediated hypersensitivity?
IgG antibodies reacting with antigen present on tissues or on the surfaces of cells
43
What happens once the antibodies have bound with the antigens in antibody mediated hypersensitivity?
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
What is the timescale for antibody mediated hypersensitivity?
The reactions may occur very quickly, but may also lead to prolonged activation
45
Give 4 examples of antibody mediated hypersensitivity reactions
* Goodpasture's syndrome * Haemolytic anaemias / Rhesus disease * Stimulating Ab's * Blocking Ab's
46
What happens in Goodpastures syndrome?
There are autoantibodies to the basement membrane in the lung and kidney
47
What disease is caused by the stimulation of antibodies?
Grave's disease *(stimulates TSH)*
48
What diseases are caused by blocking antibodies?
* Myasthenia gravis *(Blocks AchR)* * Diabetes *(blocks insulin receptor)*
49
What happens in immune complex mediated hypersensitivity?
Deposition of immune complexes, usually IgG antibodies
50
What happens when immune complexes are deposited in various tissues in immune complex mediated hypersensitivity?
They set up inflammatory reactions similar to Type II reactions *(complement activation, phagocyte Fc receptor)*
51
What are the most common sites of Type III reactions?
* Skin * Joints * Kidney
52
How does type III hypersensitivity in the skin present?
Rash
53
How does type III hypersensitivity in the joints present?
Arthritis
54
How does type III hypersensitivity in the kidney present?
Nephritis
55
Give 3 examples of diseases caused by type III hypersensitivity
* Systemic Lupus Erythematosus * Farmer's lung
56
What happens in delayed hypersensitivity?
T cells activate macrophages or cytotoxic T cells
57
What do activated macrophages/cytotoxic T cells cause?
Tissue damage
58
59
What time scale do delayed hypersensitivity reactions typically occur over?
Two to three days after exposure to antigen
60
What can cause delayed hypersensitivity reactions?
* External agents * Autoimmune reactions
61
Give two examples of diseases that are caused by a delayed hypersensitivity reaction to external agents
* Tuberculoid leprosy * Contact dermatitis
62
Give two examples of autoimmune diseases caused by delayed hypersensitivity
* Coeliac disease * Multiple sclerosis
63
What causes coeliac disease?
A delayed type hypersensitivity reaction taking place in the intestinal wall
64
What facilitates the reaction taking place in coeliac disease?
The allele HLA-DQ2
65
What is the mechanism of disease in coeliac disease?
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
What is the appearance of the damaged intestinal villi in coaelic disease?
Flattened
67
What happens if gluten is withdrawn from the diet in coeliac disease?
It reverses the process and the villi return to normal architecture
68
What is immunotherapy?
The manipulation of the immune response to treat disease
69
What can immunotherapy involve?
* Enhancing immunity * Suppressing immunity
70
What immunotherapy enhances immunity?
Vaccination
71
When is it required to suppress immunity?
To treat allergies and autoimmune conditions
72
What is the treatment for allergies?
* Anti-histamines * Allergen desensitisation
73
What are the major therapeutic effects of anti-histamines via?
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
What is sensory nerve stimulation in allergies responsible for?
Itching, sneezing etc.
75
Give 3 examples of anti-histamines
* Cetirizine * Terfanidine * Loratidine
76
When are allergies treated with allergen desensitisation?
When they are severe
77
What happens in allergen desensitisation?
Regular, subcutaneous injections of the relevant antigen are given ovr a period of weeks or months
78
What is the mechanism of antigen desensitisation?
*Not fully understood* May be due to shifting T cell response towards Th1 / inducing IgG blocking antibodies
79
How is asthma treated?
* ß2 adrenoagonists * Corticosteroids * Leukotriene receptor antagonists * Sodium cromglicate
80
What do ß2-adrenoagonists do?
Bronchodilate
81
Give an example of a ß2-adrenoagonist?
Salbutamol
82
Give an example of a corticosteroid?
Budesonide
83
What do leukotriene receptor antagonists do?
Blocks smooth muscle contraction, production of mucous, recruitment of inflammatory cells, promotion of inflammation and modulation of cytokine production
84
Give an example of a leukotriene receptor antagonist
Montelukast
85
What does sodium cromglicate do?
Helps stabilise the mast cell membrane, preventing degranulation
86
How do anti-inflammatory drugs work?
Largely by blocking or suppressing functions of non-specific inflammatory cells, or pro-inflammatory mediators produced by these cells
87
What inflammatory cells to anti-inflammatory drugs block/suppress?
* Monocytes * Macrophages * Granulocytes
88
What properties do anti-inflammatory drugs sometimes also have?
Immunosuppressive properties
89
What anti-inflammatory drugs also have immunosuppressive properties?
