Immunology Flashcards
1
Q
What does an appropriate immune response respond to?
A
Foreign harmful agents
E.g. viruses, bacteria, fungi, parasites
-> eliminate pathogens (if pathogen has already caused damage, repair quickly)
2
Q
What is the role of antigens in appropriate immune reactions?
A
Involves antigen recognition by cells of immune system
Antibody production
3
Q
What does an appropriate immune tolerance respond to?
A
Self and foreign harmless proteins
E.g. Food, pollens, other plant proteins, animal proteins, commensal bacteria
4
Q
What is the role of antigens in appropriate immune tolerance?
A
Involves antigen recognition and generation of regulatory T cells and regulatory (blocking) antibody (IgG4) production
Ag recognition in absence of ‘danger’ signals-> tolerance
5
Q
What results from antigen recognition in presence/absence of ‘danger’ signals?
A
Ag recognition in absence of ‘danger’ signals-> tolerance
Ag recognition in presence of ‘danger’ signals-> immune reactivity
6
Q
What causes type I immediate hypersensitivity?
A
Anaphylaxis
Asthma
Rhinitis= seasonal/perennial
Food allergy
7
Q
What happens in immediate hypersensitivity?
A
PRIMARY AG EXPOSURE
Sensitisation not tolerance
IgE antibody production
IgE binds to mast cells and basophils
SECONDARY AG EXPOSURE
More IgE Ab produced
Antigen cross-links IgE on mast cells/basophils
Degranulation
8
Q
What are the clinical presentations of Type II antibody-dependent hypersensitivity?
A
Depends of target tissue
Organ-specific autoimmune diseases
Autoimmune cytopenias
9
Q
What are the organ specific autoimmune diseases in Type II antibody-dependent hypersensitivity?
A
ORGAN SPECIFIC AUTOIMMUNE DISEASES
Organ-specific autoimmune diseases
Myasthenia gravis (Anti-acetylcholine R Ab)
Glomerulonephritis (Anti-glomerular basement membrane Ab)
Pemphigus vulgaris (Anti-epithelial cell cement protein Ab)
Pernicious anaemia (Intrinsic factor blocking Abs)
10
Q
What are the autoimmune cytopenias in Type II antibody-dependent hypersensitivity?
A
AUTOIMMUNE CYTOPENIAS (Ab mediated blood cell destruction)
Haemolytic anaemia
Thrombocytopenia
Neutropenia
11
Q
How do you test for specific autoantibodies in Type II antibody-dependent hypersensitivity?
A
Immuno fluorescence
ELISA e.g. anti-CCP (cyclic citrullinate peptide antibodies for rheumatoid arthritis)
12
Q
What happens in Type III immune complex mediated hypersensitivity?
A
Formation of ag-ab complexes in blood
Deposition of these formations in a tissue
Complement and cell recruitment/activation
Activation of other cascades e.g. clotting
Tissue damage (vasculitis)
13
Q
What tissue damage (vasculitis) results from Type III immune complex mediated hypsersensitivity?
A
Systemic lupus erythematosus
Vasculitides (poly artertisis nodosum, many different types)
Renal (glomerulonephritis)
Skin
Joints
Lung
14
Q
What causes Type IV delayed hypersensitivity responses?
A
Chronic graft rejection
GVHD
Coeliac disease
Contact hypersensitivity
Many others:
Asthma
Rhinitis
Eczema
15
Q
What are the three main varieties of Type IV delayed hypersensitivity responses?
A
Th1
Cytotoxic
(Th2)
16
Q
What are the mechanisms of type IV delayed hypersensitivity responses?
A
Transient/persistent ag
T cell activation of macrophages, CTLs
Much of tissue damage dependent upon TNF
17
Q
What does IL-2 act on in type IV delayed hypersensitivity responses?
A
Cytotoxic T lymphocyte (CTL)
18
Q
What does FGF act on in type IV delayed hypersensitivity responses?
A
Fibroblasts-> angiogenesis and fibrosis
19
Q
What often causes type IV delayed-type cell-mediated hypersensitivity?
A
Nickel
Contact hypersensitivity
20
Q
What immune reactants are in Type I, II, III or IV?
A
I= IgE II= IgG III= IgG IV= Th1, Th2, CTL
21
Q
What antigens are in Type I, II, III or IV?
A
I= soluble antigen II= cell-or matrix associated antigen OR cell-surface receptor III= soluble antigen IV= soluble antigen (Th1), soluble antigen (Th2), cell-associated antigen (CTL)
22
Q
What are the common features of type I-IV hypersensitivity?
A
Inflammation
23
Q
What are the features and signs of inflammation in type I-IV hypersensitivity?
A
Vasodilatation, increased blood flow
Increased vascular permeability
Inflammatory mediators and cytokines
Inflammatory cells and tissue damage
Signs= redness, heat, swelling, pain
24
Q
What causes increased vascular permeability (in inflammation due to hypersensitivity)?
A
C3a, C5A, histamine, leukotrienes
25
What cytokines are involved in inflammation due to hypersensitivity?
```
IL-1
IL-6
IL-2
TNF
IFN-y
```
26
What chemokines are involved in inflammation due to hypersensitivity?
IL-8/CXCL8
| IP-10/CXCL10
27
What is the inflammatory cell infilitrate in inflammation due to hypersensitivity?
Cell trafficking- chemotaxis
Neutrophils, macrophages, lymphocytes, mast cells
Cell activation
28
What is the prevalence of atopy in young adults in the UK?
50%
29
How can the severity of allergy vary?
From mild occasional to severe chronic or life threatening anaphylaxis
30
What are the genetic risk factors for atopics?
80% have family hx
Polygenic (50-100 genes)
Genes of IL-4 gene cluster (chr 5) linked to raised IgE, asthma, atopy
Genes of chr 11q (IgE R) linked to atopy and asthma
Genes linked to structural cells linked to eczema (filaggrin) and asthma (IL-33, ORMDL3)
31
What are the environmental risk factors for atopics?
Age (increases from infancy, peaks in teens, reduces in adulthood)
Gender (asthma more common in M children and F adults)
Family size (more common in small families)
Infections (early life infections protect)
Animals (early exposure protects)
Diet (breast feeding, anti-oxidants, fatty acids protect)
32
Which allergies are increasing in prevalence in the UK?
Asthma
Hay fever
Eczema
33
What type of inflammation is in anaphylaxis, urticaria and angioderma?
