Hypersensitivity and Autoimmune Disease Flashcards
1
Q
Type I hypersensitivity
A
- Responsible for immediate hypersensitivity typically to allergens
- Role of IgE in type I hypersensitivity, especially with regard to activating mast cell degranulation
2
Q
Type II hypersensitivity
A
- Tissue and cellular targeting by the immune system
- Role of antigen-specific IgG autoantibodies
- Mechanisms of damage induction
- Inflammatory and non-inflammatory mechanisms
- Examples
3
Q
Type III hypersensitivity
A
- Tissues targeted by type III hypersensitivity responses
- Immune complex mediated damage – spontaneity of lesion appearance
- Examples
4
Q
Atopy =
A
predisposition to allergy
5
Q
Autoimmune disease =
A
failure or breakdown of immune system that maintains tolerance to self tissues.
6
Q
Loss of tolerance in autoimmune disease is probably due to
A
abnormal selection or lack of control of self-reactive lymphocytes (B and T-cells).
Damage in different autoimmune diseases may result from different effector mechanisms
7
Q
Autoimmune disease is treated through
A
- Blanket immunosuppression
- Side-effects including infection
- Targeted selective approach – target the aberrant immune activation while leaving the rest of the immune system intact
8
Q
Autoimmune disease: the cost to individuals and society
A
- Estimated that 1 in 20 individuals in the western world suffer an autoimmune syndrome
- Typically chronic long-term disorders [low mortality but high morbidity]
- Treatments limited to dealing with the symptoms rather than curing the disease
- Treatments e.g., steroids carry their own risks
- Patients require intense, careful management and treatment costs run into billions worldwide
9
Q
Type I hypersensitivity steps
A
- Exposure to allergen occurs in the mucosal lining
- Activation of THF stimulation of IgE class switching in B cells.
- Production of IgE
- Binding of IgE to FCERI on mast cells
- Repeated exposure to allergen
- Activation of mast cell causes release of mediators
10
Q
What causes autoimmune disease?
A
No known aetiological agents
11
Q
Hypersensitivity responses
A
- Hyper response from the immune system
- Harmful immune responses that may produce tissue injury and cause serious disease
- 4 categories: Type I, II, III, IV (V)
12
Q
antibody mediated hypersensitivity include
A
Type I, II (V), and III
13
Q
T cell mediated hypersensitivity include
A
type IV
14
Q
Autoimmune diseases usually fall into hypersensitivity
A
Type II, III, and IV categories depending on the type of damage associated with the disease.
15
Q
mediators of type I hypersensitivity and types
A
Vasoactive amines, lipid mediators (histamine)
- targets vascular/smooth muscle - immediate hypersensitivity reaction (minutes after repeat exposure to allergens)
Cytokines
- causes inflammation - late phase reaction (2-4 hours after repeat exposure to allergens)
16
Q
type 1 hypersensitivity can cause
A
Vasodilation
Vascular leak
Broncho-constriction
Inflammation
17
Q
mediators of type I hypersensitivity and types
A
Vasoactive amines, lipid mediators (histamine)
- targets vascular/smooth muscle - immediate hypersensitivity reaction (minutes after repeat exposure to allergens) - IgE mediated effects
Cytokines
- causes inflammation - late phase reaction (2-4 hours after repeat exposure to allergens)
18
Q
type 1 hypersensitivity can cause
A
Immediate reaction
- Vasodilation, - Oedema - Vascular congestion
Late reaction
- Eosinophil - Neutrophil - T cell infiltrates
19
Q
type 1 hypersensitivity occurs when
A
IgE attaches to soluble antigen and causes an allergic reaction
20
Q
type 2 hypersensitivity occurs when
A
IgG attaches to the cell or matrix antigen and causes:
- AIHA
- ATP
- Rheumatic fever
21
Q
type 3 hypersensitivity occurs when
A
IgG binds to a soluble antigen causing:
- SLE
- Rheumatoid arthritis
22
Q
type 4 hypersensitivity occurs when
A
TH1 or TH2 bind to a soluble antigen causing : - inflammatory cytokinesis - chemokines - toxins leading to type 1 diabetes , MS, EA, RA
or CTL can bind to a cell antigen and cause cell death
23
Q
type 5 hypersensitivity affects
A
function rather than causing an inflammatory response.
- Antibody can stimulate receptor without ligand. eg- antibody can bind to a cell causing hormone release
- Antibody can inhibit binding of ligand to receptor. eg- antibody could bind to actylcholine receptors and cause muscles to no contract when needed
24
Q
Difference between type 2 and type 3 hypersensitivity is clear through
A
Light microscopy :
- type 2 is more scattered
- type 3 is more organised
Immunofluorescence:
- type 2 is more stringy and covers minority of cell
- type 3 is more spotty and covers majority of cell
Maybe only type 3 is seen through electron microscopy.
