Hypersensitivity & Autoimmunity Flashcards
(92 cards)
1
Q
In immune hypersensitivities, the ____ response harms the host rather than helping it.
A
secondary
2
Q
List ten immune cells involved in immune hypersensitivity reactions
A
- Neutrophil
- Basophil
- Eosinophil
- Monocyte
- Macrophage
- Natural Killer Cell (NK)
- Dendritic cell
- Mast cell
- Mature T or B cell
- Plasma cell
3
Q
What is the function of neutrophils in immune hypersensitivity reactions?
A
Phagocytosis and degranulation
4
Q
What is the function of basohils in immune hypersensitivity reactions?
A
degranulation
5
Q
What is the function of eosinophils in immune hypersensitivity reactions?
A
degranulation
6
Q
What is the function of monocytes in immune hypersensitivity reactions?
A
phagocytosis and cytokine production in blood
7
Q
What is the function of macrophages in immune hypersensitivity reactions?
A
phagocytosis, cytokine production in tissues and acting as an antigen presenting cell (APC
8
Q
What is the function of natural killer cells in immune hypersensitivity reactions?
A
Cytolysis and cytokine production
9
Q
What is the function of dendritic cells in immune hypersensitivity reactions?
A
Phagocytosis, cytokine production, acting as an antigen presenting cell
10
Q
Which two cell types have similar functions in phagocytosis, cytokine production and antigen presenting?
A
Macrophages and dendritic cells
11
Q
What is the function of mast cells in immune hypersensitivity reactions?
A
Degranulation and cytokine production
12
Q
What is the function of mature T or B cells in immune hypersensitivity reactions?
A
Adaptive immune responses
13
Q
What is the function of plasma cells (PC) in immune hypersensitivity reactions?
A
B effector cell, antibody production
14
Q
__________ are the primary immune system mediators of most hypersensitivity reactions
A
Antibodies
15
Q
Antibodies have 2 ____ chains and 2 ____ chains
A
2 heavy chains and 2 light chains
16
Q
The light and heavy chains on an antibody are held together by inter-chain _____ bonds
A
disulfide
17
Q
here are __ antigen-binding sites on antibodies
A
2
18
Q
There are/is __ effector function-controlling region(s) on an antibody
A
1
19
Q
List the three types of antibodies covered in this course
A
- IGM
- IGG
- IGE
20
Q
How many V regions are there on an immunoglobulin and how are they formed?
A
2 - formed by pairing the Vh and VL domains
21
Q
The V and C domains are based on a shared building block called the ___ domain on an immunoglobulin molecule
A
Ig
22
Q
Physical rigidity due to _____ residues in the hinge region of immunoglobulin
A
Proline
23
Q
Flexibility due to _____ residues in immunoglobulin
A
Glycine
24
Q
There are a total of __ possible heavy chain isotypes which determine the heavy chain isotype of Ig molecules
A
5
25
During primary response, cells produce Ig_
IgM
26
IgM is converted into different isotypes by changing _________ isotypes
heavy chain
27
Which antibody is involved in type I immune hypersensitivity reactions?
IgE
28
Which antibody is involved in type II immune hypersensitivity reactions?
IgG, IgM
29
Which antibody is involved in type III immune hypersensitivity reactions?
IgG, IgM
30
Which antibody is secreted in a pentamer (5 molecule) form?
IgM
31
Which antibodies are secreted in a monomer (one molecule) form?
IgG, IgE
32
FC receptors are found on which cells?
Leukocytes
33
What do FC receptors bind?
The Fc region of Ig molecules on antigens
34
IgE has which Fc region?
FcɛR
35
IgG has which Fc region?
FcγR
36
What are other names for type 1 hypersensitivity? (4)
1. IgE-mediated hypersensitivity
2. Immediate hypersensitivity
3. Allergy
4. Atopy
37
What is the primary immune system mediator for type 1 hypersensitivity, and the time to symptoms?
IgE - <1-30 minutes
38
What is the other name for type 2 hypersensitivity?
