Immunology Flashcards
1
Q
Explain how abatacept works.
A
It is a CTLA4 immunoglobulin licensed for RA.
CTLA4 is a inhibitory costimulatory molecule on the CD4 cells which binds to B7 molecules on APC (or CD 80/86).
By giving abatacept, more CTLA4 molecules are around in blood which binds to B7 strongly.
Therefore stimulatory CD28 molecules on CD4 cells are unable to bind to B7 molecules on APC, leading to immune suppression.
2
Q
Explain how ipilimumab works.
A
Opposite to abatacept.
Ipilimumab binds to CTLA4 molecules on the T cells.
These are unable to bind to CD80/86 molecules on APCs.
CD80/86 remains bound to T cell CD28, leading to continued immune response.
Important in cancer immunology.
3
Q
Explain how pembrolizumab works.
A
Blocks PDL1 on tumour cells.
PDL1-PD1 interaction leads to inhibition of T cell response.
By blocking PDL1, this interaction does not occur, therefore tumour becomes vulnerable.
4
Q
What is the importance of CD40L-CD40 interaction between B and T cells?
A
When B cells ingest antigen and processes it and presents it to CD4 T cells, activated CD4 T cells in turn expresses CD40L which binds to CD40 on B cells. This allows B cell activation and differentiation.
Absence of this interaction means B cells cannot undergo isotype switching and memory B cell generation.
This causes hyper IgM syndrome with depressed IgA, E, G but high IgM with recurrent respiratory bacterial infections and PCP and diarrhoeal illness. Needs cotrimoxazole prophylaxis, IVIG, GCSF.
5
Q
How does CD8 cytotoxic T cells kill?
A
Perforin inserted to cell membrane which causes target cell osmotic swelling and lysis.
Proteolytic enzymes called granzymes passes into the target cell and induces apoptosis via caspase nezymes.
FasL on T cell binds to Fas on target cell which can also activate caspase pathway and lead to apoptosis.
6
Q
For the following CD4 cell subtypes, name the responsible interleukin for differentiation.
Th1
Th2
Th17
Treg
A
Th1 - IL12
Th2 - IL4
Th17 - TGF beta, IL6
Treg cells - IL10, TGF beta
7
Q
For the following subtypes of CD4 cells, name the main cytokines secreted and their role.
Th1
Th2
Th17
Treg
A
Th1 - IFN gamma and TNF alpha. Antibacterial/antiviral
Th2 - IL4, IL13 - immunity to parasites and causes atopic immune response, promoting IgE production and eosinophil proliferation.
Th17 - IL 17 which acts on many places. Causes increase in antimicrobial peptide, increased barrier function and inflammation and neutrophil response. Defence against candida and staph. Overactive in psoriasis as IL17 stimulates keratinocytes.
Treg - TGF beta - tolerance and regulation
8
Q
What are the key cytokines involved in psoriasis and their targeting monoclonal antibodies?
A
- TNF alpha - etanercept, adalimumab, infliximab
- IL 12/IL 23 inhibitors - ustekinumab. U for TUwelve.
- IL-17 inhibitors - secukinumab. S for seventeen.
9
Q
What does deficiency in Th17 lead to and what are the consequences?
A
Chronic mucocutaneous candidiasis.
Recurrent skin, nail, mucosal infections as Th17 is responsible for barrier function, neutrophil response and production of antimicrobial peptide.
10
Q
Th2 cells secrete IL4, IL5 and IL13. What are their roles?
A
IL4 - promotes further T cell differentiation into Th2.
IL5 - attracts eosinophils
IL13 - B cells to promote IgE switching
11
Q
What is the causes of SCID?
A
Lack of a component essential for T cell function.
T cell is unable to respond to cytokines such as IL7, which is critical for T cell and NK cell differentiation.
Leads to increased opportunistic infections, increased risk of malignancy and autoimmunity.
Failure to thrive with chronic diarrhoea in children.
Common defects involve gamma common chain and ADA.
12
Q
Describe pathogenesis of CGD
A
Deficiency of 1 of 4 subunits of NADPH oxidase.
Mutation of gp91 on X chromosome.
This leads to inability to produce oxidative burst necessary for microbe killing.