Type I hypersensitivity (IgE mediated)
34
What type of inflammation is in idiopathic/chronic urticaria?
Type II hypersensitivity (IgG mediated)
35
What type of inflammation is in asthma/rhinitis/eczema?
Mixed inflammation
Type I hypersensitivity (IgE mediated)
Type IV hypersensitivity (chronic inflammation)
36
What do you need to express allergy disease?
Development of sensitisation to allergens instead of tolerance
Exposure to produce disease (memory response= any time after sensitisation)
37
What happens in primary sensitisation to allergens in atopic airway disease?
E.g. in airway disease- antigen is inhaled
In airway lumen, allergen picked up, processed and presented to naive T cells (CD4+) by dendritic cells
Naive T cell then differentiated to form either Th1, Th2 or T-reg cell
(Decision between the 3 pathways of differentiation= not fully understand)
T-reg cells secrete IL-10
Th1 secretes IFN-y
-> both inhibit the differentiation of the naive t-cell into Th2 cells
Th2 cells secrete IL-4 and IL-13 which stimulate the proliferation and differentiation of B cells into plasma cells (which then synthesise and release IgE)
38
What happens on secondary exposure to an allergen in allergic disease?
Memory T cells rapidly differentiate to Th2 cells-> IgE secretion from plasma cells
IgE then binds to IgE Rs on mast cells, cross-linking the Rs, causing mast cell degranulation and release of inflammatory mediators
Th2 also release IL-5 which cause eosinophils to release inflammatory mediators
39
What are eosinophils? Where are they present/ recruited from/ generated? What do they look like?
2-5% of blood leukocytes
Present in blood, most reside reside in tissues
Recruited during allergic inflammation
Generated from bone marrow
Polymorphous nucleus- two lobes
Contain large granules- toxic proteins
Lead to tissue damage
40
What are mast cells?
Tissue resident cells
IgE Rs on cell surface
Cross-linking of IgEs leads to mediator release (preformed: histamine, cytokines, toxic proteins) and newly synthesised leukotrienes and prostaglandins
41
What are neutrophils important in (allergy/atopy)?
Virus induced asthma
Severe asthma
Atopic eczema
42
What are neutrophils?
55-70% of blood leukocytes
Contain several lobes
Granules contain digestive enzymes
Also synthesize:
Oxidant radicals
Cytokines
Leukotrienes
43
What is the immunopathogenesis of asthma?
ACUTE INFLAM OF AIRWAYS
Mast cell activation and degranulation
- Pre stored mediators= histamine
- Newly synthesised mediators= prostaglandins, leukotrienes
Acute airway narrowing
```
CHRONIC INFLAM OF AIRWAYS
Cellular infiltrate (Th2 lymphocytes, eosinophils)
Smooth muscle hypertrophy
Mucus plugging
Epithelial shedding
Sub-epithelial fibrosis
```
44
What happens to the airways in asthma?
Acute airway narrowing
Airway wall edema
Mucus secretion
Vascular leakage
45
What is the two-phase response to single allergen?
Inhaled allergy (0h)
Early response (within 1h)= big reduction in PEF %
Late response (between 4-6h)= reduction in PEF%
46
What are the clinical features of asthma?
Reversible generalised airway obstruction (chronic episodic wheeze)
Bronchial hyper-responsiveness (bronchial irritability)
Cough
Mucus production
Breathlessness
Chest tightness
Response to treatment
Spontaneous variation
Reduced and variable peak flow (PEF)
47
When is wheezing worst in an asthmatic person?
On walking
| When waking up
48
What are the types of allergic rhinitis?
Seasonal- hay fever, tree pollens, grass
| Perennial- HDM, animals
49
What are the symptoms of allergic rhinitis?
Sneezing
Rhinorrhoea
Itchy nose, eyes
Nasal blockage, sinusitis, loss of smell / taste
50
What is allergic eczema?
Chronic itchy skin rash
Flexures of arms and legs
HDM sensitisation and dry cracked skin
Complicated by bacterial and (rarely) viral infections (herpes simplex)
51
What happens to eczema in adulthood?
50% clears up by 7y
| 90% clears up by adulthood
52
What are the common food allergies in infancy-3 years?
Eggs
| Cows milk
53
What are the common food allergies in children/adults?
```
Peanut
Shellfish
Nuts
Fruits
Cereals
Soya
```
54
What are mild food allergy symptoms?
Itchy lips, mouth, angioedema, urticaria
55
What are severe food allergy symptoms?
Nausea, abdo pain, diarrhoea
| Anaphylaxis
56
What is anaphylaxis?
Anaphylaxis: severe generalised allergic reaction
Uncommon, potentially fatal
Generalised degranulation of IgE sensitised mast cells
57
What are the symptoms of anaphylaxis?
Itchiness around mouth, pharynx, lips
Swelling of the lips, throat and other parts of the body
Wheeze, chest tightness, dyspnoea
Faintness, collapse
Diarrhoea and vomiting
Death if severe and untreated
58
What are the systems involved in anaphylaxis?
Cardiovascular- vasodilatation, cardiovascular collapse
Respiratory- bronchospasm, laryngeal oedema
Skin- vasodilatation, erythema, urticaria, angioedema
GI- vomiting, diarrhoea
59
How do you investigate and diagnose allergy?
Careful history essential
Skin prick testing
RAST (blood specific IgE):
- Total IgE
Lung function (asthma)
60
What is the emergency treatment for anaphylaxis?
EpiPen and anaphylaxis kit
antihistamine, steroid, adrenaline
Seek immediate medical aid
61
How is anaphylaxis prevented?
Avoidance of the known allergy
Always carry a kit and EpiPen
Inform immediate family & caregivers
Wear a MedicAlert® bracelet
62
How is allergic rhinitis treated?
Anti-histamines (sneezing, itching, rhinorrhoea)
Nasal steroid spray (nasal blockage)
Cromoglycate (children, eyes)
63
How is ezcema treated?
Emollients
| Topical steroid cream
64
How do you treat very severe allergic rhinitis and eczema?
Anti-IgE
Anti-IL4/13
Anti-IL5 mAb
65
How do you treat asthma?
1. Use short acting β2 agonist drugs as required by inhalation e.g. Salbutamol
2. Inhaled steroid low-moderate dose
- E.g. Beclomethasone/ Budesonide (50-800μg per day)
- Fluticasone (50-400μg per day)
3. Add further therapy
- Add Long acting β2 agonist, leukotriene antagonist
- High dose inhaled steroids - up to 2mg per day via a spacer
4. Add courses of Oral Steroids
- Prednisolone 30mg daily for 7-14 days
- Anti-IgE, anti-IL4/13, anti-IL-5 mAbs
66
How can immunotherapy be used in allergy?