Steroids
90
What is meant by immunsuppressive?
Inhibition of specific immune cells and their mediators
91
What is the result of some types of anti-inflammatory drugs also having immunosuppressive properties?
The distinction between the two is not always clear
92
What do corticosteroids represent?
A major class of anti-inflammatory and immunosuppressive drugs in clinical use
93
What are corticosteroids structurally related to?
The glucocorticoid steroid hormone cortisol
94
How can corticosteroids be administered?
* Topically * Creams * Inhalers * Drops * Systemically * Oral * Parenteral
95
What are the immunomodulatory effects of corticosteroids?
* Leukocyte trafficking * Functional effects
96
What is the effect of leukocyte trafficking?
* Increased neutrophils * Reduced lymphocytes *(especially T cells)* and monocytes
97
What are the functional immunomodulatory effects of corticosteroids?
* 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
What are the types of corticosteroid drugs?
* Glucocorticoids * Mineralocorticoids
99
What are the side effects of glucocorticoids?
* Diabetes * Cushing's * Adrenal suppression / acute adrenal insufficiency in abrupt withdrawal * Osteoporosis * Avascular necrosis of head of femur * Mental disturbances
100
What are the side effects of mineralocorticoids?
* Hypertension * Sodium and water retention * Potassium loss
101
What are the immunosuppressive side effects of corticosteroids?
* Increased susceptibility to infections * Impaired wound healing
102
What are the other side effects of corticosteroids?
* Obesity and muscle wasting * Growth arrest in children
103
What do non-steroidal anti-inflammatory drugs (NSAIDs) represent?
A wide group of drugs that is one of the most frequently prescribed worldwide
104
What properties do NSAIDs have?
Both analgesic and anti-inflammatory properties
105
Give 4 types of NSAID
* Salicyclic acid * Propionic acid derivatives * Non-Propionic acid derivatives * Selective COX-2 inhibitors
106
What is the best known and most common type of NSAID?
Salicyclic acid
107
Give an example of a salicyclic acid
Aspirin
108
Give two examples of propionic acid derivatives?
* Ibuprofen * Naproxen
109
Give two examples of non-propionic acid derivatives
* Indomethacin * Diclofenac
110
Give two examples of selective COX-2 inhibitors
* Celocoxib * Etoricoxib
111
What are the main anti-inflammatory properties of NSAIDs due to?
The inhibition of cyclooxygenase in the production of prostaglandins
112
What is the major side effect of older NSAIDs?
GI toxicity
113
What is the major side effect of newer NSAIDs?
CVS effects
114
What kind of molecule is TNF-α?
A pro-inflammatory cytokine
115
What does TNF-α play a central role in?
The pathogenesis of a number of autoimmune diseases
116
Give two examples of diseases where TNF-α plays a crucial role in the pathogenesis
* Rheumatoid arthritis * Crohn's disease
117
Give two drugs used against TNF-α related diseases
* Infliximab * Etanercept
118
What is infliximab?
A humanised monoclonal antibody against TNF-α
119
What is infliximab used to do?
Treat Crohn's disease and rheumatoid arthritis
120
What is etanercept?
Soluble, recombinant, human TNF-α receptor fusion protein
121
What is etanercept used to do?
Treat rheumatoid arthritis
122
What is a side effect of anti-TNF-α drugs?
Reactivation of latent tuberculosis
123
What does the reactivation of latent TB with ant-TNF-α drugs show?
The important protective effect of TNF-α in this condition
124
Why were cytotoxic and anti-proliferative drugs introduced into clinical practice?
For the treatment of cancer in the 1950's
125
What properties was it discovered that cytotoxic and anti-proliferative agents had?
Immunosuppressive
126
What can the immunosuppressive properties of cytotoxic and anti-proliferative drugs be used to do?
Treat autoimmune disease and try and inhibit organ transplant rejection
127
What are side effects of cytotoxic and anti-proliferative drugs due to?
The agents targeting all proliferating cell types
128
What are the side effects of cytotoxic and anti-proliferative agents?
* Cytopenias * GI toxicities * Reduced fertility
129
Give 4 examples of cytotoxic and anti-proliferative agents
* Azathioprine * Methotrexate * Cyclophosphamide * Mycophenolate Mofetil
130
What do azathioprine and methotrexate act on?
Cells in the S phase
131
At what cell stage is cyclophosphamide toxic?
All
132
What does cyclophosphamide predominantly act on?
Active cells *rather than resting*
133
What does Mycophenolate Mofetil do?
*New anti-proliferative agent* that blocks the synthesis of guanine nucleotides
134
What is the advantage of Mycophenolate Mofetil?