Leads to recurrent infections with staph and aspergillus requiring chronic antibiotic therapy and immunization.
13
Q
Which cells express HLA class I?
A
HLA class I are A, B and C. Expressed by all cells except RBCs and some neuronal cells. Responsible for presentation of peptides to CD8 T cells.
14
Q
Which cells express HLA class II?
A
HLA DP, DQ, DR.
Expressed only by specialized APCs such as macrophages, B cells and dendritic cells.
Presents peptides derived from ingested extracellular antigens.
15
Q
What is the aim of MHC/HLA class I pathway?
A
It is essential for elimination of virally infected cells.
Internal viral proteins are processed and presented via HLA class 1 surface proteins.
CD8 T cells recognizes the viral protein and kills the virally infected cell via perforin/granzyme pathway.
16
Q
What is the aim of MHC/HLA class II pathway?
A
Restricted to APCs who process exogenous antigens and presents the processed molecule via HLA type II receptors.
Role is activation of CD4 cells.
17
Q
Describe 4 roles of NK cells.
A
- Kills virally infected cells via:
a. Ab dependent cell mediated cytotoxicity
b. Loss of MHC expression - Kills tumour cells that have lost MHC expression
- Releases IFN gamma to activate adaptive immune system - mainly stimulates macrophages and favours Th1 differentiation.
- Protects from viral infection in the pregnant uterus.
18
Q
Describe ADCC in NK cells
A
NK cells have a receptor for IgG.
When IgG binds to viral antigen expressed on surface of infected cells, NK cells are activated and kills the cell vial perforin-granzyme or Fas pathway.
19
Q
How does NK cells kill cells that have lost MHC expression?
A
When a virus infections a cell, they down regulate MHC as a means of escape.
NK cells have 2 receptors - killer activating receptors which recognizes the target cell molecules, and killer inhibitory receptors.
NK cells have a killer inhibitory receptors which recognizes MHC cells - prevents self killing.
When MHC is lost - inhibitory signal is lost, and NK cells kill the cell.
note: RBCs are not attacked due to lack of activating receptor.
20
Q
Features of DiGeorge syndrome?
A
CATCH-22
Cardiac abnormalities (especially ToF) Abnormal facies Thymic aplasia Cleft palate Hypocalcaemia/hypoparathyroidism due to hypoplasia or absence of parathyroid gland
21
Q
3 Advantages of killed vaccine?
A
- Less likelihood of contamination
- Do not revert to virulence
- Heat stable
22
Q
3 Advantages of live vaccines?
A
- Given by natural route of infection and induce IgG/IgA response
- Is contagious therefore may spread immunity to people who were never vaccinated
- More durable response, often life long
23
Q
Distribution of IgA1 and IgA2
A
IgA1 predominates in airways
IgA2 predominates in colon
Equal amounts in small bowel
IgA1 is predominant in serum
24
Q
6 Contraindication to allergen specific immunotherapy
A
- Poorly controlled asthma or FEV1 <70%
- Malignancy
- Autoimmune disease
- Pregnancy
- Acute infection
- Beta blocker use - can amplify the severity of the reaction and make the treatment of systemic reactions more difficult
25
Differentiate 3 types of HAE and their relevant laboratory findings.
Type 1 - reduced C1INH level, low C4, normal C1q level
Type 2 - normal or elevated C1INH level but reduced function, low C4 and normal C1q
Type 3 - Normal C4 and C1q level, normal C1INH function/level, needs genetic testing for factor XII mutation
26
Define positive and negative selection in the thymus
Positive selection - only T cells with TCR capable of interacting with self MHC are permitted to survive. Others will be useless. Occurs in thymic epithelial cells in cortex
Negative selection - T cells with TCR showing high affinity for self antigens are deleted. Occurs both in cortex and medulla, mediated by BM derived dendritic DCs and macrophages.
27
Role of AIRE
Expression of tissue specific antigens occurs at low levels in the thymus for the purposes of positive/negative selection and this is mediated by AIRE (autoimmune regulator) which regulates thymic regulation of peripheral antigens.