Effective for single antigen hypersensitivities
- Venom allergy - bee or wasp stings
- Pollens
- HDM
- Antigen used is purified
Subcutaneous immunotherapy (SCIT)
- 3 years needed
- Weekly/monthly 2hr clinic visits
Sublingual immunotherapy (SLIT)
- Can be taken at home
- 2-3yrs enough
67
Why do corneas fail?
Degenerative disease, infections, trauma
68
Why do skin/composite organs fail?
Burns, trauma, infections, tumours
69
Why does bone marrow fail?
Tumours, hereditary diseases
70
Why do kidneys fail?
Hypertension, diabetes, glomerulonephritis, hereditary conditions
71
Why do livers fail?
Cirrhosis (viral hepatitis, alcohol, auto-immune, hereditary conditions), acute liver failure (paracetamol)
72
Why do hearts fail?
Coronary artery or valve disease, cardiomyopathy (viral, alcohol), congenital defects
73
Why do lungs fail?
COPD)/emphysema (smoking, environmental), interstitial fibrosis/interstitial lung disease (idiopathic, autoimmune, environmental), cystic fibrosis (hereditary), pulmonary hypertension
74
Why do pancreases fail?
Type I diabetes
75
Why does the small bowel fail?
Mainly children (short gut), hereditary conditions or related to prematurity (in adults- Crohn’s, vascular disease)
76
What are the types of transplantation?
```
Autografts
Isografts
Allografts
Xenografts
Prosthetic graft
```
77
What is an autograft?
Transplant within the same individual
78
What is an isograft?
Transplant between genetically identical individuals of the same species
79
What is an allograft?
Transplant between individuals of the same species (can be deceased and living donor)
80
What is a xenograft?
Transplant between individuals of different species
E.g. heart valves (pig/cow), skin
81
What is a prosthetic graft?
Transplant with plastic and metal
82
Where is a transplanted kidney placed?
Normally right ileac fossa
Below diseased kidneys (normally left in)
83
What are the common transplants by the NHS?
```
Kidney
Pancrease
Cardiothoracic
Liver
Intestinal
```
84
What kinds of organs/cells can be transplanted?
Solid organs (kidney, liver, heart, lung, pancreas)
Small bowel
Free cells (bone marrow, pancreas islets)
Temporary: blood, skin (burns)
Privileged sites: cornea
Framework: bone, cartilage, tendons, nerves
Composite: hands, face, larynx
85
Who are the donors for allografts?
Deceased
- DBD
- DCD
Living
- BM, kidney, liver
- Genetically related or unrelated
86
What kinds of deceased donors are there?
BDB= donor after breath death (heart-beating, brain dead)
- RTA, massive cerebral haemorrhage
- Confirm brain death (can't be reversible)
- Harvest organs and cool to minimise ischaemic damage
DCD= donor after cardiac death (non-heart beating donors)
- Heart stopped before organ harvest
- Longer period of warm ischaemia time
- Suitable for kidney
87
What are the criteria for DBD (heart-beating) deceased donors?
Irremediable structural brain damage of KNOWN cause
```
Apnoeic coma (not due to
depressant drugs, metabolic or endocrine disturbance, hypothermia and neuromuscular blockers)
```
Demonstrate lack of brain stem function (check pupils, cornea, eye movements, CNs, gag reflex, respiratory movements)
88
Which deceased donors are excluded from giving organs?
Viral infection (HIV, HBV, HCV)
Malignancy
Drug abuse, overdose or poison
Disease of the transplanted organ
89
What happens to removed organs to be transplanted?
Removed organs are rapidly cooled and perfused
Absolute maximum cold ischaemia time for kidney 60h (ideally <24h)
Much shorter for other organs (except
cornea 96h, longer with cryopreservation)
90
What is the process of transplant selection (listing)?
Referral of patients to transplantation centres for assessment
MDTs assess suitability for transplantation- eligibility criteria
Patient is placed on the NHS Transplant List
Contraindications
- Too early to be placed on waiting list
- Co-morbidity- medical, psychiatric, surgical (e.g. CV disease, malignancy, compliance)
- Patient does not want a transplant
91
How are transplants allocated?
National guidelines
Evidence based compute algorithm
Time on waiting list (super-urgent transplants supersede)
What is the best use for organ in terms of patients survival and graft survival?
92
What is NHSBT?
NHS blood and transplant
NHSBT monitors allocation
93
After time on waiting list, which factor is most important in choosing who gets an available kidney allograft from a (DBD)?
1. Distance between retrieval centre and transplantation centre
2. Size matching between donor and recipient
3. Sex matching between donor and recipient
4. Tissue matching between donor and recipient (histocompatibility)
5. Age of recipient
6. Good age match between recipient and donor
4. Tissue matching between donor and recipient (histocompatibility)
94
What are the 5 tiers of patients in kidney donation?
Paediatric or adult
| Highly sensitised or not
95
What are the 7 elements in kidney allocation?
```
Waiting time
HLA match and age combined
Donor-recipient age difference
Location of patient relative to donor
HLA-DR homozygosity
HLA-B homozygosity
Blood group match
```
96
How does allocation of donor organs vary nationally and locally?
```
NATIONAL- to individual, ranked patients
Kidneys= DBD donors
Livers= super urgent patients only
Pancreas
Bowel
Heart= urgent patients only
```
```
LOCAL/REGIONAL
Kidneys= DCD donors
Livers= elective patients (+DCD)
Hearts= elective patients
Lungs= all patients
```
97
In England, what proportion of potential donors after brain death without any medical contraindication to donation go on to donate organs?
1. 100%
2. 75%
3. 50%
4. 25%
3. 50%
98
What was the main obstacle to donation (of DBD patients)?
1. Patient not tested for brain death on ICU (organisational failure)
2. Patient confirmed brain-dead; contraindications to use of organ found
3. Family not approached for consent (organisational failure)
4. Family approached but declined consent to donation
4. Family approached but declined consent to donation
99
What are the strategies to increase transplantation activity?
COORDINATION
Bereavement service and family interviews
A&E/ICU involvement for potential donors
DECEASED DONATION
Marginal donors e.g. DCD, elderly, sick
```
LIVING DONATION (increasing, also increased elderly)
Transplantation across tissue compatibility barriers
Exchange programmes: organ swaps for better tissue matching
```
FUTURE
Xenotransplantation
Stem cell research
100
What is the average half-life of a kidney transplant?