25
Graves disease affects
TSH receptor.
Mechanism of disease:
- Antibody-mediated stimulation of TSH receptors
Manifestation:
- Hyperthyroidism
26
Systemic lupus erythematosus
Target antigen:
- DNA nucleo-protein
Mechanism of disease:
- Complement, FcR mediated inflammation
Manifestation:
Nephritis, arthritis, vasculitis
27
type 4 hypersensitivity basics
Cytokine-mediated inflammation leads to inflammation and then tissue injury
T-cell mediated cytotoxicity causes cellkilling and tissue injury
28
T-cell mediated immunologic disease include:
- Type 1 diabetes
- Rheumatoid arthritis
- Multiple sclerosis
29
T-cell mediated immunologic disease:
| Type 1 diabetes
T cell specificity:
- Islet cell antigens (GAD65, insulin)
Animal models:
- Non Obese Diabetic (NOD) mouse
30
T-cell mediated immunologic disease:
| Rheumatoid arthritis
T cell specificity:
- Joint synovial antigen (Type 2 collagen)
Animal models:
- Collagen induced arthritis
31
T-cell mediated immunologic disease:
| Multiple sclerosis
T cell specificity:
- Myelin basic protein MOG PLP
Animal models:
EAE
32
Are some individuals susceptible to developing autoimmune disease because of their genetic background?
Can you simply catch an autoimmune disease? In other words is the environment you inhabit more important for disease susceptibility than your genetic background?
In virtually all autoimmune diseases it seems to be a bit of both.
33
Twin concordance studies
| If an HLA allele is responsible for an AI then monozygotic twins should
both develop it if prone and its incidence in dizygotic twins should be high.
T1D
monozygotic 35-50%
dizygotic 5-6%
HLA alleles are important but not solely responsible - other unknown environmental and genetic factors have a role in T1D
34
Ankylosing spondylitis HLA molecule
is B27.
| Relative risk is 90-100%
35
Genetics vs. Environment in hypersensitivity
- Genetic background of an individual may pre-dispose them to an autoimmune disease
- Complex, multi-factorial, and by no means the whole story
- there are risk factors that are independent of genetic
background
- Environmental factors
- the most likely by far is prior infection
- Other factors may include drugs, trauma, food
36
Rheumatic fever good evidence of
molecular mimicry:
- Streptococcal A
- Antibodies bind M protein in 2-3 weeks
- Antibodies crossreact withcardiac myosin
- And causes Myocarditis
37
Immunological tolerance =
state of indifference or non-reactivity towards a substance that would normally be expected to excite an immunological response
State of unresponsiveness to specific antigen:
- Antigens can be self or foreign
- Prevents adaptive responses that are damaging (immune pathology) - B cells and T cells
- Can be exploited by microbes and tumours
Pregnancy, transplantation, autoimmune disease and cancer
38
immunological tolerance can lead to
t cells being autoimmune or productive immunity
39
Systemic autoimmune disease
Autoimmune processes diffuse; is spread throughout the body
| Affects more than one organ - not necessarily the same ones in different individuals
40
Organ specific autoimmune disease
Autoimmune process directed against one organ
Type 1 Diabetes - pancreas
Autoimmune Thyroiditis
41
Systemic lupus erythematosus
Relapsing and remitting chronic systemic disease
- Primarily affects women in 20’s - 60’s
- male:female ratio 1:10
- DR2/DR3 HLA risk factor (2-3)
- C2 or C4 complement deficiency seen in 10% of patients
42
glomerulonephritis
Immune complex mediated damage of glomeruli can lead to this disease
43
The lupus erythematosus cell (LE cell) Macrophages engorged with
apoptotic neutrophils
44
Type 1 diabetes
Diabetes arises from a deficiency or inadequate function of insulin
This leads to glucose metabolism abnormalities
- Initially ketoacidosis, thirst, excess urine
- Renal failure, heart disease, blindness, neuropathy
- Destruction of the insulin-producing b cells of the islets of Langerhans in the pancreas
Main therapy - insulin replacement
45
In type 1 diabetes, Islet damage is mediated mainly by
CD4+ Th1 T-cells that are reactive with islet autoantigens
46
In type 1 diabetes, Candidate autoantigens include
insulin and glutamic acid decarboxylase (GAD65)
47
In type 1 diabetes, Early stages of disease
clears signs of necrosis and lymphocyte infiltration (CD4 and CD8)
Autoantibody in blood with specificity for islet cell antigens and insulin
48
Hypersensitivity responses can be defined as
damaging responses produced during normal immune responses
49
Chronic activation can lead to q
autoimmune disease – different effector mechanisms influence the disease phenotype
50
Autoimmune disease =
a failure or breakdown of immune system that maintains tolerance to self tissues
51
Loss of tolerance is probably due to
abnormal selection or lack of control of self-reactive lymphocytes (B and T-cells)
