Immunology Flashcards
Explain how abatacept works.
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.
Explain how ipilimumab works.
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.
Explain how pembrolizumab works.
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.
What is the importance of CD40L-CD40 interaction between B and T cells?
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.
How does CD8 cytotoxic T cells kill?
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.
For the following CD4 cell subtypes, name the responsible interleukin for differentiation.
Th1
Th2
Th17
Treg
Th1 - IL12
Th2 - IL4
Th17 - TGF beta, IL6
Treg cells - IL10, TGF beta
For the following subtypes of CD4 cells, name the main cytokines secreted and their role.
Th1
Th2
Th17
Treg
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
What are the key cytokines involved in psoriasis and their targeting monoclonal antibodies?
- TNF alpha - etanercept, adalimumab, infliximab
- IL 12/IL 23 inhibitors - ustekinumab. U for TUwelve.
- IL-17 inhibitors - secukinumab. S for seventeen.
What does deficiency in Th17 lead to and what are the consequences?
Chronic mucocutaneous candidiasis.
Recurrent skin, nail, mucosal infections as Th17 is responsible for barrier function, neutrophil response and production of antimicrobial peptide.
Th2 cells secrete IL4, IL5 and IL13. What are their roles?
IL4 - promotes further T cell differentiation into Th2.
IL5 - attracts eosinophils
IL13 - B cells to promote IgE switching
What is the causes of SCID?
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.
Describe pathogenesis of CGD
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.
Which cells express HLA class I?
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.
Which cells express HLA class II?
HLA DP, DQ, DR.
Expressed only by specialized APCs such as macrophages, B cells and dendritic cells.
Presents peptides derived from ingested extracellular antigens.
What is the aim of MHC/HLA class I pathway?
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.
What is the aim of MHC/HLA class II pathway?
Restricted to APCs who process exogenous antigens and presents the processed molecule via HLA type II receptors.
Role is activation of CD4 cells.
Describe 4 roles of NK cells.
- 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.
Describe ADCC in NK cells
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.
How does NK cells kill cells that have lost MHC expression?
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.
Features of DiGeorge syndrome?
CATCH-22
Cardiac abnormalities (especially ToF) Abnormal facies Thymic aplasia Cleft palate Hypocalcaemia/hypoparathyroidism due to hypoplasia or absence of parathyroid gland
3 Advantages of killed vaccine?
- Less likelihood of contamination
- Do not revert to virulence
- Heat stable
3 Advantages of live vaccines?
- 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
Distribution of IgA1 and IgA2
IgA1 predominates in airways
IgA2 predominates in colon
Equal amounts in small bowel
IgA1 is predominant in serum
6 Contraindication to allergen specific immunotherapy
- 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
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
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.
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.
3 cardinal manifestations of APECED
- Chronic mucocutaneous candidiasis
- Autoimmune hypoparathyroidism
- 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.
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.
4 mechanism of suppression by Treg cells
- CD25 sops up IL-2 and restricts access by conventional T cells
- CTLA-4 binds to CD80/86 (B7) on APCs and
- Produces inhibitory cytokines IL10, TGF beta
- Cytolysis of macrophages and T cells via granzyme B/perforins
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
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.
What does raised tryptase indicate?
Raised tryptase indicates mast cell degranulation - however it does NOT distinguish between IgE and non-IgE mediated causes.
Fruits associated with latex allergy
Banana Chestnut Avocado Kiwifruit Papaya Fig Melon
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.
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
Lack of neutrophils result in:
High grade infections with staph, gram negative bacteria, and invasive fungal infections such as invasive aspergillosis, systemic candidiasis.
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
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
4 major causes of B cell immunodeficiencies
CVID
Bruton’s X linked agammaglobulinaemia
Hyper IgM syndrome
IgA deficiency
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
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.