1. 2.5 years
2. 5 years
3. 10 years
4. 20 years
3. 10 years
101
What are the most relevant protein variations in clinical transplantation?
ABO blood group
| HLA coded on Chr6 by MHC
102
What does HLA stand for?
Human leukocyte antigens
103
What does MHC stand for?
Major histocompatibility complex
104
What is the ABO blood group?
Way of grouping blood
A and B proteins on RBCs (and endothelial lining of blood vessels in transplanted organ)
Naturally occurring anti-AB antibodies
105
What RBC type, antibodies in plasma and antigens in RBC are present in someone with A blood?
RBC type= A
Antibodies in plasma= Anti-B
Antigens in RBC= A antigen
106
What RBC type, antibodies in plasma and antigens in RBC are present in someone with B blood?
RBC type= B
Antibodies in plasma= Anti-A
Antigens in RBC= B antigen
107
What RBC type, antibodies in plasma and antigens in RBC are present in someone with AB blood?
RBC type= AB
Antibodies in plasma= None
Antigens in RBC= A and B antigens
108
What RBC type, antibodies in plasma and antigens in RBC are present in someone with O blood?
RBC type= O
Antibodies in plasma= Anti-A and Anti-B
Antigens in RBC= None
109
What would happen if a heart from a B donor was given to a patient with blood group A?
Patient serum contains naturally occurring anti-B antibodies (circulate, pre-formed)
Bind to B blood group antigens on donor epithelium
-> Antibody-mediated rejection
110
What does the antibody activate to lead to an immune response in transplants?
Antibody activates complement pathway and macrophages
111
What does ABO-incompatible transplantation involve?
```
Remove the antibodies in the recipient (plasma exchange)
Good outcomes (even if the antibody comes back)
```
Can be done for kidney, heart, liver
112
What is HLA?
Human leukocyte antigens
Cell surface proteins on highly variable portion
Variability= important in defence (against neoplasia and infections)
113
How are foreign antigens recognised?
Foreign protein binds to antigen presenting cell (which has HLA)
T cells see peptides exhibited on a defined framework
If HLA isn't match-> recognised as foreign
114
What are the classes of HLA and where are they expressed?
Class I (A,B,C)= expressed on all cells
Class II (DR, DQ, DP, DM, DO)= expressed antigen-presenting cells but also can be up-regulated on other cells
115
Why is HLA (ABC) described as highly polymorphic?
Lots of alleles for each locus
Each individual has most often 2 types for each HLA molecule
116
How many mismatches can there be in HLA matching?
0-6
117
What effect does minimising HLA differences between donor and recipient on transplant outcome?
Minimising difference-> improved transplant outcome
118
Why is exposure to foreign HLA molecules dangerous?
Exposure to foreign HLA molecules -> immune reaction to the foreign epitopes
The immune reaction can cause immune graft damage and failure -> rejection of organ
119
How can organ rejection be confirmed?
Most common cause of graft failure (why we use immunosuppressive drugs)
Diagnosis= histological exam of graft biopsy
120
What kinds of organ rejection are there?
```
Hyperacute
Acute
Chronic
T-cell mediated
Antibody-mediated
```
121
What happens in T-cell mediated organ rejection?
Graft infiltration by alloreactive CD4+ cells
Cytotoxic T cells
- > Release of toxins to kill target (Granzyme B)
- > Punch holes in target cells (Perforin)
- > Apoptotic cell death (Fas -Ligand)
Macrophages
- > Phagocytosis
- > Release of proteolytic enzymes
- > Production of cytokines
- > Production of oxygen radicals and nitrogen radicals
122
What happens in antibody-mediated organ rejection?
Antibody against graft HLA and AB antigen (anti-HLA antibodies bind to donor HLA antigens)
Antibodies arise
- Pre-transplantation (“sensitised”)
- Post-transplantation (“de novo”)
Involved C4d
123
When does antibody-mediated organ rejection often happen?
After a lot of transfusions, pregnancy or if already had a graft
124
Why is post transplant monitoring for rejection important?
To look for deteriorating graft function
Subclinical
125
What can be used to monitor for deteriorating graft function in organ transplantation (kidney, liver and lung)?
Kidney transplant= rise in creatinine, fluid retention, hypertension
Liver transplant= rise in LFTs, coagulopathy
Lung transplant= breathlessness, pulmonary infiltrate
126
How can organ rejection be prevented?
Maximise HLA compatibility
| Life-long immunosuppressive drugs
127
What do immunosuppressive drugs target?
T cell activation and proliferation
B cell activation and proliferation
Antibody production
128
What does Bortezomib do?
Proteosome inhibitor
Has anti T cell actions but causes plasma cell apoptosis
129
What is the standard immunosuppressive regime?
PRE-TRANSPLANTATION
Induction agent= T cell depletion or cytokine blockade
FROM TIME OF IMPLANTATION
Base line immunosuppression
Signal transduction blockade, usually a CNI inhibitor Tacrolimus or Cyclosporin, sometimes mTOR inhibitor (Rapamycin)
Antiproliferative agent: MMF or Azathioprine
Corticosteroids
```
IF NEEDED (ACUTE REJECTION)
T cell mediated= steroids, anti-T cell agents
Antibody-mediated= IVIG, plasma exchange, anti-CD20, anti-complement
```
130
What are the risks of immunosuppression?
Infection
Tumours
Drug toxicity
131
What are common types of post transplantation infection?
CONVENTIONAL
Increased risk= bacterial, viral, fungal
```
OPPORTUNISTIC
Cytomegalovirus
BK virus
Pneumocytis
Carinii
```
132
Give examples of post transplantation malignancy
Skin cancer (e.g. squamous cell carcinomas)
Post transplant lymphoproliferative disorder (driven by Epstein Barr)
Others
133
What is autoimmunity?
Adaptive immune responses against self (particularly lymphocytes- by autoantigens)
134
How does normal autoimmunity become autoimmune disease?
Genetic and environmental factors
Breakdown of self tolerance
135
What factors cause autoimmune disease?
Genes= twin studies, GWAS (e.g. 40 key loci in SLE)
Sex= women more susceptible
Infections (inflammatory environment)
Diet (obesity, high fat, effects on gut microbiome)
Stress
Microbiome (perturbation may help trigger autoimmune disease)
136
What are the mechanisms of autoimmunity?
