Immunology Flashcards
Azathioprine
MOA: Purine antimetabolite, impairs lymphocyte proliferation
Interacts with allopurinol and febuxostat 0> increased risk of bone marrow toxicity
Side Effects: Myelosuppression, mouth ulcers, oesophagitis, Hepatitis, photosensitivity, hypersensitivity syndrome (SJS/TEN, Pneumonitis), Interstitial Nephritis
Cyclophosphamide
MOA: Alkylating agent -> cytotoxic to lymphocytes by interfering with DNA cross linking
Immune response to live vaccine
Humoral and cellular response
High affinity antibodies with long term immune memory
Immune response to killed, subunit and toxoid vaccines
Response not as strong as live vaccines as pathogen can’t replicate. Primarily induce humoral response.
Need multiple doses to induce effective response, and boosters required.
Q fever vaccine can revert to wild type (exception to rule)
Immune response to conjugated vaccines
Polysaccharide + protein conjugate
T cell dependent response driven by conjugate
Vaccination and steroids
Live vaccines can be given if dose <20mg/day (or equivalent)
If given within one month of dose this high, risk of incomplete seroconversion.
After ceasing long term steroids (>2 weeks at >20mg/day), need to wait 1 month before vaccination
Management of accidental live vaccine administration to immunocompromised patient
Immunology input
IVIg to mop up vaccine
Mannose binding lectins
Pattern recognition molecules
Bind to mannose and N-acetyl glucosamine on microbes
Active complement cascade via lectin pathway
T cell negative selection
Removal of T cells at risk of causing autoimmunity by testing against self antigen by APCs
T cell positive selection
T cell receptors tested for ability to bind to MHC on APCs in thymus
If can’t bind to MHC, anergy triggered
MHC Class I
HLA-A, B, C
Present on all nucleated cells
Target for CD8+ cytotoxic T cells
MHC Class II
HLA- DR,DQ, DP
On antigen presenting cells
Target for CD4+ T helper cells
Immune response to intracellular pathogens, viral, bacterial infection
IL-12 and IFN-gamma release -> Th1 CD4+ T cell recruitment -> IFN-gamma and TNF-alpha release -> Macrophage recruitment
Immune response to Parasitic infection
IL-4 release -> Th2 CD4+ T cell recruitment -> IL-4, IL-5, IL-13 release -> Eosinophil recruitment
What type of infection are patients with asthma/atopy being treated with monoclonal antibodies at particular risk of?
Parasitic infection - most monoclonal antibodies block eosinophil activity
CD3
Present on all T cells
Role of C3a and C5a
Chemotaxis
Role of C3b
Opsonisation
Role of C5b
Formation of MAC alongside C6-C9
Triggers for alternative complement pathway
Endotoxins typically (lipopolysaccharides)
Others:
Aggregated Ig
Plant and bacterial polysaccharides
Radiographic contrast media
C3 nephritic factor
Some acute phase proteins
What protects host cells against complement?
DAF (Decay accelerating factor) and MCP (membrane cofactor protein): breakdown C3 convertase
HRF (Homologous restriction factor) C8 binding protein and CD59: prevent formation of MAC on host cells
NK Cell Regulation
Answer ####
Roll of Toll Like Receptors
Help a dendritic cell determine whether antigens are related to damage or foreign material, and thus whether they need to be presented
What is the key costimulation receptor for Dendritic Cells?
CD80/86 on DCs binds to CD28 on Naive Th cells in Lymph Node alongside interaction between MHC II and TCR
What chromosome are the genes for HLA on?
Chromosome 6
What is encoded as part of the HLA/MHC gene?
Class I: A, B, C, (E)
Class II: DP, DQ, DR
Class III: Complement C2 and C4, HSP70, TNF
What is required for MHC-I expression?
Beta 2 microglublin
What two receptors present on different immune cells have a very similar structure?
MHC-II and TCR
Where are the antigens presented by MHC-II predominantly found?
Extracellular/exogenous
Where are the antigens presented by MHC-I predominantly found?
Endogenous/intracellular/cytosol
What interleukin is released by naive Th cells to stimulate replication?
IL-2
What cytokines do Th1 cells produce?
IFN gamma, TNF-alpha
What cytokines to Th2 cells produce?
IL-4, IL-5
What cytokines do Th17 cells produce?
IL-17
What mechanisms do cytotoxic T cells use to induce apoptosis
Granzyme activity via Perforins
CD95L/CD95 interaction
What is the role of CTLA-4 and PD1/PDL1?
Bind to costimulatory receptors with greater affinity than their usual ligands to prevent activation of apoptotic signals
CD5
Present on B1 subset, do not produce memory cells, only produce IgM
What is the costimulatory signal for B cells?