Mutation in AIRE leads to APECED (Autoimmune polyendocrinopathy with candidiasis and ectodermal dystrophy) - AR disease, failure to express tissue specific antigen and failure to delete T cells specific for multiple tissue antigens. Results in lymphocytic infiltration of multiple tissues and multiple autoantibodies.
28
3 cardinal manifestations of APECED
1. Chronic mucocutaneous candidiasis
2. Autoimmune hypoparathyroidism
3. Autoimmune Addison's disease
AIRE is responsible for deletion of high affinity T cells and induction of thymic regulatory T cells.
Autosomal recessive disorder due to mutated AIRE gene which results in failure to express tissue specific antigens and failure to delete T cells specific for multiple tissue antigens, leading to autoimmune phenomena.
29
Define IPEX and its cause.
IPEX - immune dysfunction, polyendocrinopathy, enteropathy, X linked.
Defect of FoxP3 which is a master regulator of Treg cells and is responsible for their development and function.
Leads to Autoimmune endocrinopathy including diabetes, thyroiditis, also haemolytic anaemia, diarrhoea leading to FTT, ITP, autoimmune neutropenia, atopic features, lymphadenopathy and splenomegaly.
30
4 mechanism of suppression by Treg cells
1. CD25 sops up IL-2 and restricts access by conventional T cells
2. CTLA-4 binds to CD80/86 (B7) on APCs and
3. Produces inhibitory cytokines IL10, TGF beta
4. Cytolysis of macrophages and T cells via granzyme B/perforins
31
What does CD 80/86 (B7.1/7.2) bind to?
CD28 on T cells - leads to activation
| CTLA-4 on T cells - leads to delayed deactivation
32
Cephalosporin cross reactivity
Can be allergic to common beta lactam ring or R side chain. Higher cross reactivity in 1/2nd gen especially between amoxicillin and cephalexin/cefaclor as they share the same R1 side chai.
33
What does raised tryptase indicate?
Raised tryptase indicates mast cell degranulation - however it does NOT distinguish between IgE and non-IgE mediated causes.
34
Fruits associated with latex allergy
```
Banana
Chestnut
Avocado
Kiwifruit
Papaya
Fig
Melon
```
35
Mechanism of allergy in aspirin and NSAIDs
Preferential shunting of arachidonic acid metabolism from COX1/2 mediated to 5-lipooxygenase, resulting in increased production of leukotrienes including LTC4, LTD4, LTE4.
36
Features of T cell immunodeficiencies
Infections with intracellular organisms:
Fungi eg especially with mucosal candida (due to lack of Th17 cells)
Viruses - CMV, VZV, HSV, Protozoa such as PJP (due to lack of Th1 cells)
Listeria
37
Lack of neutrophils result in:
High grade infections with staph, gram negative bacteria, and invasive fungal infections such as invasive aspergillosis, systemic candidiasis.
38
Consequences of following complement deficiencies:
```
C1q/r/s deficiency
C4
C2
C3
Properdin
C5-9 complex
```
C1q/r/s deficiency - SLE
C4 - SLE, GN
C2 - SLE, GN, vasculits
C3 - recurrent pyogenic infections, GN, immune complex diseases
Properdin - Neisseria infections
C5-9 complex - disseminated Neisseria infections
39
How would you assess T cell immunodeficiency syndromes?
Check T cell subsets % and count
CD3 - present in ALL T cells - usually 70% of lymphocytes
CD4 - helper T cells, usually about 70% of all CD3 cells
CD8 - increased in viral conditions such as HIV, acute EBV.
CD4:8 ratio is usually 2:1
40
4 major causes of B cell immunodeficiencies
CVID
Bruton's X linked agammaglobulinaemia
Hyper IgM syndrome
IgA deficiency
41
Features of CVID
Treatment?
Most common primary immunodeficiency
2 peaks of age of onset - 1-5 years, then 18-25 years
Deficiency in IgG AND IgA or IgM
B cell count is usually NORMAL
Recurrent sinopulmonary infections/GIT involvement leading to chronic/recurrent diarrhoea and malabsorption, autoimmunity, 400x risk of NHL, bronchiectasis and amyloidosis as a consequence of chronic infection.