Adaptive immune response against self (same as immune against pathogens)
T cell tolerance broken in autoimmune disease
Chronic because always have self tissue
Effector mechanisms (e.g. those of hypersensitivity reactions- type II, III and IV)
137
How many chronic autoimmune disorders have been identified?
About 100
138
What percentage of people have autoimmune disease?
8%
139
What percentage of people with autoimmune diseases are women?
80%
NB. not the case in UC or T2DM
140
What is the hygiene hypothesis?
Study that states a lack of early childhood exposure to infectious agents, symbiotic microorganisms (such as the gut flora or probiotics) and parasites increases susceptibility to allergic diseases by suppressing the natural development of the immune system
141
What are the most important autoimmune diseases?
```
Rheumatoid arthritis
T2DM
MS
SLE
ATD (autoimmune thyroid disease) e.g. Hashimoto's and Grave's
```
142
What is the target of Graves' disease?
Thyroid
143
What is the target of Hashimoto's thyroiditis?
Thyroid
144
What is the target of T2DM?
Pancreas
145
What is the target of Goodpasture's syndrome?
Kidney
146
What is the target of pernicious anaemia?
Stomach
147
What is the target of primary biliary cirrhosis?
Liver, bile
148
What is the target of Myasthenia gravis?
Muscles
149
What is the target of dermatomyositis and polymyositis?
Skin and muscles
150
What is the target of vasculitis?
Blood vessels
151
What is the target of Rheumatoid arthritis?
Joints
152
What is the target of SLE?
Multiple targets
153
How can you describe autoimmune reactions in humans?
Organs affected
Involvement of specific autoantigens
Types of immune response
154
What causes autoimmune haemolytic anaemia?
TYPE II= antibody to insoluble antigen
Autoantibodies against red blood cells
Result in clearance or complement-mediated lysis of autologous erythrocytes
Direct link between autoantibodies and disease
155
What are the 3 main immune reactions known to play a direct role in the pathology of human autoimmune disease?
Antibody response to cellular or extracellular matrix antigen (Type II)
Immune complex formed by antibody against soluble antigen (Type III)
T-cell mediated disease (Delayed type hypersensitivity reaction, Type IV)
156
What happens in autoimmune thrombocytopenia purpura?
TYPE II= antibody to insoluble antigen
Autoantigen= platelet integrin gpIIb:IIa
Leads to abnormal bleeding
157
What happens in Goodpasture's syndrome?
TYPE II= antibody to insoluble antigen
Autoantigen= non-collagenous domain of basement membrane collagen type IV
Leads to glomerulonephritis, pulmonary haemorrhage
Can detect with fluorescent anti-IgG stain
158
What happens in Pemphigus vulgaris?
TYPE II= antibody to insoluble antigen
Autoantigen= epidermal cadherin
Leads to blistering of skin
159
What happens in acute rheumatic fever?
TYPE II= antibody to insoluble antigen
Autoantigen= steptococcal call wall antigens, antibodies cross react with cardiac muscle
Leads to arthritis, myocarditis, late scarring of heart valves
160
What happens in Graves' disease?
TYPE II= antibody to insoluble antigen
Autoantigen= thyroid-stimulating hormone receptor
Leads to hyperthyroidism
161
What happens in Myasthenia gravis?
TYPE II= antibody to insoluble antigen
Autoantigen= ACh R
Leads to progressive weakness
162
What happens to the immune complex in SLE?
SLE
Immune complex deposition in glomerulus
163
What is the main difference between type II and type III immune response?
II= injury caused by anti-tissue antibody e.g. tissue injury (involves neutrophils and macrophages)
III= immune complex-mediated tissue injury e.g. vasculitis (involves neutrophils)
164
What happens in SLE?
Type II= immune complex disease deposited in glomerulus
Autoantigen= DNA, histones, ribosomes, snRNP, scRNP
Leads to glomerulonephritis, vasculitis, arthritis
165
What causes insulin-dependent diabetes mellitis?
Type IV= T-cell mediated
Autoantigen= pancreatic beta cell
Leads to B cell destruction
166
What causes insulin-dependent rheumatoid arthritis?
Type IV= T-cell mediated
Autoantigen= unknown synovial joint antigen
Leads to joint inflammation and destruction
167
What causes MS?
Type IV= T-cell mediated
Autoantigen= myelin basic protein, proteolipid protein
Leads to brain degeneration (demyelination), weakness and paralysis
168
What is the normal T-cell response to antigens?
Antigen presented to T cells by MHC expressed on surface of antigen presenting cells
Leads to proliferation and function
169
How do we know T cells are involved in autoimmune disease initiation?
HLA associations strongly imply a role for T cells in initiating autoimmune disease
170
How can the study of cows provide evidence for the concept of tolerance against self?
Non-identical cow twins have different blood group antigens and so would be expected to react to each others cells and tissues
Adult cattle tolerate blood transfusions from a non-identical twin
They also accept skin grafts from each other
Show tolerance against self
171
Why is timing important in mice studies to show the concept of tolerance against self?
Spleen and marrow cells need to be given from donor to neonate (not adult) to prevent rejection of skin graft
Medawar et al, 1953
172
How can mouse studies show that tolerance has specificity?
Spleen and bone marrow cells given to neonate from mouse 1 as neonate (mouse 2)
Skin graft from mouse 1 rejected when mouse 2 is adult
173
What is immunological tolerance?
Acquired inability to respond to an antigenic stimulus
| 3 As= acquired, antigen specific and active process in neonates
174
How does self tolerance work?
Central tolerance
Peripheral tolerance
- Anergy
- Active suppression (regulatory T cells)
- Immune privilege, ignorance of antigen
175
What happens if self tolerance fails?
Central or peripheral tolerance mechanism fails
| Leads to autoimmune disease
176
What is central tolerance? What cells are involved?
Central tolerance is the mechanism by which newly developing T cells and B cells are rendered non-reactive to self
Lymphoid progenitors make immature B cells and pre T-cells
Pre T-cells to thymus then exported to periphery
B cells- immunoglobulin secreting plasma cells
177
What do T cells recognise?
Peptides presented on MHC in the thymus
T cell can bind strongly to MHC I or II and then destroy it (even if it's self)
178
Does central tolerance fail in autoimmune disease?
Yes in APECED
```
Autoimmune
PolyEndocrinopathy-
Candidiasis-
Ectodermal
Dystrophy
```
179
What is APECED?