CD40 on B cells binds to CD40L on Th cells alongside MHC-II/TCR interaction
What are the light chain gene segments of antibodies?
Kappa and Lambda. Two present in each antibody, but will both be the same type (i.e. either two kappa or two lambda)
What Ig bind most efficiently to complement?
IgM, IgG3 > IgG1 > IgG2
What is antibody affinity and avidity?
Affinity: strong binding
Avidity: lots of binding sites (e.g. IgM’s pentameric structure binds with high avidity, but low affinity)
IgA
Two types:
IgA1: in serum
IgA2: forms dimeric structure and found in mucosal areas with protective secretory piece which protects it from enzymatic activity
Type 1 Hypersensitivity
IgE mediated
Mostly immediate reactions
Th2 predominant environment - IL-4 mediates IgE production with help from IL-5
IL-5 primes eosinophils to migrate in response to chemotactic factors
Soluble antigen binds to neighbouring IgE on mast cells → crosslinking → mast cell activation → degranulation
Anaphylaxis, hay fever, hives, seasonal allergies, shellfish/peanut allergy, eczema
Most “allergic reactions” are type 1
Type 2 Hypersensitivity
IgG mediated cytotoxic hypersentivity
Cell bound antigens
Antibody dependent cellular toxicity
IgG binds to surface antigen on target cell → T cell or complement mediated cell death
May be opsonic adherence via FcR, Complement mediated, also MAC
Examples: Red blood cell transfusion reaction with mismatched blood type; erythroblastosis faetalis; hyperacute graft rejection thyrotoxicosis
Type 3 Hypersensitivity
Immune complex mediated
Soluble antigen
Deposition of antigen-antibody complexes in tissue → complement activation → neutrophil attraction → inflammation
Essentially the immune complexes can’t be phagocytosed when they are embedded in tissue, driving an inflammatory response
Examples: GN, RA, SLE
Type 4 Hypersensitivity
T cell mediated
Soluble and cell bound antigens
Th1 cells sensitised to antigens → exposed to antigen → cytokine release → Macrophage and CD8+ T cell activation
IFN-gamma and GM-CSF key to response - Th1 environment
Clinical: Contact dermatitis, Tuberculin reaction, T1DM, MS, RA
> 80% of drug allergies are Type IV (SJS and TEN)
Mechanism of Penicillin allergy
IgE mediated Type 1
ACEi allergy mechanism
Bradykinin
Mechanism of NSAID allergy
Type II hypersensitivity: cell bound antigen (don’t fully understand this mechanism)
Tryptase for Anaphylaxis
Most specific diagnostic test for mast cell activity and thus anaphylaxis
Should be done 60-90 minutes post reaction, and okay in first 4 hours
Histamine drops too quickly to be useful, can du urinary histamine metabolites
Gold standard test for food allergy
Oral food challenge
Skin prick testing has high NPV
Types of Adverse Drug Reactions
Type A: pharmacological, i.e. related to drug action (80%)
Type B: hypersensitivity (10-15%)
- Majority T cell mediated, and thus not immediate. rash including SJS and TEN. DOn’t interact directly with drug, is mostly via haptens
- Immediate reactions IgE mediated: anaphylaxis, bronchospasm
Key causes of DRESS
Carbamazepine, Allopurinol, Doxycycline, Phenytoin, Dapsone
Most common end organ involvement: Hepatic
HLA associated with Allopurinol hypersensitivity
HLA-B58
Key mediator of angioedema, the pthway activated and means of prevention
Bradykinin
Activates complement via classical pathway
Hereditary Angioedema types, treatment
Problems with C1 esterase
C3 levels normal, C4 often low
Icatibant can be given - recombinant C1 inhibitor
FFP can also help
Key: loss of inhibition of C1 → unchecked complement activation
Mechanism of ACEi angioedema
Blockade of ACE → reduced bradykinin degradation → accumulation → angioedema
mTOR Inhibitors
Everolimus and Sirolimus
block mTOR (mechanistic target of rapamycin) kinase -> bloackade of cell cycle progression -> prevents cytokine induced B and T cell proliferation
Used to prevent solid organ transplant rejection and Tuberous Sclerosis
Which cytokines are not upregulatory?
