Immunology Flashcards
1
Q
Define allergic disorder
A
Immunological process that results in immediate and reproducible symptoms after exposure to an allergen
2
Q
What type of hypersensitivity reaction is allergy usually
A
Type 1 IgE mediate
3
Q
Define sensitisation
A
Detection of specific IgE to an allergen either by skin prick or in vitro blood test
- Determines risk of allergic disorder but not synonymous with clinical symptoms of allergy
4
Q
Which is more common, allergic disease or sensitisation
A
Sensitisation
10% population has detectable IgE against peanuts but ~2% have peanut allergy
5
Q
Th response to parasites, worms, allergens or venoms
A
Functional feature recognition (e.g. protease release and damage of epithelial surfaces)
–> Th2 immune response
6
Q
Th response to microbial structures (bacteria, viruses and fungi)
A
PAMPs (structural feature) recognised by TLR on dendritic cells and macrophages
–> Th1 + Th17 response
7
Q
Th1 response
A
Characterised by INF gamma or Il-2
8
Q
Mechanism that follows epithelial cell damage by allergen/worms/venom
A
Epithelial cells secrete signalling cytokines (IL-1a, -15, -33 & TSLP)
- -> Cytokines act on lymphocytes (Th2, Th9 and innate lymphoid cells)
- -> Lymphocytes secrete effector cytokines (IL-4, 5, 9, 13) = signature Th2 cytokines
- -> Effector cytokines communicate with effector cells (eosinophils and basophils) to expel allergen/worm
Signalling cytokines also act on Tfh2
- -> Tfh2 secretes IL-4 and IL-21
- -> Il-4, 21 act on B cells to help make antibodies (IgE and IgG4)
9
Q
Single tier system of immune system where sensor cells mediate effector arm of immune system
* Biological and drug targets in allergic disease
A
Cross linking of IgE receptor by allergen causes mast cell to release mediators which act on target cells (leaky endothelium, smooth muscle contraction, itching of skin /nasal cavity) to expel allergen and restore epithelial barrier
- Histamine*
- Leukotrienes*
- Prostaglandins
- Proteases
10
Q
Oral route vs skin - effect on immune tolerance
A
Oral: Treg cells secreting Il-10. Il-10 stimulates IgG. Treg cells derived from GI mucosa inhibit IgE synthesis to keep immune system balance
Skin: Disrupted skin barrier (atopic dematitis, fillagrin mutation) –> allegen accesses dermis. Dendritic cell in dermis tells T cells to secrete Il-4 and other type 2 cytokines –> IgE antibody.
(Important in allergic march)
11
Q
Causes of allergic disorder rise
A
Hygiene hypothesis
Lack of vitamin D in infants
Diet (lack of omega and linoeic fatty acids, delayed introduction of peanuts and eggs)
High conc of dietary advanced glycation end products and proglycating sugars (immunes system mistakes as causing tissue damage)
12
Q
Clinical features of IgE response
A
Minutes - 3hrs after exposure to allergen
Skin: angioedema, urticaria, flushing, itching
Resp: cough, SOB, wheeze, congestion, red watery itchy eyes
GI: Nausea, vomiting, diarrhoea
CNS and vasc: Hypotension, sense of doom
AT LEAST 2 organs involved usually
REPRODUCIBLE
Clinical hx to select what allergen should be tested by skin prick/blood test
13
Q
Allergic disease tests separated by elective or in acute episode
A
ACUTE
- Serum mast cell tryptase levels
ELECTIVE
- SKin prick tests
- Lab measurement of allergen specific IgE
- Component resolved diagnostics
- Challenge test
14
Q
Skin prick test
What is result of a positive test?
Prior to test what meds should be stopped and why?