Rare autoimmune disease which affects the endocrine glands
Thyroid
Kidneys
Chronic mucocutaneous candidiasis
Gonadal failure
Diabetes mellitus
Pernicious anaemia
180
What causes APECED?
Failure to delete T cells in thymus (so persistence of autoreactive cells)
Due to mutations in TF AIRE (autoimmune regulator) gene
AIRE is important for expression of 'tissue-specific' genes in the thymus
Involved in negative selection of self reactive T cells in thymus
181
What are most autoimmune diseases associated with?
Multiple defects and genetic traits
E.g.
Genes affecting induction of tolerance (B lymphocyte activation: CD22, SHP-1) autoantibody production
Apoptosis (Fas, Fas-ligand): failure in cell death
Clearance of antigen (Complement proteins C1q, C1r and C1s): abundance/persistence of autoantigen
182
Outline T cell selection in the thymus
Dependent on MHC: peptide: T-cell receptor (TCR) interaction
Most cells die by neglect: no or very weak recognition
Negative selection occurs for cells with high affinity TCRs, which die by apoptosis
Surviving cells are MHC-restricted, with low/intermediate affinity for self-peptide
Only 5% survive selection
183
Outline B cell selection in the bone marrow
Crosslinking of surface immunoglobulin by polyvalent antigens expressed on bone marrow stromal cells facilitates deletion
184
When are antigens expressed if not the thymus or bone marrow?
Some may be expressed after immune system has matured
185
What is anergy?
Absence of costimulation
T cells need costimulation for full activation (e.g. by CD80, CD86 and CD40)
Absent on most cells of the body
Without costimulation then cell proliferation and/or factor production does not proceed
Subsequent stimulation leads to a refractory state termed ‘ANERGY’
186
What is immunological ignorance?
Occurs when:
Antigen concentration is too low in the periphery
Relevant antigen presenting molecule is absent (most periph cells are MHC class II negative)
At immunologically privileged sites where immune cells can't normally penetrate (e.g. eye, CNS, PNS and testes)
187
Give an example of failure of immunological ignorance?
Sympathetic opthalmia
Trauma to one eye-> release of sequestered intraocular protein antigens
Released intraocular antigens are carried to lymph nodes and activate T cells
Effector T cells return via bloodstream and attack antigen in both eyes
188
What do autoreactive T cells that don't respond to the autoantigen respond to? Examples
Controlled by other cell types
```
Regulatory T cells:
CD4
CD25
CTLA4
FOXP3
```
189
What is IPEX?
Failure in regulation of peripheral tolerance (accumulation of autoreactive T cells)
Immune dysregulation, Polyendocrinopathy, Enteropathy and X-linked inheritance syndrome
Fatal recessive disorder presenting early in childhood
Mutation in the FOXP3 gene which encodes a transcription factor critical for the development of regulatory T-cells
190
What are the symptoms of IPEX?
```
Early onset insulin Dependent diabetes mellitus
Severe enteropathy
Eczema
Variable autoimmune phenomena
Severe infections
```
191
How can infections affect the tolerant state?
Molecular mimicry of self molecules (activation of T cells)
Activation of APCs
Induce changes in the expression and recognition of self proteins
Induction of co-stimulatory molecules or inappropriate MHC class II expression: pro-inflammatory environment
Failure in regulation : effects on regulatory T-cells
Immune deviation: shift in type of immune response e.g. Th1-Th2
Tissue damage at immunologically privileged sites
192
What does the induction and maintenance of peripheral tolerance depend on?
```
Site of antigen expression (MHC expression, immune privilege)
Timing of antigen expression
Amount of antigen expression
Costimulation
T cell help for B cell responses
Regulation
```
Infections may help break tolerance by a variety of mechanisms
193
What is paraneoplastic cerebellar degeneration (PCD)?
Autoimmune reaction targeted against components of the CNS mostly to Purkinje cells (motor neuron type in cerebellum)
Leads to neurological symptoms e.g. severe vertigo, unintelligible speech, truncal and appendicular ataxia
194
How do cancer and immunology relate?
Certain tumours can express antigens that are absent from (or not detectable in) corresponding normal tissues
The immune system can, in principle, detect these antigens and launch an attack against the tumour
This may result in auto-immune destruction of normal somatic tissues
Also, some people have very small cancers or microscopic colonies of cancer cells (has immune control stopped it?)
Transplantation has lead to melanomas (donors were controlling tumours, recipient can't)
Men have more risk of malignant cancers, women have stronger immune response
Immunosuppression leads to increased malignancy risk
195
What is the main aim of immunotherapy?
Tries to enhance immune responses to existing cancer
196
What is the cancer immunity cycle? What cells are involved?
1. Release of cancer cell antigens (cancer cell death)
2. Cancer antigen presentation (dendritic cells/APCs)
3. Priming and activation (APCs and T cells)
4. Trafficking of T cells to tumours (CTLs)
5. Infiltration of T cells into tumours (CTLs, endothelial cells) (TIL)
6. Recognition of cancer cells by T cells (CTLs, cancer cells)
7. Killing of cancer cells (immune and cancer cells)= IMMUNE SELECTION PRESSURE
197
What usually initiates cancer?
Multiple sporadic events over time
E.g. irradiation, chemical mutagens, spontaneous DNA replication errors, tumour virus-induced changes in genome
198
What happens in cancer?
Cancer initiated
Aberrant regulation of apoptosis and cell cycle results in tumour growth
Tumour growth EVENTUALLY results in inflammatory signals
Innate immunity recruited (dendritic cells, macrophages and NK cells)
Then draining lymphnode
Subsequent recruitment of adaptive, antigen-specific immunity (B and T cells)
199
What are the requirements for activation of an adaptive
| anti-tumour immune response?
Local inflammation in the tumour
Expression and recognition of tumour antigens
200
What are the problems with immune surveillance of cancer?
Takes the tumour a while to cause local inflammation
Antigenic differences between normal and tumour cells can be very subtle
201
What could cancer immunotherapy do?
Can we ‘teach’ the adaptive immune system to selectively detect and destroy tumour cells?
I.e. if spontaneous activation needs not met
202
How do immune responses to tumours have similarities with those infected with viruses?
T cells can ‘see’ inside cells, and can
| recognise tumour-specific antigens
203
What is the function of MHC class I/II molecules?
'Display’ contents of cell for surveillance
| by T cells e.g. infection, carcinogenesis
204
Give examples of proteins that can cause cancer?