Direct antibody-mediated cytotoxic hypersensitivity
39
What is the other name for type 3 hypersensitivity?
Immune complex-mediated hypersensitivity
40
What is the primary immune system mediators for type 2 hypersensitivity, and the time to symptoms?
IgG or IgM - 5 to 8 hours
41
What is the primary immune system mediators for type 3 hypersensitivity, and the time to symptoms?
IgG or IgM - 4 to 6 hours
42
What is the mechanism of type 1 hypersensitivity?
Allergens cross-link IgE bound on mast cells and basophils, inducing degranulation
43
What is the mechanism of type 2 hypersensitivity?
IgG or IgM bind to cell-bound antigen - cell is destroyed either by:
1. Phagocytosis
2. Complement activation
3. ADCC
44
What is the mechanism of type 3 hypersensitivity?
Immune complexes trigger complement activation
Phagocyte FcR engagement leads to release of lytic mediators
45
Give examples of type 2 hypersensitivity reactions
1. Hemolytic anemias
| 2. Goodpasture's syndrome
46
Give examples of type 3 hypersensitivity reactions
1. Arthus reaction
2. Aspects of rheumatoid arthritis
3. Aspects of systemic lupus
4. Erythematosus (SLE)
47
Describe the sensitisation stage of type 1 hypersensitivity (10)
1. Allergen breaches tissue barrier
2. Allergen phagocytosed by immature dendritic cell
3. Immature dendritic cell travels to lymph node
4. Mature DC presents antigens which are recognised by naive T cells which then become activated and differentiate into Th2 effector cells that help activate B cells
5. Activated T and B cells leave the lymph node and travel to where allergen entered body
6. Th2 cells produce cytokines 4,5,13 that instruct plasma cells to produce IgE
7. IgE binds directly to allergens or to FcɛRs on mast cells - mast cells sensitised in the effector stage
8. Excess IgE taken up by lymphatics
9. IgE encounters basophils in the blood and binds to FcɛRs to sensitise them
10. IgE encounters mast cells in other tissues and binds to FcɛRs to sensitise them
48
Describe the effector stage of type 1 hypersensitivity - early phase reaction (6)
1. Allergen enters tissue where sensitised mast cells are present
2. Allergen binds IgE molecules attached to mast cells via FcɛRs
3. Mast cells degranulate and secrete cytokines/chemokines
4. Breakdown of mast cells releases PAF
5. Tissue-specific symptoms of allergic response occur
6. Additional leukocytes recruited (e.g eosinophils and sensitised basophils)
49
Describe the effector state of type 1 hypersensitivity - late phase reaction (4)
1. Leukocytes recruited
2. Th2 effector cells, activated mast cells and basophils produce cytokines that promote eosinophil recruitment and activation of eosinophils
3. Cross-linking of Ig-bound FcRs with allergen results in the release of mediators from eosinophils and basophils that promote tissue damage
4. Recruited neutrophils and macrophages release inflammatory mediators that result in tissue destruction
50
List 4 genes that influence susceptibility to allergic asthma
1. PAMP
2. PRR
3. SMAD3
4. TSLP
51
List 5 therapies for type 1 hypersensitivity and how they function
1. Antihistamines - bind histamine receptors on target organs
2. Lipoxygenase antagonists - block production of leukotrienes from innate immune cell membranes
3. Bronchodilators - block mast cell degranulation and promote smooth muscle relaxation
4. Corticosteroids - inhibit cytokine production
5. Anti-IgE immunotherapy - therapeutic mAbs that bind human IgE to reduce free IgE
52
IgG and IgM are good activators of the _____ complement pathway
classical complement pathway
53
The classical complement pathway leads to ___ formation
MAC
54
Anaphylatoxins produced from the classical complement pathway include:
C3a, C4a, C5a
55
Describe the process of immune complex-mediated hypercensitivity (aka type 3 hypersensitivity)
1. Antibody binds antigen in the blood (immune complex)
2. Insoluble immune complexes form by cross-linking that lodge in small vessels
3. Immune complexes enter tissues (kidneys, joints) and drives local inflammation/tissue damage
56
Describe the process of immune complex deposition in the kidneys (5)
1. Platelets/basophils induced to release vasoactive mediators which increases vascular permeability
2. Small immune complexes pass through
3. Large immune complexes attach to the basement membrane
4. Platelets aggregrate, forming microthrombi which attracts neutrophils
5. Frustrated phagocytosis where the neutrophil fails to phagocytose and instead deposits granules, resulting in basement membrane damage.