Treat with IVIg - trough ~5g/L for reduced infection, trough of ~7g/L for well-being
42
Features of X-linked agammaglobulinaemia
Like CVID but earlier onset ~6 months and ABSENT B cells and no lymphoid tissue.
Mutation/absence of Bruton's TYR kinase gene leading to B cell development blockade at Pre-B-I stage.
Family history is present in 50% - rest are de novo mutations.
- Absolute immunoglobulin deficiency with B cell count of 0
- No plasma cells or germinal centres in tissue biopsy.
- B cell precursors are present in the marrow
- Measure Btk expression by flow cytometry and can also do genetic analysis of Btk gene.
43
IgA deficiency
Absence of IgA +/- IgG subclass due to dysregulation in Ig isotype class switching during B cell activation.
Associated with CVID. Other causes include drugs such as phenytoin, intrauterine infection with TORCHS organism.
Infection risks just like CVID/XLA - sinopulmonary, giardiasis.
Normal B cell count, absent IgA.
Treat with prompt Abx use. NOT IVIG as problem is not systemic but mucosal defect. Transfuse with IgA deficient donor or triple washed cells.
44
Disease associations with IgA deficiency?
Atopic disease - asthma
GIT disease - IBD, coeliac disease
Autoimmune disorders - RA, SLE, DMS, Sjogrens, ITP, pernicious anaemia.. etc
45
Hyper-IgM syndrome
X linked disease
Absent CD40-CD40L signal in T and B cell collaboration which elads to failure of B cell isotype switching and memory B cell generation.
Results in recurrent bacteria infections esp PJP and acute/chronic diarrhoea
Depressed IgA, IgG, IgE, but normal/increased IgM
Flow cytometry for surface CD40L
Treat with IVIG, Bactrim prophylaxis.
46
Describe idiopathic CD4 lymphopenia
Low CD4 count, HIV excluded.
T cell type infections occur including disseminated VZV, cryptococcal pneumonia/meningitis, MAC infection, oesophageal candidiasis
CD4 count below 300/uL or 20% of lymphocytes
No secondary cause.
Can consider prophylaxis of opportunistic infections.
47
Describe chronic mucocutaneous candidiasis
Chronic, recurrent candida infection affecting skin, nails and mucosae, oesophagus and lungs.
Laboratory diagnosis will show lack of Th17 cells.
Subtype includes APECED, CMC with thyroid disease
48
Describe SCID
Paediatric condition with recurrent opportunistic infections such as PCP, protozoal, viral and fungal infections, FTT, chronic diarrhoea. Increased risk of malignancy.
Lack of component essential for T cell function - such as gamma-common chain, adenosine deaminase.
Also, given lack of T cell help, also has no B cell function hence 'severe combined'
Labs will show absent T cells and NK cells but B cells present
Decreased immunoglobulins with decreased specific antibody response.
Treat with bone marrow or stem cell transplantation.
If the main defect is adenosine deaminase deficiency (in 20% of SCID) - can consider enzyme replacement therapy.
49
Name 3 causes of T cell immunodeficiencies
1. Idiopathic CD4 lymphopenia
2. Chronic mucocutaneous candidiasis
3. SCID
50
Di George Syndrome
Thymic hypoplasia due to failure of development of 3rd and 4th pharyngeal arches.
Variable degree of T cell immunodeficiency.
Characterized by CATCH-22:
```
Cardiac abnormalities
Abnormal facies
Thymic hypoplasia
Cleft palate
Hypocalcaemia
22q11-pter deletion
```
51
Wiscott-Aldrich syndrome
X linked disease characterized by:
1. Thrombocytopenia with small platelets
2. Eczema, eosinophilia, food allergies
3. Recurrent infections - respiratory tract and severe viral illnesses.
Defective WASP gene involved in cytoskeletal reorganization eg during T cell activation.
52
Ataxia telangiectasia
Complex AR multisystem disorder characterized by cerebellar ataxia, telangiectasia, sinopulmonary infections, mental and growth retardation, and increased malignancy risk.
Defect in ATM gene which is critical in cell cycle control and DNA damage response.
Lab diagnosis will show decreased T cells, normal B cells, thymic hypoplasia, variable decrease in immunoglobulins especially IgA.