VIRAL
Epstein Barr virus
Human papillomavirus
MUTATED CELL PROTEINS
TGF-B receptor II
205
What viruses can cause cancer opportunistically?
Opportunistic malignancies in immunosuppression
EBV-positive lymphoma: Post-transplant immunosuppression
HHV8-positive Kaposi sarcoma: HIV
206
What viruses can cause cancer in immunocompetent individuals?
HTLV1-associated leukaemia/lymphoma
HepB virus- and HepC virus-associated hepatocellular carcinoma
Human papilloma virus-positive genital tumours (tumour cells express viral antigens)
207
How is cervical cancer induced and maintained?
By E6 and E7 (intracellular antigens) oncoproteins of HPV
Tumour cells express viral antigens
208
What is the drug for HPV vaccination?
Gardasil 9
Surface proteins, incorporated into VLPs
209
What is the relationship between consequences of cervical HPV infection and HPV-specific T cell immunity?
HPV16
- Strong immunity-> clearance HPV-infection, immunological memory
- (MINORITY) Immune failure-> cervical neoplasia (no or non-functional immunity)
- Preventative vaccination
210
Explain the concept of tumour-associated antigens giving named examples, and explain how they differ from tumour-specific antigens
Tumour-associated antigens (TAA) derive from normal cellular proteins which are aberrantly expressed (timing, location or quantity)
Because they are normal self proteins, for an immune response to occur tolerance may need to be overcome
211
What are ectopically expressed autoantigens? Example
Expressed where they shouldn't be
Cancer-testes antigens (developmental antigens)= silent in normal adult tissues except male germ cells
MAGE family (associated with melanoma)
212
What is HER2 associated with?
Human epidermal growth factor receptor 2 (HER2): overexpressed in some breast carcinomas
213
What is Mucin 1 (MUC-1) associated with?
Membrane-associated glycoprotein, overexpressed in very many cancers
214
What is carcinoembryonic antigen associated with?
Normally only expressed in foetus/embryo, but overexpressed in a wide range of carcinomas
215
What tumour-associated antigens are associated with prostate cancer?
Prostate-specific antigen (PSA)
Prostate-specific membrane antigen (PSMA)
Prostatic acid phosphatase (PAP)
216
What is tyrosinase?
Differentiation type antigen
Many people have poor self tolerance (not expressed sufficiently in thymus)
Could be useful in immunotherapy (studies carried out for melanoma, accompanied by auto-immune skin depigmentation vitiligo)
217
What are the two major problems of targeting tumour-associated auto-antigens for T cell-mediated immunotherapy of cancer?
Auto-immune responses against normal tissues
Immunological tolerance
- Normal tolerance to auto-antigens
- Tumour-induced tolerance
218
Summarise approaches being used and developed for tumour immunotherapy, including antibody-based therapy, tumour vaccination and immune checkpoint blockade
Antibody-based therapy
Therapeutic vaccination
Immune checkpoint blockade
Adoptive transfer of immune cells
Combinations of above
219
What are the types of monoclonal antibody-based therapy?
Naked e.g. Herceptin (anti-HER2)
Conjugated e.g. to a radioactive particle (zevalin, anti-CD20 linked to yttrium-90) or toxic drug (kadcyla, anti HER2 linked to cytotoxic drug)
Bi-specific antibodies e.g. genetically engineered to combine 2 specificities
220
What is the FDA-approved vaccine to treat cancer?
(Not by NICE, but for sale in UK)
Provenge for advanced prostate cancer
Cytokine that stimulates patients WBCs leading to DC maturation and enhanced PAP-specific T cell responses
221
What is the aim of the immune checkpoint blockade?
Reduce or remove negative regulatory controls of existing T cell responses (rather than directly stimulating new responses)
Targets CTLA-4 and PD-1 pathways
E.g. Ipilimumab (anti CLTA4), Nivolumab (anti PD1)
222
What is adoptive transfer of cells (ACT)?
T cell source (patient)
Non-specific TIL expansion, antigen-specific expansion and genetic engineering
Culture
Expansion
Re-infusion (into patient)
223
What are CARs?
Chimeric antigen receptors are engineered receptors
Graft an arbitrary specificity onto an immune effector cell (T cell)
224
Outline the basic microanatomy of the skin
Stratum cornea
Epidermis
Dermis (papillary, reticular, hypodermis)
Subcutaneous tissue
With sweat glands, sebaceous gland, hair follicle and blood vessels
225
What are the layers of the epidermis?
From superficial to deep
Stratum corneum= dead keratinocytes, at surface these flake off
Stratum lucidum
Stratum granulosum= living keratinocytes
Stratum spinosum= living keratinocytes with dendritic cells
Stratum basale= dividing keratinocyte (stem cell), tactile cell, melanocyte
Dermis= sensory nerve ending
226
Outline the proliferation of keratinocytes
Basal cell
Prickle cell
Granular cell
Keratin
227
Describe the structure of the stratum corneum. What is the function?
Corneocytes and lipids
Important for barrier function of skin
228
What layer of the skin is defective in eczema?
Stratum corneum
229
What gene is commonly mutated in eczema?
Filagrin gene
230
What are the types of eczema?
Atopic
Seborrhoeic
discoid
Allergic contact
231
What is atopic eczema? (Biology and types)
Defective barrier function of the skin-> dry skin
Defective barrier allows penetration of irritants, allergens (dust) and pathogens (s. aureus)-> inflammation of skin
Filagrin gene mutations 10% cases
Common, relapsing and remitting
Very common itchy skin condition (dermatitis)
Onset often within first 6 months of life
Many children will grow out of it
232
What is atopy? Give examples of atopic diseases
Atopy= tendency to develop hypersensitivity
Atopic diseases= eczema, asthma, hayfever
233
What is the atopic march?
The incidence of atopic diseases by age
Eczema and food allergy peak very early (before 5y) and then decline
Asthma peaks later (approx 5y) then slower decline
Rhinitis increases from 5y-10y and slightly declines
234
What factors affect atopic eczema?
INTRINSIC
Defects in epidermal skin barrier e.g. filaggrin gene mutations
EXTRINSIC= penetration of exogenous agents
Allergens, irritant and pathogens
Mast cell degranulation-> releases histamine
235
What immunological components are involved in atopic eczema?
ACUTE
Activation of CD4+ lymphocytes and the TH2 immune response
CHRONIC
Activation of CD4+ and CD8+ lymphocytes and the Th1 immune response
Mast cell degranulation-> releases histamine
236
What is palmar hyperlinearity a sign of?