57
List the four mechanisms of tolerance
1. Clonal deletion (central tolerance)
2. Clonal regulation (peripheral)
3. Suppression (peripheral)
4. Ignorance
58
What is the purpose of central tolerance?
Process by which T cells are selected for in the thymus - prevents production of autoreactive B and T cells
59
Describe the process of positive selection in central tolerance
Lymphocytes are positively selected based on their affinity of interaction with the self MHC complex expressed on cortical epithelial cells - a T cell that does not recognise self at all will undergo "death by neglect" - apoptosis
60
Describe the process of negative selection in central tolerance
Thymic epithelial cells express extra-thymic antigens (ie antigens normally expressed by other organs)
Lymphocytes are negatively selected based on their affinity of interaction with self antigen-MHC complexes presented by dendritic cells and thymic epithelial cells at the cortical/medullary junction
A T cell which receives very strong signals (autoreactive) will undergo apoptotic death - killed by dendritic cells and bone marrow derived macrophages
However, some weakly autoreactive cells escape
61
Most thymocytes bear TCRs that fail to bind self _____ or do so very weakly - constitute around 80% of population
pMHC
62
Thymocites with TCRs that bind strongly to self pMHC are removed by ______ selection - constitute around 20% of population
negative
63
Positive selection preserves a total of around _ - _% of T cells
1-2%
64
A T cell which receives a "weak signal" will survive and be selected to become an _______ cell (e.g CD4+ or CD8+ T cell)
effector
65
A T cell which interacts with self antigen-MHC complexes expressed on medullary epithelial cells, and receives and "intermediate signal" (potentially autoreactive" becomes a _____________ cell, an immunosuppressive cell.
natural T regulatory cell (nTreg)
66
What is the purpose of nTreg cells?
Suppression of autoreactive lymphocytes
67
If Tregs are deleted, what will result?
Autoimmunity
68
Describe the process of B cell central tolerance (4)
1. B cell precursor rearranges its immunoglobulin genes - generation of B-cell receptors in the bone marrow
2. Negative selection in bone marrow - immature B cell bound to self antigen is removed
3. B cell migration to peripheral lymphoid organs - mature B cell bound to foreign antigen becomes activated
4. Antibody secretion and memory cells in bone marrow + lymphoid tissue - activated B cells gie rise to plasma cells and memory cells
69
Describe the process of naive Th cell activation (6)
1. TCR on naive Th cells bind antigenic peptide displayed on MHC class II molecules on dendritic cellls
2. Signals sent to nucleus and CD40L is upregulated on Th cells - binding of CD40 on dendritic cell, leading to upregulation of B7 molecule on dendritic cell
3. Signal 2 sent to Th cell nucleus when B7 molecules bind costimulatory CD28 on the Th cell
4. Th cells express IL-2 and its receptor
5. IL-2/IL-2R signalling results in a 3rd signal to Th cell nuclus
6. Th cell now activated and proliferates to generate Th effector cells
70
Describe the process of B cell activation by antigen (4)
1. Signal 1 delivered following antigen binding to surface B cell receptor (BCR)
2. Antigen bound to the BCR complex is internalised/processed to generate peptide-MHC class II complex that binds TCRs
3. CD40L binds to CD40 on B cell, resulting in costimulatory signal 2 to induce cytokine receptor expression
4. Cytokines expressed by Th cell bind receptors on B cell, leading to signal 3 and B cell activation
71
What are the 4 requirement for an autoimmune disease to occur?