A
Use standard skin test solution and POSITIVE CONTROL (histamine) and NEGATIVE CONTROL (diluent)
- Measure local wheal and flare response to controls and allergens
Positive test = >3mm than -ve control
Stop antihistamines 48hrs before
15
Q
Why use -ve control in skin prick tests and what is used
A
To check there isn’t spontaneous mast cell activation and granule release e.g. in dermatographism
16
Q
CI to skin prick test
A
Do not perform if RECENT ANAPHYLAXIS
Bloods instead
17
Q
Advantages of skin prick tests
A
High -ve predictive value
Size of wheals correlates with higher probability for allergy
Rapid
Cheap and easy
18
Q
Serum specific IgE blood test indication
A
Can't stop antihistamines Dermatographism Extensive eczema Hx of anaphylaxis Borderline skin prick tests
19
Q
Serum specific IgE blood test method
A
Allergen bound to sponge
Add patients serum
Fluorescently tagged Anti-IgE antibody added
Amount of IgE/anti-IgE measured by fluorescent light
20
Q
Advantages of serum specific IgE blood test
A
Conc of specific IgE can be used to preduct which children may outgrow allergy and should be given oral food challenge
V goof negative predictive value (but lots of false +ve)
Higher values more likely to be associated with allergic disorder so can triage pts who don’t need oral food challenge
21
Q
Component resolved diagnostics (CRD)
Method and use
A
Blood test to detect IgE to single protein component
- For peanut and hazelnut alleger
SEED STORAGE peanut and hazelnut allergen components target heat and proteolytic STABLE protein and usually with SEVERE allergic reaction
(opposite for birch pollen homologue)
22
Q
Criteria for anaphylaxis diagnosis
A
Anaphylaxis is highly likely when any 1 of the following 3 criteria are fulfilled:
- Acute onset of an illness (minutes to hours)
Involvement of SKIN , MUCOSAL TISSUE OR BOTH, (i.e., generalised hives, pruritus, or flushing, swollen lips-tongue-uvula) and at least 1 of the following: RESP COMPROMISE (i.e., dyspnoea, wheeze-bronchospasm, stridor, reduced peak expiratory flow [PEF], hypoxaemia) or REDUCED BP OR ASSOCIATED SYMPTOMS (i.e., hypotonia/collapse, syncope, incontinence) - Occurrence of 2 or more of the following symptoms or signs after exposure to a likely allergen (minutes or hours)
Involvement of skin, mucosal tissue, or both (i.e., generalised hives, pruritus, or flushing, swollen lips-tongue-uvula)
Respiratory compromise (i.e., dyspnoea, wheeze-bronchospasm, stridor, reduced PEF, hypoxaemia)
Reduced BP or associated symptoms of end-organ dysfunction (i.e., hypotonia/collapse, syncope, incontinence)
Persistent GI symptoms (i.e., crampy abdominal pain, vomiting)
Reduced BP after exposure to a known allergen (minutes to several hours) - Systolic BP of <90 mmHg or >30% decrease from baseline.
23
Q
Mechanism of IgG anaphylaxis
+ Examples
A
Macrophages and Neutrophils
Mediators: Histamine and PAF
Caused by: Biologics, Blood and IgG transfusions
Often requires large quantities of the allergen or systemic introduction
24
Q
How do neuromuscular drugs, quinolones , opiates and NSAID induce anaphylaxis
A
Act on specific MAST CELL receptor
Mediators: Leukotriene + Histamine
25
Conditions that can mimic anaphylaxis
```
Chronic urticaria, angioedema (ACEi)
MI, PE
Severe asthma, vocal cord dysfunction, inhaled FB
Anxiety/panic disorder
Carcinoid and phaeochromocytoma
Scromboid toxicity
Systemic mastocytosis
```
26
Treatment of anaphylaxis
1. IM Adrenaline outer thigh (300microgram adult dose, 150 child)
2. Adjust body position
3. 100% Oxygen
4. Fluid replacement
5. Inhaled Bronchodilators
6. Hydrocortisone (100mg IV) to prevent late response
7. Chloropheniramine 10mg IV for skin rash
27
Mechanisms of anaphylaxis treatment
a1 receptor: Peipheral vasoconstriction to reverse low BP and mucosal oedema
B1 receptor : Increase HR, contractility, BP
B2 receptor: Relax bronchial smooth muscle and reduce inflammatory mediator release
28
After acute management of anaphylaxis
Refer to allergy/immunology clinic
Investigate cause
Written sheet on: Recognising symptoms, avoiding triggers, indications for emergency self treatment with EpiPen
Prescribe emergency kit to manage
Copy of management plan and training for patient, carers, school staff and GP
Utilise support groups
Encourage to acquire a Medic Alert braclet
29
Food allergy
vs
Food intolerance
Specific immune response that occurs reproducibly on exposure to a given food
vs
Non immune reactions which include metabolic, pharmacological and unknown mechanisms
30
Food allergy types
IgE Mediated (anaphylaxis, OAS)
Mixed IgE and cell mediated (atopic dermatitis)
Non IgE mediated (coeliac)
Cell mediated (contact dermatitis on exposure)
31
Important risk factor for food allergy
| - allergy test even in absence of clinical hx
Moderate/severe atopic dermatitis
32
Managing food allergy
1. Avoid
2. Emergency management
3. Prevention
33
IgE mediated food allergy syndromes
1. Anaphylaxis
- Peanut, tree nut, shellfish, milk and eggs most common
2. FOOD ASSOCIATED EXERCISE INDUCED ANAPHYLAXIS
- If exercise within 4-6hrs of ingestion
- comonl wheat, shellfish, celery
3. DELAYED FOOD INDUCED ANAPHYLAXIS TO BEEF, PORK, LAMB
4. ORAL ALLERGY SYNDROME
- limited to oral cavity, swelling and itch
- Onset after pollen allergy established
- Commonly stone fruits, veg, nuts (but not if cooked - heat labile agents detected by component allergen test)
34
Which infectious disease kills the most people world wide
HIV
35
What is HIV-1