Filagrin gene mutation
Eczema (and dry skin)
237
Where does infantile atopic eczema occur?
Often on face and areas where baby can rub
| Face also has problem of food spillage
238
Where are the common sites of eczema outbreaks?
```
CHILDREN
Hands, wrists, elbows, forearms
Feet, back of calves and knees
Neck and chest
Cheeks
Scalp
```
ADULTS
Hands, wrists, elbows, upper arm shoulder area
Back of knees
Neck
Face
Also minor on trunk and front of legs (excluding knee)
239
What is lichenification in eczema?
Chronic stratching-> thicken skin (lichenified)
| Skin markings easily seen
240
What is eczema herpeticum?
Virus easily proliferates onto skin in patient with eczema
241
What often colonises severe eczema?
S. aureus colonises eczema everywhere and makes it worse
242
What is seborrhoeic eczema? Where does it occur?
Very common type of eczema affecting babies and adults
Often not itchy
Overgrowth of malassezia species of yeast on the skin with associated skin inflammation
(Commensal so naturally occur but overproliferation leads to reaction between yeast and skin)
Rash has a distinctive distribution including nasolabial folds, eyebrows, scalp, central chest and sometimes axillae and groins
243
What is allergic contact dermatitis?
e.g. Nickel allergy or cosmetics can induce eczema where it is in contact with skin
People with atopic eczema are more likely to develop this
Also commonly to henna or hair dye with black dye (PPD)
Can lead to sensitization which would cause severe local allergic reaction and be permanently sensitized to hair dye
244
What is discoid eczema?
Pattern of eczema in patients with dry skin who have overwashed or been in dry climate -> (dry it out)-> eczema patches look like discs
245
What is psoriasis?
Inflammatory dermatosis
Starts in teens or 40s/50s
Appears as salmon pink plaques
246
What are the types of psoriasis?
Chronic plaque
Guttate
Palmoplantar pustulosis
Generalised pustular psoriasis
30% have psoriatic arthritis too
247
What causes psoriasis?
Genetic susceptibility and environmental triggers
Many genes are implicated including PSOR1
T lymphocytes move out of blood vessels into the dermis and initiate the release of cytokines, e.g. TNFa
Epidermis becomes thickened and produces more keratinocytes than normal, neutrophils infiltrate the epidermis and lymphocytes infiltrate the dermis
Triggers include infections, drugs and stress
248
Outline the histology of psoriasis
```
Hyperkeratosis
Parakeratosis
Acanthosis
Inflammation
Dilated blood vessels
Scales and plaques
```
249
Where do psoriasis lesions usually appear?
```
Scalp
Face
Armpit
Elbows
Trunk
Groin and genitals
Buttocks
Knees
```
250
What are psoriasis vulgaris soles?
Well-demarcated, erythematous plaques with thick, yellowish scale and desquamation
Occur on sites of pressure e.g. plantar feet (similar lesions were present on the palms)
Symmetrical because inflammatory process
251
What can happen to the nail in psoriasis?
Subungual hyperkeratosis (keratinisation under nail)
Dystophic nail
Loss of cuticle
Oncholysis (nail split away from nail bed)
Pitting (holes in nails)
252
What is guttate psoriasis?
Starts with strep sore throat
Genetic susceptibility
Leads to outbreak of psoriasis
253
What is palmoplantar pustolosis?
Neutrophils congrWegate and form pustules
| On hand
254
What is generalised pustular psoriasis?
Widespread involvement of skin
Superficial pustules
Each of these are pustules filled with lots of neutrophils
Fever and malaise, high heart rate
Life threatening (need immunosuppressant)
255
What is acne?
Very common condition which mainly affects teenagers and young adults
Disease of the pilosebaceous unit of the skin
256
What causes acne?
Multifactorial pathogenesis
Hyperkeratinisation of the epidermis in the infundibulum of the hair follicles
Accumulation of dead keratinocytes in the lumen of the hair follicle
Increase sebum production stimulated by androgens
Proliferation of propionibacterium acnes within the pilosebaceous unit
Rupture of the inflamed pilosebaceous unit, with further inflammation of the surrounding skin
```
OTHER
Comedone formation
Genetic predisposition
Propionibacteria acnes
Androgenic stimulation (increased sebum production by sebaceous gland)
```
257
What are the key clinical features of acne?
Open and closed comedones
Papules
Pustules
Nodules and scars on the face, chest and back
258
What is the difference between whiteheads and blackheads?
Whiteheads= closed comedones
Blackheads= open comedones
259
Where is the basement membrane?
```
Between epidermis and dermis
Attaches them (involves anchoring fibrils)
```
NB. Ectoderm-> epidermis and mesoderm-> dermis)
260
What is bullous pemphigoid?
Autoimmune bullous inflammatory condition (causes tense blisters= bullae)
Due to splitting away of epidermis from dermis
Most common in elderly
261
What are the clinical features of bullous pemphigoid?
Intense pruritus
Followed by the development of tense blisters (bullae) on an erythematous background of skin or mucous membranes
Itchhy and distressing
Risk of infections and sepsis without treatment
(Treat with oral and topical steroids)
262
What is the immunological basis of bullous pemphigoid?
IgG autoantibodies to basement membrane antigens BP180 (type XVII collagen) or BP230 result in cleavage of the skin at the dermo epidermal junction leading to sub epidermal blisters
Epidermis splits away from dermis
263
What is epidermolysis bullosa?
Defective proteins attaching dermis and epidermis
Genetic blistering skin disease
Can be mild excess blistering or severe (in babies- held and touched-> shin shearing-> blistering and scarring)
264
What is pempigus vulgaris?
Uncommon autoimmune bullous inflammatory disease
Usually affects middle aged individuals (especially Middle Eastern or Asian)
265
What are the clinical features of pempigus vulgaris?
Flaccid blisters which easily break
| Leave erosions and crusted lesions
266
What is the immunological basis of pempigus vulgaris?
IgG autoantibodies bind to epidermal cell surface proteins desmogleins 1 and 3
Leads to loss of cell-cell adhesion (acantholysis) within the epidermis
Causes flaccid blisters in the skin or mucous membranes
267
What forms the connections between keratinocytes?
Between keratinocyte plasma membranes= desmogleins and desmocollins
Attach in attachment plaque of keratinocyte to plasophilin, plakoglobin and desmoplakin
Also Keratin intermediate filaments within keratinocyte