1. Escape of autoreactive clones from thymus
2. Autoreactive clones encounter self-antigens
3. Peripheral tolerance failure
4. Autoreactive tissue damage
72
What are autoantibodies?
Antibodies that recognise self-antigen
73
Are autoantibodies common?
Yes - natural autoantibodies are common
74
What are sequestered antigens? What happens if they are released?
A self-antigen not ordinarily available for recognition by the immune system, such as of the eyes or sperm. Release via trauma or infection could mean the body treats them as foreign and launches an autoimmune attack
75
Give two examples of pathogenic sequestered antigen release
1. Sympathetic Ophthalmia - damage to eye exposes hidden antigens and causes immune damage to good eye
2. Autoimmune Orchitis - damage to testicle by trauma or mumps exposes hidden antigens and causes immune damage to good testicle
76
Type __ hypersensitivity is organ specific, whilst type __ hypersensitivity is systemic
Type II hypersensitivity is organ specific, whilst type III hypersensitivity is systemic
77
Give an example of pathological molecular mimicry and the process behind it (4)
Acute rheumatic fever
1. Group A streptococcal post-infection complication
2. M proteins share epitopes with proteins in synovium, heart muscle and heart muscle
3. Antibody-mediated type II hypersensitivity generates tissue damage and inflammation
4. Arthritis, heart valve damage
78
List 5 types of organ-specific autoimmunity
1. Goodpastures Syndrome
2. Myasthenia Gravis
3. Pemphigus
4. Idiopathic Thrombocytopenic Purapura (ITP)
5. Addisons Disease
79
Describe goodpastures syndrome and what causes it
Organ-specific autoimmunity - antibodies against type IV collagen in basement membrane (glomeruli, alveoli)
- kidney dysfunction, bleeding in lungs
80
Describe Myasthenia Gravis and what causes it
Antibodies block acetylcholine receptors
| - muscle weakness
81
Describe Pemphigus and what causes it
Antibodies against intracellular adhesion molecule (desmogleins) between keratinocytes
- blisters
- can lead to fatal infections
82
Describe Idiopathic Thrombocytopenic Purapura (ITP) and what causes it
Antibodies against platelets
| - increased tendency to bleed
83
Describe Addisons Disease and what causes it
Destruction of adrenal cortex, decrease in steroid hormones
84
List two thyroid autoimmune diseases
1. Graves disease
| 2. Hashimoto's disease
85
What is Graves disease?
Autoantibodies bind the thyroid-stimulating hormone receptor
| - acts as agonist = hyperthyroidism
86
What is Hashimoto's disease?
Autoantibodies against thyroglobulin and thyroid peroxidase
- complement activation and cytotoxic T cell driven attack
- hypothyroidism
87
List 3 types of systemic autoimmune diseases and where they occur
1. Kidneys - glomerulonephritis
2. Skin - rash
3. Joints - arthritis
88
Describe systemic lupus erythematosus (SLE)
- Inflammation in skin, joints, blood vessels, kidneys - widespread
- photosensitivity ("light allergy")
- Antinuclear autoantibodies (ANA) - anti DNA, anti RNA, anti nuclear proteins
89
How does Systemic Lupus Erythematosus (SLE) occur?
1. Nucleosomes from apoptotic cells
2. Defective clearance
3. Activated histone-specific T cells provide help to activate anti-DNA specific B cells
4. Immune complexes form
5. Bind heparin sulfate in glomerular basement membrane
90
Treatments for autoimmune diseases are split into either _____ or _____
replacement or suppression
91
Describe the three replacement treatments
1. Type 1 diabetes - replacement of insulin
2. Hashimotos - thyroxine replacement
3. Addisons - glucocorticoid and mineralocorticoid replacement
92
Describe the two suppression treatments
1. Systemic Lupus Erythematosus (SLE) - immunosuppressive drugs
- corticosteroids
- azathioprine
- cyclophosphamide
2. Rheumatoid Arthritis - immunosuppressive drugs
- corticosteroids
- anti-inflammatory drugs (NSAIDS)
- anti-TNF and anti IL-1 antagonists