IL-10, TGF-beta
General Effects of cytokines
- upregulation of immune response
- Induce cell growth
- Affect T and B cells
- Affect expression of cell surface molecules important in cell communication
- interact via high affinity receptors on surface of cells
Characteristics of cytokines
SOluble, intercellular messengers
Low molecular weight, secreted proteins
Produced by diverse range of cells
Act in autocrine, paracrine or distance manner
Effective at very low concentrations
Transient
Pleiotrophic
IL-1 Function
Produced by macrophages and fibroblasts
Function:
- Proliferation of activated T and B cells
- Induction of IL-6, IFN-gamma, GM-CSF
IL-2
Produced by T cells
Stimulates growth of activated T, B cells
Activation of NK cells
IL-3
Produced by T cells and macrophases
Stimulates:
- Mast cell growth
- Growth and differentiation of haematopoietic precursor cells
IL-4
Produced by T cells and Mast cells
Function:
- Isotype switch from IgG to IgE
- Characterises Th-2 subset of interleukins
IL-5
Produced by Th2 subset T cells and Mast cells
Functions:
- IgM, IgA production
- Eosinophil and activated B cell proliferation
IL-6
Produced by Macrophages, T helper cells, mast cells, fibroblasts
Function:
- Induction of acutephase proteins
- Growth and differentiation of haematopoietic stem cells
GM-CSF
Produced by macrophages, T cells, endothelium, mast cells
Functions:
- Colony growth
- Activates macrophages, neutrophils, eosinophils
TNF-alpha
Produced by macrophages, T cells
Functions:
- Activates macrophages
- Tumour cytotoxicity
- Cachexia
TNF-Beta
Produced by CD4 T cells
Functions
- Induction of acute phase proteins
- Antiviral and anti-parasite activity
- Activation of phagocytes
- Induction of pro-inflammatory cytokines
IFN-Alpha
Produced by leukocytes
Functions
- Antiviral
- Upregulated MHC-I
IFN-gamma
Produced by T cells
Functions:
- Antiviral macrophage activation
- Upregulated MHC molecules
- Stimulates CTL differentiation
- Antagonises IL-4 effects
- Characterises TH1 subset
What cell type has CD25?
Activated T cells
Cell surface markers on Immature thymic cells
Tdt
Double positive CD4/CD8
Double negative CD3
Cell surface markers on T cells
TCR, CD3, CD2
CD4 (Th, interacts with MHC-II)
CD8 (Tc, interacts with MHC-I)
Cell surface markers on B cells
CD19, CD20
MHC- II
sIgM, or sIgG on memory B cells
Complement receptors: CD35, CD21
Cell Surface Markers on Macrophages
MHC-II
CD35
CD32 (Fc receptor for IgG)
CD11b
Cell surface markers on Dendritic Cells
MHC-II
CD11c/b
CD1a
Cell surface markers on Neutrophils
CD35
FcR
Ly6C
Cell surface markers on Mast cells
FcR for IgE
CD45
Present on all leucocytes
CD45RA → naive T cell
CD45RO → memory T cell
Immune response to viruses
Type 1 IFN produced early by innate immune system → limit viral replication
NK cells
Cytotoxic cells → IFN-gamma aids development
Neutralising antibodies
Immune response to Bacteria
Phagocytosis - opsonisation by Ab and C components
CD4 T cell cytokines - aid Ab production, Ab class switching and memory development
Antibody mediated neutralisation of bacterial exotoxins
Immune responses to Protozoa and worm infections
Mostly immunosuppressive
Immune system is cause of most host damage
High IgE (Th2) associated with worm infections
Can develop anaphylaxis if large quantities of Ag released, e.g. hydatid cyst rupture
Eosinophilia
No vaccines
Immunisation prior to splenectomy
Encapsulated organisms key. Have polysaccharide antigen. Should have these vaccines at least 2 weeks prior to an elective splenectomy.
Strep pneumoniae
Neisseria meningitidis
Haemophilis influenzae
Live attenuated vaccines
BCG, Sabin (polio), Measles, mumps
Never administered to immunocompromised individuals
Predisposition to Atopy
HLA-Dw2
Environmental pollutants can increase IgE levels and inihibit T cell function + tolerance induction
Polymorphisms in IL-4 promoter region can lead to increase IgE production
C3a and C5a anaphylotoxins
Can mimic a Type 1 hypersensitivty reaction, by also stimulating mast cell degranulation → same outcome as IgE cross linking on mast cells
However this is not Type 1 hypersensitivity
Some drugs can activate this - alternative complement pathway
What Th subset is predominant in Sarcoidosis?
Th1
What infections does complement deficiency predispose to?
Increased susceptibility to encapsulated gram negatives, particularly Neisseria as well as Haemophilis.
Severe pyogenic infecitons and immune complex disease common issues.
Effects of T cell Deficiency
Poor response to fungal, viral and intracellular bacteria
Prolonged graft survival
Di George: failure in thymic development
Effects of B cell deficiency
Increased susceptibility to pyogenic infections due to reduced opsonisation by antibodies and impaired phagocytosis
Impaired response to bacterial toxins
X gammaglobulinaemia (Bruton’s)
CVID