Retrovirus
Genes composed of RNA molecules
Primarily infects immune system cells causing immunodeficiency and AIDS
36
How does HIV replicate
Intracellular using RT to convert RNA into DNA which is integrated into host cell's genes
37
Organisation of HIV-1 virion
Co receptor
Receptor on cell wall which facilitates entry
Antigen for non-neutralising antibodies
Target for drugs that inhibit an enzyme that breaks down proteins
Retrovirus with CD4 T cells as preferred host targets angtigen
Co receptor = CXCR4/CCR5
Receptor on cell wall which facilitates entry - gp120
Antigen for non-neutralising antibodies - p24 gag IgG
Target for drugs that inhibit an enzyme that breaks down proteins - protease
38
Phases of immune response to transplanted graft
1. Recognition of foreign antigen
2. Activation of antigen specific lymphocytes
3. Effector phase of graft rejection - activated lymphocytes cause organ damage and rejection
39
Most relevant proteins variations in clinical transplantation
1. ABO blood group
2. HLA (coded on chr 6 by MHC)
Also are minor histocompatibility genes
40
2 major components to rejection
```
T cell mediated
Antibody mediated (B cells)
```
41
What is HLA and it's role
human leukocyte antigen
Are cell surface proteins
Presentation of foreign antigens on HLA molecules to T cells (to activate T cells)
42
HLA classes and variability
Class 1: A, B, C
- Expressed on all cells
Class 2: DR, DQ, DP
- Expressed on APC but also can be up-regulated on other under stress
HIGHLY POLYMORPHIC (variable) as 100s of alleles for each locus (everyone has 2)
43
Problem with HLA in transplant
Variability in HLA molecules in the population provides a source for immunisation against the transplanted organ
44
HLA structure
```
alpha and beta chains
class 1: 3 alpha, 1 beta
class 2: 2 alpha, 2 beta
```
Both have a peptide binding groove (area of high variability concentrated here)
45
How many potential HLA molecules on your cell surface
12
DR, DQ, DP, A, B, C
1 copy from each parens
46
Which HLA types used in transplant and why.
A, B and DR because most variable, most immunogenic
Mismatches expressed as minimum
0:0:0
to maximum
2:2:2
47
Mechanism of T cell mediated rejection
Phase 2 - T cell activation by foreign antigen (presented through MHC to CD3 receptor)
--> specific T cells activated
--> Produce Il-2
Cytokines stimulate activation and proliferation of T cells
48
What happens when a T cell is activated?
| transplant lec
```
Proliferate
Produces cytokines (IL-2)
Helps activating CD8+ T cells
Helps antibody production
Recruits phagocytic cells
```
49
Which APC is involved in activating T cells in transplant mediated rejection?
Where does this occur?
Both donor and recipient
Some in grafted organ
A lot in lymph nodes (by circulating naive T cells) - Will come into contact with APC, mount immune reaction against epitope being presented, become activated. T cells re-enter the circulation and hone to the graft - 3rd phase with organ damage.
50
Cells involved in T cell mediated rejection
| Their mechanism of action
CD4+ T cells:
- graft infiltration by alloreactive T cells
Cytotoxic T cells (CD8+):
- Release toxin to kill target
- Granzyme B
- Punch holes in target cells
- Perforin
- Apoptotic cell death
- Fas-ligand
Macrophages
- Phagocytosis
- Release proteolytic enzymes
- Produce cytokines
- Produce oxygen radicals and nitrogen radicals
51
Phages of antibody-mediated rejection
1. Exposure to foreign antigen
2. Proliferation and maturation of B cells with antibody production
3. Effector phase; antibodies bind to graft EPITHELIUM
52
Antibody mediated rejection in kidneys.
Microcirculation gets lined with antibodies - injury to microcirculation. (capillaries of glomerulus and around tubules, arterial)
53
Which auto-antibodies are important in rejection and which are naturally occurring?
Anti-A or anti-B - naturally occurring
| Anti-HLA - not naturally occurring
54
Complement role in rejection
| Which type of rejection
Recruited to site of antibodies
Cause phagocytosis or lysis
C3a and C5a recruit lots of inflammatory cells
In antibody-mediated rejection
55
Prevention and treatment of graft rejection
Prevent
- AB/HLA matching
- Screening for anti-HLA antibodies
- Immunosuppression: dampen the immune system of recipient
Treating
- More immunosuppression
56
Important to consider with immunosuppression in rejection
Balance need with risk of infection, malignancy, drug toxicity
57
AB/HLA matching
In who
How
Important for which organ transplants
For all organ transplants
Encourage living donation from blood relatives
PCR-based DNA sequence analysis (of HLA allele sequence)
Kidney and Bone marrow
Not so much for heart and lung
58
Screening for antibodies in transplantation
Types of assays
Before
At time of transplant
After transplant - repeat to check for new antibody production regularly
1. Cytotoxic assay
2. Flow cytometry
3. Solid phase assays - most common - refined read out of different epitopes and intensity for each
59
Treatment of rejection
T cell mediated rejection options
1) Steroids
2) Calcineurin inhibhitors e.g. cyclosporine + tacrolimus
3) Cell cycle inhibition e.g. azathioprine and mycophenolate mofetil
4) Monocolanal antibodies against CD3 T cell receptor e.g. antithymocyte globulin, OKT3
5) Alemtuzumab
6) Daclizumab against CD25 (the Il-2 receptor)
60
Calcineurin inhibitors mechanism of action
Examples
Uses
Immune suppression - preventing interleukin-2 (IL-2) production in T cells.