53
Describe MHC restriction
CTLs are restricted to recognize a specific antigen presented on a specific MHC molecule.
Ie, if the same antigen was presented on a different MHC, it cannot recognize it.
Also, if the paired MHC molecule presented a different antigen, it cannot recognize it.
54
What is the difference between B and T cells in terms of their antigen recognition?
B cells can recognize intact antigens while as T cells require antigen to be processed and expressed with HLA molecule - class II for CD4, Class I for CD8.
55
Name 3 antigen presenting cells
Macrophages, dendritic cells, B cells
56
Describe steps involved in antigen presentation via MHC class I pathway
```
Viral proteins are synthesized in the cytoplasm.
Degraded and processed into peptides by proteasomes
Peptides are then transported to ER where assembly of peptide-class I complex occurs
Exocytosis of the peptide-class I complex to the surface where it is recognized by CD8 cells
```
57
Describe how HSV, CMV and adenovirus subverts class I antigen presenting pathway
HSV - produces TAP inhibitor protein which prevents peptide transport to ER
- TAPs transport free cytoplasmic peptides into ER
CMV - accelerates transport of peptides out of ER therefore reduces their chance of binding to MHC.
Adenovirus - produces a protein that anchors MHC in the ER and prevents surface expression
58
Role of dendritic cells
Role of plasmacytoid dendritic cells
Superb APCs - present as sentinels in skin, heart, kidney. Initially specialized to capture antigens. Once they capture antigens they mature into cells specialized for Ag presentation. Migrates to T cell rich areas such as LN and spleen to activate T cells.
pDCs are distinct lineages of conventional DCs.
Not as good in capture and presentation of Ag, however produces large amounts of IFN in response to viral infections and induce rapid antiviral state.
59
Why are there diversity in MHC molecules?
Evolved because it increases the chance that at least one peptide from a pathogen can be presented to T cells.
60
Describe the mechanism of T cell rejection in solid organ transplantation
Dendritic cells from donor or host travel to the allograft and sample donor antigens.
Following this, travels to spleen or LN where it activates recipient CD4 T cells.
CD4 T cells travel to graft where it sets up Th1/Th17 mediated inflammation with recruitment of CD8 T cells for cell mediated cytotoxicity.
61
Mechanism of action of MMF
Converted to mycophenolic acid in the liver and prevents purine synthesis pathway (which is increased by 10x in activated T cells). This results in prevention of DNA synthesis.
MMF is now preferred over CsA or Tacrolimus as they are relatively more lymphocyte selective.
62
Mechanism of action of calcineurin inhibitors
Major side effects?
Activation of TCR leads to activation of calcineurin which promotes cytokine secretion and T cell proliferation. CsA and tacrolimus blocks activated calcineurin preventing this from happening.
Infection, reactivation of CMV, BK nephropathy
Cancers - 20% at 10 years.
Especially virus associated cancers - PTLD associated with EBV, Cutaneous SCC mediated by HPV, Kaposi sarcoma associated with HHV8
63
Mechanism of action of mTOR inhibitors
Blocks the signalling pathway elicited by IL-2 in the activated T cell (ie, more downstream target compared to calcineurin inhibitors)
64
Pathogenesis of GVHD
Risk factor in development of GVHD?
Treatment?
Either via direct or indirect allorecognition:
Direct- host DC present to donor T cells (host DCs persist for several weeks after HSCT)
Indirect - donor DC present host antigen to donor T cells
For GVHD to occur, requires genetically different donor and host, donation of T cells and immunosuppressed host.
T cells are not removed from the stem cell graft as they help to assist in engraftment of the transplanted cells, suppress EBV associated PTLD, and also has graft versus disease effect which is useful.
Major risk factor - 60-80% GVHD in unrelated HSCT with one MHC mismatch. 40% in FULLY MHC MATCHED sibling HSCT.
Treat with prednisone. Prevent GVHD with tacrolimus or CsA.
65
What is the difference between HSCT and solid organ transplant?
HSCT is associated with severe initial neutropenia, initial mucositis/gastroenteritis, and prolonged lymphopenia.