It has a degree of selectivity for lymphocytes
135
Why does Mycophenolate Mofetil have a degree of selectivity for lymphocytes?
As proliferating lymphocytes rely heavily on the de nova generation of guanine
136
Give 8 immunological diseases in which cytotoxic drugs are used
* Organ transplant rejection * Rheumatoid arthritis * Systemic lupus erythematosus * Systemic Vasculitis * Wegener's Granulomatosis * Polymyositis * Membranous and membroproliferative glomerulonephritis * Inflammatory bowel disease
137
Give 3 examples of T-cell selective immunosuppressants
* Cyclosporine * Tacrolimus * Rapamycin
138
What is the mechanism of action of cyclosporine and tacrolimus?
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
What is the mechanism of action of rapamycin?
Blocks cellular protein called **mTOR** Inhibits IL-2 production *Also has anti-proliferative effects*
140
What is a potential use for the anti-proliferative effects of rapamycin?
Cancer therapy
141
What is the result of the cyclosporine and tacrolimus, and rapamycin working in different ways?
They can be used together for greater effect
142
What are cyclosporine, tacrolimus and rapamycin widely used in?
The prevention of organ transplant rejection, and in certain T-cell driven autoimmune conditions
143
What cytokines are biological immune response modifiers?
* Interferon-α * Interferon-ß * IL-2 * Granulocyte Colony Stimulating Factor (G-CSF)
144
Give 5 conditions interferon-α can be used to treat
* Chronic Myelogenous Leukaemia * Hairy cell Leukaemia * Follicular lymphoma * AIDS-related Kaposi's Sarcoma * Chronic infections of hepatitis B and C
145
What can interferon-ß be used to treat?
Relapsing, remitting multiple sclerosis
146
What can IL-2 be used to treat?
Metastatic renal cancer
147
How can G-CSF be used clinically?
* Mobilise granulocytes when neutropenia is a problem * Increase bone marrow progenitor cells in the blood for harvesting prior to stem cell transplantation
148
What has systemic administration of a number of cytokines proven to be?
Highly toxic
149
Give a potential toxic consequence of systemic administration of cytokines
Capillary leak syndrome in IL-2 therapy
150
Give two examples of cytokine inhibitors
* Infliximab * Etanercept
151
What do infliximab and etanercept inhibit?
TNF-α
152
What is given in replacement immunoglobulin therapy?
Intravenous immunoglobulin
153
When is replacement immunoglobulin therapy used?
Primary and secondary antibody deficiencies
154
Give 4 diseases where intravenous immunoglobulin has a therapeutic benefit?
* Kawasaki disease * Idiopathic thrombocytopenia * Guillain-Barre syndrome * Chronic Inflammatory Demyelinating Polyneuropathy
155
What are monoclonal antibodies?
Antibodies of a single specificity
156
What produces monoclonal antibodies?
Fusion of an antigen specific B cell clone with an immortalised plasma cell line
157
How are monoclonal antibodies produced?
1. Hyper-immunise mice with an antigen 2. Harvest splenic B-cells 3. Fuse with immortalised plasma cell line 4. Humanise antibodies
158
What is meant by humanising antibodies?
Engineering a human antibody so it contains the antigen specificity of the mouse antibody
159
What are the potential mechanisms of action of therapeutic monoclonal antibodies?
* 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
Give 8 examples of monoclonal antibodies used therapeutically
* Infliximab * Herceptin * Omalizumab * Alemtuzumab * Palivisumab * Basiliximab * Bevacizumab * Rituximab
161
What is the target antigen for infliximab?
TNF-α
162
What diseases is infliximab used to treat?
* Rheumatoid arthritis * Crohn's disease
163
What is the target antigen for herceptin?
Her-2 *(EGF receptor)*
164
What is herceptin used to treat?
Her-2+ Breast cancer
165
What is the target antigen for omalizumab?
IgE
166
What is omalizumab used to treat?
Severe allergic asthma
167
What is the target antigen for alemtuzumab?
CD52 *(most WBCs)*
168
What is alemtuzumab used to treat?
Chronic lymphocytic leukaemia
169
What is the target antigen for palivisumab?
RSV F-protein
170
What is palivisumab used for?
RSV prophylaxis in 'at risk' children
171
What is the target antigen for basiliximab?
CD25 *(IL-2 receptor)*
172
What is basiliximab used to treat?
Organ transplant rejection
173
What is the target antigen for bevacizumab?
VEGF
174
What is bevacizumab used to treat?
Tumour angiogenesis in colorectal cancer
175
What is the target antigen for rituximab?
CD20 *(B-cell)*
176
What is rituximab used to treat?
* B-cell leukaemia/lymphoma * Some severe autoimmune diseases

Z Old Infection IGNORE (23 decks)

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