Cyclosporine, Tacrolimus
61
Treatment of rejection
Antibody-mediated rejection options
1) Plasma exchange (physically remove antibody from circulation)
2) Anti-CD20 (rituxumab)
3) Target cytokines that promote B cell activation and growth (palivizumab)
4) Proteosome inhibitors
5) Complement inhibitors
62
Transplant immunosuppression
| Summary
Induction agents
Baseline agents
Treatment of acute rejection
63
Indications from HSC transplant
Haem and lymphoid cancers
| Acquired or inherited deficiencies in marrow cells e.g. errors of metabolism or immunodeficiencies
64
HSC transplant - process outline
| And worry about..
Eliminate host immune response (total body irriadiation; cyclophosphamide; other drugs)
Replace with own or HLA matched donor bone marrow
Allogenic HSCT leads to reaction of donor lymphocytes against host tissue
GVHD prophylaxis for all patients - methotrexate/cyclosporine
65
GVHD cause
Presentation
Treatment
Injury by preparative regime before HSCT
Mainly manifests in skin, liver and gut
Corticosteroids
66
Risks of HSCT beside GVHD
```
Infection
Malignancy
- Viral associated x 100: Kaoposi's sarcoma (HHV8), lymphoproliferative disease (EBV)
- Skin cancer x 20
- Risk of other cancers x 2/3
```
67
Classification of immunodeficiemcies
1. Primary (single gene mutation)
2. Secondary (e.g infecion, malnutrition, drugs, haem malignancy) - more common.
3. Physiological (neonates, pregnancy, old age)
68
Secondary immune deficiencies
1. Infection: HIV, measles, mycobacterium
2. Biochem: Malnutrition, specific mineral deficiency, renal impairment
3. Malignancy: Myeloma, Leukaemia, Lymphoma
4. Drugs: Corticosteroids, Cytotoxic agents, antiproliferative immunosuppresants
69
Clinical features suggestive of immunodeficiency
2 major
or
1 major and recurrent minor infections
in one year
70
Cells of the innate immune system
+ soluble components
Polymorphonuclear cells
Monocytes + macrophages
Dendritic cells
NK cells
Complement
Cytokines
Acute phase proteins
71
Properties of phagocytes
```
Express pattern recognition receptors
Express Fc receptors
Express cytokine/chemokine receptors
Secrete cytokines and chemokines
Have phagocytic capacity
```
72
Polymorphonuclear cell properties
Short lived
```
Same as phagocytes:
Express pattern recognition receptors
Express Fc receptors
Express cytokine/chemokine receptors
Secrete cytokines and chemokines
Have phagocytic capacity
```
+ Release enzymes, histamine, lipid mediators of inflammation from granules
73
Monocytes and macrophages properties
```
Same as phagocytes:
Express pattern recognition receptors
Express Fc receptors
Express cytokine/chemokine receptors
Secrete cytokines and chemokines
Have phagocytic capacity
```
+ Capable of presenting processed antigen to T cells
Longer lived than neutrophils
74
Reticular dysgenesis
Inheritance
Mutation
Failure of stem cells to differentiate along myeloid or lymphoid lineage
= Most severe form of SCID
No lymphocytes, neutrophils, monocytes, platelets
Autosomal recessive
AK2
Fatal in v early life unless BMT
75
Kostmann syndrome
Inheritance
Mutation
Failure to of neutrophil maturation - congenital neutropenia
Autosomal recessive
HAX1
No neutrophils, normal leukocyte adhesion markers, DHR can't do as no neutrophils and no pus
76
Cyclic neutropenia
Inheritance
Mutation
Episodic neutropenia every 4-6 weeks
Autosomal dominant
ELA-2
77
Leukocyte adhesion deficiency
| FBC changes
Defect of phagocyte migration. Neutrophils lack CD18 and fail to exit from blood stream
V high neutrophil in blood
Absence of pus formation
78
Chronic granulomatous disease
Clinical signs
Failure of oxidative killing mechanism
Deficiency of component of NADPH oxidase - can't generate oxygen radicals.
Excessive inflammation with persistent neutrophil/macrophage accumulation
without degradation of antigen
Granuloma formation
Lymphadenopathy + Hepatosplenomegaly
79
Tests of chronic granulomatous disease
```
Nitroblue tretrazolium (NBT) test - yellow to blue if interaction with HPO
Dihydrorhodoaminde test - fluorescent if oxygen free radicals
```
Both -ve in chronic granulomatous disease
80
Il-12, Il-12 receptor, IFNg or IFNg receptor deficiency
Normal mechanism of these cytokines
Increased risk of
Cytokine deficiency
Infected macrophages produce Il-12.