Therefore at high risk of bacterial, fungal and viral infection such as CMV, HSV, VZV, often reactivation.
66
5 contraindications to skin prick testing
1. Severe eczema
2. Dermatographism
3. Antihistamines, TCA, topical steroids use in <72 hours
4. Severe anaphylaxis to an antigen
5. Unstable/persistent asthma
67
Management of anaphylaxis
1. IVF
2. O2 and salbutamol/nebulized adrenaline
3. IM adrenaline
4. Steroids
5. Given Glucagon if Pt is on beta blockers
68
Indications for desensitization in insect sting allergy
Duration of desensitisation process?
1. Severe life-threatening reaction AND specific IgE +/- SPT
2. Occupational/geographical isolation in lesser reactions
Note: Specific IgE is less sensitive than SPTs
20% of patients with negative SPTs have positive specific IgE and vice versa.
Poor correlation between size of SPT/ID reaction or specific IgE and severity of the reaction
Most continue desensitization with aim of 100 ug per dose for 3-5 years. Relapse is less likely after 5 years.
69
4 functions of complements
1. Cytolysis
2. Opsonization via C3b
3. Initiate inflammatory response - via release of anaphylatoxins C3a C4a C5a
4. Immune complex clearing - coating with complements results in enhanced solubility, reduced size and increased clearance from the circulation.
70
Describe the mechanism of alternate complement activation.
Constant low grade generation of C3b from C3 occurs - and this is the most important step!
C3 takes on H2O spontaneously to become C3i
C3i binds to factor B to become C3iB
C3iB is converted by factor D to release Ba and to become C3iBb
C3iBb is able to convert many C3 to C3b - so called fluid phase C3 convertase
C3b - if it binds to microbial surface, then binds factor B which is further cleaved by factor D to release Ba
C3bBb remains on the microbial surface which acts as a C3 convertase and activates further C3
C3bBb then binds to C3b to become C3bBb3b - which is a C5 convertase
C3b - if it doesn't bind to microbial surface, is degraded by water.
71
How is C1q activated? (3)
1. Binds directly to some bacteria - eg lipoteichoic acid on gram positive bacteria
2. Binds to CRP
3. Binds to Ab specifically IgG and IgM, NOT IgA, E or D
(requires >2 IgG bound)
72
Describe mechanism of activation of classical complement pathway
Cq1 binds to either Ab, directly to bacteria or to CRP to undergo conformational change and cleaves and activates C1r and C1s.
C1s then converts C4 and C2 to activate them to C4b and C2b
C4bC2a acts together as C3 convertase to convert into C3b and C3a
C4bC2aC3b acts as a C5 convertase.
73
Describe difference between type 1 and 2 acquired recurrent angioedema.
Type 1 - associated with B cell lymphoproliferative disorders, results in consumption of C1INH
Type 2 - associated with autoimmune diseases or idiopathic. Autoantibodies against C1INH.
Unlike HAE, C1q levels are reduced (normal in HAE)
74
Describe type III HAE.
Due to gain of function mutation in factor 12
Factor 12 is associated with formation of kallikrein and plasminogen and bradykinin synthesis.
Oestrogen related, and exclusively in women.
75
How does cobra venom work?
Mimics C3b!
Binds B and converted by factor D in serum to become C3bBb and activates further C3 into C3b.
Results in widespread complement consumption.
76
Action of belimumab
B-cell activating factor (BAFF), also called B-lymphocyte stimulator (BLyS), is required for the development and survival of B cells. In SLE, BAFF is overexpressed. Researchers theorize that BAFF overexpression causes autoimmune B cell proliferation and survival, which causes SLE.
Belimumab is a human antibody that binds to BAFF, preventing BAFF from binding to B cells. Without the survival factor BAFF, B cells commit suicide, and no longer contribute to the autoimmune damage of SLE.
77
Action of icatibant
Bradykinin is a peptide-based hormone that is formed locally in tissues, very often in response to a trauma. It increases vessel permeability, dilates blood vessels and causes smooth muscle cells to contract. Bradykinin plays an important role as the mediator of pain. Surplus bradykinin is responsible for the typical symptoms of inflammation, such as swelling, redness, overheating and pain. These symptoms are mediated by activation of bradykinin B2 receptors.