Il-12 induces T cells to secrete IFng
IFNg feeds back to macrophages to stimulate TNFa production
- Activated NADPH oxidase and oxidative killing pathways
Mycobacterium
Salmonella
81
Phagocyte deficiencies predispose to which type of infections
Bacterial + fungal i.e. extracellular
- Staph, enteric bacteria
- Candida albicans, aspergillus
82
Phagocyte deficiency treatment
Infection tx
- Prophylaxis: septrin (bacteria); itroconazole (fungal)
- Oral/IV antibiotics as needed
Definitive tx
HSCT
83
Chronic granulomatous disease tx
Definitive
Interferon gamma therapy
- Increases macrophage capacity for killing via non-oxidative pathway
84
No neutrophils, Normal leukocyte adhesion markers, no pus
Kostmann
85
High neutrophils, leukocyte adhesion markers absent, DHR normal, no pus
LAD
86
Normal neutrophils, normal adhesion markers, abnormal NBT, pus
Chronic granulomatous disease
87
Normal neutrophils, normal adhesion markers, normal NBT, pus
IL12/IFNg pathway deficiency
88
NK cell deficiency predisposes to
Tx
Viral infection: Herpes, HSV 1+2, VZV, EMV, CMV, papillomavirus
? in trial
Prophylactic antivirals e.g. acyclovir
Cytokines?
HSCT in severe phenotypes
89
Complement deficiency predisposes to
```
Bacterial infection
- particularly encapsulated bacteria (NHS)
Neisseria meningitides
Haemophilus influenza
Streptococcus pneumonia
```
90
Which condition is early classical complement pathway deficiency associated with
Treatment
SLE
C1q, C1r, C1s, C2, C4
- C2 most common - almost all patients with C2 deficiency have SLE
local inflammation in skin, joints and kidney
Treatment:
- Analgesia
- Steroids
- Cyclophosphamide
91
Which complement pathways are dependent on acquired immune response (antibodies)
Classical pathway
92
How are the 3 different complement pathways activated
Classical: Formation of antigen-antibody immune complexes
MBL: MBL binding to microbial cell surface carbohydrates. Directly simulates classical, involving C4 and C2
Alternative: Binding of C3 to bacterial cell wall components . Constantly at low level of activation that is negatively regulated. Involved factors B, I and P
93
Components of complement that are measured
| Functional complement tests and what they measure
C3, C4
CH50 classical: C1, C2, C4, C3, C5-9
AP50 alternative: B, D, Properidin, C3, C5-9
94
Properidin deficiency
+C3, +C4, +CH50, -AP50
95
C9 deficiency
+C3, +C4, -CH50, -AP50
96
SLE
+/-C3, -C4, +/-CH50, +AP50
97
C1q deficiency
+C3, +C4, -CH50, +AP50
98
ADA deficiency
Inheritance
Phenotype
Type of SCID (16.5%) - Adenosine Deaminase deficiency (required for cell metabolism in lymphocytes)
Autosomal recessive
V low/absent T cells
V low/absent B cells
V low/absent NK cells
99
X-linked SCID
| Phenotype
45% of all SCID - commonest - mutation of gamma chain of Il-2 receptor --> inability to respond to cytokines causes early arrest of T cell and NK cell development and production of immature B cells.
V low/absent T cells
V low/absent NK cells
Normal or increased B cells but low Igs (will have IgM but no so much of others)
100
Clinical phenotype in SCID
Unwell by 3 months - infections of ALL types
Failure to thrive
Unusual skin disease
- colonisation of infants empty BM by maternal lymphocytes ->GVHD
FH of early infant death
101
CD8+ T cell function
Which peptides do they recognise?
Which infections are they important in providing immune response?
Cytotoxic - kill cells directly
- Perforin (pore forming) and granzymes
- Expression of Fas ligand - triggers death pathway
- Secrete cytokines IFNg, TNFa
Peptides from intracellular proteins with HLA class 1 (A, B, C)
Viral infections and tumours
102
CD4+ T cell function
Which peptides do they recognise?
Which infections are they important in providing immune response?
Helper cells
- Help development of B cell response
- Help development of some CD8+ T cell responses
Peptides from extracellular proteins presented on HLA class II molecules (DR, DQ, DP)
Extracellular pathogens
103
DiGeorge syndrome
Dysmorphic features
Genetic abnormality
Development defect of pharyngeal pouch
High forehead, low set abnormally folded ears, cleft palate, small mouth and jaw, hypocalcaemia, oesophageal atresia, underdeveloped thymus, complex congenital heard disease
Deletion at 22q11.2
104
Effect of DiGeorge syndrome on immune cells
Normal B cells
Reduced T cells
- Homeostatic proliferation with age
Immune function only mildly impaired and improves with age
105
MHC class II deficiency
Selection of CD4+ T cells in thymus requires MHC class II expression. If absent, won't get CD4+ T cells.
106
Bare lymphocyte syndrome type
Defect
Clinical phenotype
Defect in a regulatory protein of Class II gene expression - absent expression of MHC class II molecules
Profound CD4+ cell deficiency
Normal CD8+ cells
Normal B cells - IgM normal
Low IgG/IgA due to lack of class switching
Unwell by 3 months. Failure to thrive. All types of infection. FH of early infant death
107
Pneumocystis pneumonia (PCP)
Requires which cell for infection control
Occurs in which disease
CD4 T cells
HIV
108
Investigating T cell deficiency
```
Total WCC and differentials
Lymphocyte subsets (FACs)
Immunoglobulins
Functional tests
HIV test
```
109
Low CD4 T cell, Low CD8 T cell, Low NK cel, low/norm B cell, low/norm IgM, low IgG
X-linked SCID
110
Low CD4 T cell, Low CD8 T cell, norm NK cell, norm B cell, norm IgM, low/norm IgG
DiGeorge
111
Low CD4 T cell, norm CD8 T cell, norm NK cell, norm B cell, norm IgM, low IgG
BLS type 2
112
Management of T cell immunodeficiencies
```
Aggressive infection tx
HSCT
- In SCID
- In BLS (replace class II deficient APCs)
Enzyme replacement therapy
- In ADA SCID
Gene therapy
Thymic transplant
- In DiGeorge syndrome
```
113
Structure of immunoglobulins
Specifically
IgA
IgM
2 heavy chains + 2 light chains
- Antigen recognised by Fab of both heavy and light chains
- Effector function determined by constant region of the heavy chain (Fc)
```
IgA = dimer
IgM = pentamer
```
114
Antibody function and which rich parts of the antibody are involved
Fab mediated: Identifying pathogen/toxin
| Fc mediated: Interact with other components of immune response to remove pathogens - complement, phagocytes, NK cells
115
Bruton's x linked agammaglobulinemia
Genetic abnormality
Clinical phenotype
Abnormal BTK gene
Pre B cells cannot mature - no mature B cells or antibodies (after 3 months)
Boys present in first few years of life
Recurrent bacterial infections espesh NHS
Viral, fungal, parastic infections
Failure to thrive
116
Hyper IgM syndrome
Genetic abnormality
Mutation in CD40 ligand gene
X-linked
CD40 ligand expressed by activated T cells
- involved in T-B cell communication
No help by T cells for class switching of B cells
- Normal B cell number
- Normal T cell number but activated don't express CD40L
- Elevated serum IgM
- Low IgA, IgE, IgG
117
Clinical phenotype of x-linked hyper IgM
Boys preesnt in first few years of life
Bacterial infections espesh NHS
Parasite infections
Subtle abnormality in T cell function predisposes to Pneumocyctitis jorevic, autoimmune disease and malignancy
118
Common variable immune deficiency
Clinical presentation
Group of disordes where there is failure of differentiation/function of B lymphocytes
LOW IgG
Low IgA, IgE
Widespread immune dysregulation - autoimmune and inflammatory
119
Selective IgA deficiency
Predisposes to which infections
Deficiency of mucosal barriers. IgA deficiency
Resp and GI infections in 30%
120
Investigation B cell deficiencies
Total WCC and differential
Lymphocyte subsets
Serum immunoglobulins and protein electrophoresis
B cell function tests
121
Use of protein eletrophoresis in immunology
Production of IgG is a surrogate marker to CD4 T cell helper function
If no gamma band - no antibodies - Brutons x-linked agammaglobulinaemia
122
Management of B cell immunodeficiencies
Aggressive prophylaxis/tx of infection
Immunoglobulin replacement if required
Immunisation
- for selective IgA deficiency only
123
Steroids mechanism of immune modulation
- Glucocorticoid steroids
Actions
- Block phospholipase A2, so there is less prostaglandin production and less inflammation
- Blocks phagocyte recruitment and phagocytosis
- Keeps lymphocytes sequestered in lymphoid tissue (T cells > B cells)
Effects on blood:
- neutrophilia
- lymphopenia
124
Cyclophosphamide mechanism of action
Cytotoxic agent
Alkylating agent - alkylates guanine on DNA, preventing DNA replication
- Acts on B-cells more than T-cells
- Used in antibody-mediated disease e.g. SLE
Side-effects
- haemorrhagic cystitis can occur due to toxic metabolite acrolein
- Malignancy - bladder, haem
- Anti-proliferative - hair loss, sterility, BM suppression
- Infection: PCP
125
Mycophenolate mofetil
- Binds de novo guanosine analogue synthesis
- Main use is post-transplant but also autoimmune and vasculitis
Main worry - risk of reactivated infection
- HSV reactivation
- JC virus + progressive multifocal leukoencephalopathy
TERATOGENIC
126
Azathioprine
Metabolised in the liver to 6-mercaptopurine
- This is a purine analogue, blocks de novo purine synthesis
- Affects T-cells more than B-cells
Indications
- Autoimmune disease e.g. SLE
- Autoinflammatory disease e.g. Crohn's