Icatibant acts as a bradykinin inhibitor by blocking the binding of native bradykinin to the bradykinin B2 receptor.
78
# Define:
Hypersensitivity
Allergy
Give examples of non-IgE mediated allergies
Hypersensitivity - objectively reproducible symptoms or signs initiated by exposure to a defined stimulus at a dose tolerated by normal subjects (ie, overreaction)
Hypersensitivity can be caused by allergic or non allergic mechanisms (eg exercise, cold)
Allergy - hypersensitivity reaction initiated by an immunological mechanism.
Allergy can be IgE mediated, or non IgE mediated.
Non IgE mediated allergies include contact dermatitis (T cell), gastroenteropathy (caused by eosinophils), IgG mediated (allergic alveolitis).
IgE mediated allergies can be further subdivided into atopic causes and non-atopic causes.
79
Definition of atopy
Immunological reactivity in which IgE is readily produced in response to ordinary exposures (skin contact, ingestion, inhalation) to common allergens of the subject's environment.
Atopy by itself does not imply presence of disease, but a reflection of the immunological state of the individual.
80
What are the two key signals required for IgE isotype switching in T and B cell interactions?
1. IL-4 and IL13 - shares receptor together. Has multiple actions including B cell IgE class switching, increased eosinophil survival and migration, direct effect on bronchial smooth muscles causing bronchoconstriction
2. CD40 ligand
Allergen binds to allergen specific IgM on B cells.
B cells present to TH2 cell TCR.
T cells then express IL4 and IL13 and CD40 ligand
These two signals then trigger transcription and DNA recombination resulting in class switching from IgM to IgE.
81
Name 4 preformed granules in mast cells
1. Histamine
2. Heparin
3. Tryptase
4. Chymase
82
How does immunotherapy work?
high dose allergen exposure during immunotherapy results in immune deviation from Th2 to Th0/1 response. This results in:
1. Suppression of Th2 response with further environmental allergen exposure
2. Promotes generation of Treg cells which produce IL10 and TGF beta, which promote preferential switching of B cell responses to IgG and IgG4 antibodies
3. Increase in IgG may also inhibit IgE facilitated allergen binding to APCs
83
What is the role of house dust mite immunotherapy in allergic asthma?
HDM sublingual immunotherapy improved time to 1st moderate-severe exacerbation during ICS reduction
Decrease in exacerbation at 6 months - absolute reduction of 10%
84
Chronic idiopathic urticarial and angioedema
Spontaneous daily to almost daily urticarial and angioedema >6 weeks, not allergy related
Due to increased sensitivity of mast cells to spontaneous or physical activation.
Responds to high dose antihistamines.
Should avoid oral/systemic steroids.
85
ARA criteria for hypersensitivity vasculitis
3 out of 5 of following
1. Age >16 years
2. Temporal relationship with causative drug (usually sulphonamides, penicillins, cephalosporins, allopurinol, phenytoin)
3. Palpable purpura
4. Maculopapular rash
5. Perivascular neutrophils on skin biopsy
86
C-ANCA
Cytoplasmic granular fluorescence with central accentuation. Directed against PR3.
90% in GPA
30% in MPA
Correlates with ENT, URT disease, high relapse rate.
87
P-ANCA
Perinuclear staining with nuclear extension. Directed against MPO.
70% in MPA
10% in GPA.
Associated with low relapse rate. P-ANCA usually disappears and never recurs.
88
How does PTU cause drug induced ANCA associated vasculitis?
PTU accumulates in neutrophils and binds to MPO, changing its structure and making it more antigenic.
Usually after 18 months of therapy. Seen in 30% of patients with Graves disease.
If mild disease, withdraw causative agent with careful follow up. If multiorgan involvement, short course of steroids with possibly further immunosuppressants.
89
Incidence of P-ANCA in IBD
P ANCA is more commonly seen in UC compared to Crohns - 70% vs 10% in Crohns. Can be useful in distinguishing between the two in undifferentiated IBD.
90
What does TLRs recognize?
PAMPS - pathogen associated molecular patterns
DAMPS - danger associated molecular patterns (released by necrotic or stressed cells). Mediates sterile inflammation.