Side-effects
- Some people can get complete bone marrow suppression - associated with TPMT polymorphism
- They cannot metabolise azathioprine, so it builds up in bone marrow and causes pancytopenia
127
Anti-thymocyte globulin
MOA
Uses
Side effects
uman thymocytes injected into rabbits
- Rabbits produce a number of thymocyte antibodies
- Serum containing anti-thymocyte antibodies can be injected into humans
Effects
- T-cell depletion
- inhibits T-cell activation
- Inhibits T-cell migration
Uses
- NOT SPECIFIC
- Can be used in allograft rejection e.g. renal/heart transplant
Side-effects
- Infusion reactions
- Leukopenia
- Malignancy
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Basiliximab
Anti-CD25 antibody
- Targets IL-2, so IL-2 cannot acts on T-cells
- Blocks T-cell proliferation and function
Uses
- prophylaxis for allograft rejection (given before and after transplant surgery)
Side-effects
- Infusion reactions
- Leukopenia
- Malignancy
129
Abatacept
Fusion protein of CTLA4 and human IgG Fc
- Blocks binding of CD80 and CD86 on APCs, with T-cells
- used in rheumatoid arthritis
Side-effects
- Infusion reactions
- Leukopenia
- Malignancy
130
Rituximab
Anti-CD20 antibody
- Depletes B-cells, but not plasma cells
Uses
- Lymphoma
- Rheumatoid arthritis
- SLE
Side-effects
- Infusion reactions
- Infection, especially JC virus and PML
- Exacerbation of CVD
131
Natalizumab
Anti-alpha 4 integrin antibody
- Alpha-4 is part of an integrin complex with B1/B7
- The integrin complex is involved in leukocyte arrest, adhesion and migration
- Natalizumab block leukocyte migration to tissue
Uses
- Highly active relapse-remitting MS
- Crohn's disease (in the past, not anymore)
Side-effects
- Infusion reactions
- Infection - HIGH RISK of JC virus and PML
- hepatotoxic
- Malignancy
132
Toclizumab
IL-6 antibody
- Wide immunosuppressive effect, as IL-6 is involved in macrophages, T-cells, B-cells and neutrophils
Uses
- Castleman's disease (IL-6 producing tumour)
- Rheumatoid arthritis - very effective
Side-effects
- infection
- hepatotoxic
- dyslipidaemia
- malignancy
133
Cytokine therapy
IFN-alpha - Hep B, Hep C, Kaposi Sarcoma, CML
IFN-beta - Bechet's disease
IFN-gamma - chronic granulomatous disease
134
What is immunopathology
Examples
Damage to host caused by immune response
- EBV = Pathogen - adaptive response via cytokines
- Abscess = Pathogen - innate response via neutrophils
- Ankylosing spondylitis = No obvious pathogens - innate response via cytokines
- Anaemia due to haemolysis secondary to ant-RBC antibodies = adaptive response via antibodies
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Monogenic autoinflammatory disease
Mutations in a gene encoding a protein involved in a pathway associated with innate function (abnormal signalling that involves Il-1 and TNF-alpha)
Gain of function in Cryopyrin (NALP3)
- Muckle wells
- Familial cold-autoinflammatory syndrome
- Chronic infantile neurological articular syndrome
Loss of function in Pyrin marenostrin (MEFV)
- Familial mediterranean fever
Both lead to Increased activation and inflammation
- ASC -> procaspase 1 -> IL-1, NFkB (->TNFa) , Apoptosis
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Familial mediterranean fever
Monogenic autoinflammatory disease
Loss of function in Pyrin marenostrin (MEFV)
```
Periodic fevers for 48-96h
Peritonitis
Pericarditis
Arthritis
Rash
```
Long term risk of amyloidosis, nephrotic syndrome and renal failure
Rx: Colchicine
Otherwise:
- Anakinra (anti IL-1)
- Etanercept (TNFa inhibitor)
137
Monogenic autoimmune diseases
Mutation in a gene that encodes a protein involved in a pathway associated with adaptive immune cell function
APECED
- Autosomal recessive mutation in AIRE
- Autoimmune T cells
- Candida, hypoparathyroid, Addison
IPEX
- X linked defect in Fox P3 (needed for TReg)
- Autoantibodies
- Diarrhoea, dermatitis, diabetes, death
- + Hypothyroid
ALPS
- Mutations in fas pathway (TNFRS56) = no T cell death
- Autoimmune cytopenia
- Splenomegaly, lymphadenopathy, lymphoma
138
Polygenic autoimmune disease HLA associations
```
Goodpastures - HLA DR15
T1DM - HLA DR3/4
RA - HLA DR4/1
Graves disease - HLA DR3
SLE - HLA DR3
```
139
Polygenic autoimmune disease T cell activation associations
PTPN22 (suppresses T cell activation)
- Without -> more T active T cells -> SLE, T1DM, RA
CTLA4 (negative regulator of T cells)
- Without --> SLE, T1DM, RA, Thyroid
140
Chron's polygenic auto-inflammatory associations
Treatment
IBD1 gene on Chr16 = NOD2/CARD15
- In 30% of Chron's patients
NOD2 = microbial sensor that stimulates NFkB and inflammatory response. Presnet in cytoplasm of myeloid cells.
Corticosteroids
Azathioprine
Anti-TNF
Anti IL12/23
141
Ankylosing spondylitis mixed pattern disease
HLA B27
accounts for <50% of genetic risk
Inflammation at sites of high tensile forces
- Sacroiliac joints
- Achiles tendon
- Low back pain and stiffness
- Uveitis
- Enthesitis (sites where tendons/ligaments insert into bone)
Treatment
- Anti-TNFa
- Anti-IL17
- Anti IL12/23
142
Gel and coombs classification of hypersensitivity
T1: Immediate IgE mediated
T2: Antibody reacts with cellular antigen
- Rh haemolytic anaemia
- Goodpastures (GBM)
- Pemphigus vulgaris (epidermal cadherin)
- Graves (TSH receptor)
- Myasthenia gravis (Ach receptor)
- Pernicious anaemia (parietal cells)
- RA? (CCP)
T3: Antibody reacts with soluble antigen to form an immune complex
- SLE
- RA (RF and anti-CCP)
- Cyroglobinaemia
T4: Delayed hypersensitivity - T-cell mediated
- RA
- T1DM (pancreatic beta cell antigen)
- MS (myelin basic protein/ proteolipid protein)
143
Anti-nuclear antibody (ANA) disorders
dsDNA
- SLE. ANA stain is homogenous
ENA+ve (extractable nuclear antigen): SPECKLED
- Ro, La, Sm, RNP = SLE
- Ro, La = Sjogren's
- Scl 70 = Diffuse systemic sclerosis. ANA stain is nucleolar
- Centromere = Limited sclerosis. Ana stain is centromere
Cytoplasmic
- Jo1 = Myositis, Dermatomyositis
144
Acute urticaria
Causes
- 50% idiopathic
- 50% due to food, drugs, latex, viral, febrile illness
IgE mediated reaction with wheals. Completely resolves in 6 weeks
Dx is clinical. Can do skin prick test
Treatment
AVOID allergen
GIVE antihistamines
145
Allergic rhinitis
SEASONAL (tree, pollen, fungal, spores);
Perennial aka all the time (pets, houst dust, mites)
Occupational
Nasal itch + obstruction
Sneezing
Anosmia
Eye symptoms
Dx: Pale blue swollen nasal mucosa
- Skin prick test and RAST
Treatment
- Allergen avoidance
- Antihistamines
- Steroid nasal spray
- Eye drops
- Oral steroids
- Ipatropium nasal spray
- Grass pollen desensitisation
146
Oral allergy syndrome
Birch pollen, fruits, melon, celery (cross reactivity)
Symptoms LIMITED to mouth. 2% get anaphylaxis
Dx
- Clinical
- ? Skin prick
Management
- Avoid food
- Wash mouth if ingested
- Anti-histamine
147
Secukinumab
- Antibody to IL-17A
Uses
- Psoriasis - very effective
- Psoriatic arthritis - very effective (as effective as TNFa)
- Ankylosing spondylitis
Side-effects
- Infection (TB)
148
Denosumab
Antibody binds to the RANK ligand
- RANK-L usually binds to RANK on osteoclasts to stimulate bone resorption
- Denosumab reduces bone resorption
Uses
- Effective 2nd line treatment for osteoporosis (After alendronate)
Side effects
- Injection site reactions
- Infection - mildly immunosuppressive
- AVN of jaw
- Long-term increased risk of atypical femoral fractures
149
Ustekinumab
- Antibody that binds to p40, a subunit shared by IL-12 and IL-23
- Depleted IL-12 and IL-23
- This blocks IL-17 expression by T-cells
Uses
- Psoriasis (very effective)
- Psoriatic arthritis
- Crohn's disease
NOT useful in Rheumatoid arthritis
Side-effects
- Injection site reactions
- Infections (TB)
150
Anti-TNF alpha antibodies
Infliximab
Adalimumab
Certolizumab
Golimumab
These bind to circulating TNFa, so TNFa cannot bind to target cells
Uses:
- Crohn's disease
- Rheumatoid arthritis
- V. effective in reducing pain in ankylosing spondylitis
- Psoriasis
Side-effects
- Injection site reactions (given IV or SC)
- Infections (HBV, HCV, TB)
- T-cell depletion leading to lupus-like conditions
- Increased risk of skin cancer (but not solid tumours)
151
Etanercept
- Fusion of TNFa receptor p75, with human IgG antibody
- This acts as a decoy receptor so that TNFa cannot bind to its target receptor
```
Uses
- Same as TNFa receptor, but not used in Crohn's
e
Side-effects
- Same as above
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