91
Mechanism of action of cyclosporine A/tacrolimus
Binds to immunophilin which then binds to calcium/calcineurin-calmodulin comlex and inhibits dephosphorylation of NFAT.
NFAT is a transcriptional factor for IL-2 and other cytokines such as IL3 and 4, TNF alpha.
92
How does cyclosporine affect MMF level?
MMF undergoes enterohepatic recirculation which produces a secondary peak at 6-12 hours after the dose. Cyclosporine educes AUC by interfering this pathway.
93
Mechanism of action of MMF
MMF is a selective non competitive reversible inhibitor of inosine monophosphate dehydrogenase which is a key enzyme in de novo synthesis of guanosine nucleotide. B and T cells are critically dependent on this pathway as they are not able to utilize the salvage pathway. Hence B and T cells are affected selectively.
94
How does sirolimus differ from tacrolimus?
Sirolimus binds to FKBP 12 immunophilin as well but this complex has no affinity to CN/CM complex. It instead binds to mTOR and inhibits T and B cells as well as non immune cells such as fibroblasts, viruses, malignant cells.
95
Explain antibody dependent cell mediated cytotoxicity (ADCC)
ADCC operates via 2 mechanisms:
1. Cytotoxic cells with Fc receptors for immunoglobulins can bind to the antibody and lyse target cells which are coated with antibody.
2. Direct leukocytes into the area of the damage
IgG directs NK cells and neutrophils - they release cytokines and granule proteins on encounter with antibody coated targets
Also IgE targeted against parasites.
96
Which cells undergo VDJ rearrangements?
Only B and T cells
97
Cytokines involved in atopy
IL4, IL5, IL13
IL4 promotes Th2 cell growth
IL4 and 13 promotes IgE class switching
IL5 promotes eosinophil recruitment to site of inflammation
98
What history points towards type 1 hypersensitivity reaction? (ie, IgE mediated)
Urticaria, angioedema, anaphylaxis.
99
Samter's triad
Aspirin sensitivity
Asthma
Nasal polyps
100
Pathogenesis of chronic granulomatous disease
Deficiency of 1 of 4 subunits of NADPH oxidase resulting in lack of respiratory burst of neutrophils necessary for killing of intracellular organisms.
101
Hyperacute rejection
Caused by pre-existing antibodies within the recipient to donor antigens that attack graft endothelium, activate complement, endothelial necrosis, platelet deposition and local coagulation.
Due to development of donor HLA antigens or ABO group antigens.
Patients develop anti-HLA antibodies due to previous pregnancy, blood transfusion, or transplant.
Before transplantation, recipient serum is cross matched against donor cells.
For ABO preformed antibodies, can undergo perioperative removal of antibodies from the recipient.
For HLA preformed antibodies, transplant is usually not performed as risk of rejection is high even if attempts are made for desensitization.
102
Incidence of cancers with immunosuppression in solid organ transplanation
20% at 10 years
More associated with CNIs. mTOR inhibitors may be protective.
Especially virus associated cancers:
EBV associated PTLD
Cutaneous SCC due to HPV
Kaposi sarcoma due to HHV 8
103
Which food allergy represent contraindication to influenza vaccine?
Egg allergy.
MMR vaccine is OK.
104
Serum tryptase - rise and fall
Rises to peak in 60-90 minutes, persist for upto 5 hours.
However if persistent elevation, think of systemic mastocytosis.
Can be elevated with general mast cell degranulation.
105
Mechanism of action of C1 esterase inhibitor
Serine protease inhibitor.
| Binds to C1r:C1s and causes them to dissociate from C1q, and limits time available to activate C4 and C2.
106
Hereditary angioedema
Due to deficiency of C1 esterase inhibitor.
Lack of inhibitor results uncontrolled activation of C1, resulting in activation and consumption of C2 and C4 and release of vasoactive mediators, mainly kinins.
C3 levels are typically normal.
C1q levels are normal in hereditary forms. Decreased in acquired forms due to consumption.
Presents with recurrent attacks of oedema which are NON PRURITIC, NON URTICARIA, usually resolves within 72 hours.
