REVISION SESSION (not finished) Flashcards
Draw the tree of blood cells.
pluripotent stem cell Lymphoid --> Bcell/Tcell Myeloid --> - granulocyte --> neutro/eosino/basophils - monocyte --> macrophage - megakaryocytic --> platelets - erythroblast --> erythrocyte
What are the three ‘layers’ of immunology?
immune barrier
innate immunity
adaptive immunity
What are the three types of immune barriers?
physical e.g. skin
chemical e.g. tears, bile acids, gastric acid
mechanical e.g cilia, mucosal surface
Give three examples of a defect in a physical immune barrier that can lead to infection
Hickman line
IV cannula
eczema
What is innate immunity?
What immune cells or other processes is it mediated by?
What does is it control and what does it cause?
- initial response to injury or infection
- mast cells, macrophages, complements
- controls infections and causes inflammation
Draw Venn diagram of innate and adaptive immune cells.
Innate - dendritic cell - macrophage - granulocytes - - complement protein Adaptive - B cell - T cell CD4+ and CD8+ Both - NK cell - gammadelta T cell
What occurs immediately in injury/early infection/
histamine release from mast cells
What are the roles of histamine?
vasodilation of blood vessels - increases blood flow
increase vascular permeability - immune cell extravasation
Describe the effects of mast cell activation
Activation of smooth muscle cells --> vasodilation Activation of endothelial --> up regulation of adhesion molecules --> breakdown of tight junctions --> exocytosis of Weibel-Palade bodies --> inflammatory mediator production/secretion Mediator release --> cellular recruitment --> vascular leakage --> clot prevention Extravasation of Leukocytes - neutrophils, DC's, NK cells, etc. Leakage of plasma proteins - IgG, complement, etc.
What are PAMPs and PRRs?
Give examples of PRRs
Part of innate immune response PAMP = Pathogen Associated Molecular Pattern PRR = Pattern Recognition Receptors - Scavenger receptors - Mannose, CD36 - TLR receptors - TLR 2,4,5
What is the relevance of My88?
Common protein in cascade following binding of PAMP to TLR.
This cascade ultimately activates the genes in the nucleus to up regulate inflammatory cytokines (IFN and others)
Genetic defects in My88 results in immunodeficiency as no upregulatroy genes and these patients can have severe infection but with no appropriate acute phase response. They don’t get a temperature when they have an infection.
What is the role of chemokines and cytokines?
They recruit more immune cells to site of inflammation.
Stimulate production of acute phase protein in liver
Give examples of 3 cytokines and 3 chemokines
Chemokines - CXCL8 - CXCL9/10/11 - CCL3 Cytokines - TNFalpha - IL-1beta - IL-6
What are the acute phase proteins in the liver?
Increase: - CRP - hepcidin - complements Decrease: - albumin
Where do Il/1B, IL-6 and TNFaplha act?
lvoer bone marrow endothelium hypothalamus fat, muscle dendritic cells
In innate immunity, by what 3 mechanisms is killing mediated?
- NADPH oxidase
- Reactive nitrogen species
- Lysosomal killing
When are neutrophils important?
in acute inflammation for killing
Neutrophil defects leads to ………… ………..
What are 3 common causes of this?
neutropenic sepsis
- chemotherapy
- immunosuppression - tranplant, chronic inflammation
- leukocyte adhesion deficiency
Describe the steps of neutrophil recruitment
- Rolling adhesion
- selectins - Triggering
- chemokine receptors
- integrin activation - Firm adhesion
- activated integrin bind to ICAM on endothelium - extravasation
- squeezes between endothelial cells
What is complement?
What role does it play?
How many ways can it be activated?
Is it easily activated?
- soluble protein in blood produced in the liver
- play a significant role in protecting against bacterial infection
- activated by three main pathways, all of which converge
- easily activated, so there are inhibitor proteins to prevent this
What are the 3 pathways of complement activation?
- Classical Pathway - antigen:antibody complexes
- MB-Lectin Pathway - lector binding to pathogen surfaces
- Alternative pathway - pathogen surfaces
What are the 3 effects of complement activation?
Which proteins are responsible for each?
- C3a, C5a = Recruitment of inflammatory cells
- C3b = Opsonisation of pathogens
- C5b-C9 = Killing of pathogens (MAC’s)
Name the results of some complement deficiencies.
C1, C2, C4 = immune complex disease such as SLE
S5b - C9 = neisseria meningitides infection causing meningitis
How is acute inflammation resolved?
- neutrophil apoptosis / necrosis
- wound healing
What happens if acute inflammation doesn’t resolve?
you get chronic inflammation
What is chronic inflammation characterised by?
- lymphocyte infiltrate
- lead to impaired wound healing
- fibrosis and angiogenesis
Chronic inflammation occurs when acute phase cannot be resolved. Give two examples of when this might happen
Persistant infection e.g. TB
Autoimmune disease e.g. RA, SLE
What is granulomatous inflammation?
formalised structure of activated macrophages, other immune and epithelial cells that surround and wall off the pathogen e.g TB
Which cells mediate adaptive immunity?
What do they do?
dendritic cells
- engulfs antigen in inflamed tissue through surface receptor
- drains to lymph nodes to stimulate B and or T cells
- activation of adaptive immune system
What 2 things does the activation of the adaptive immune system require?
- antigen recognition - by MHC and TCR/BCR
- co-stimulatory molecules and cytokine signatures
What T cells do MHC 1 and 2 act with?
MHC 1 = CD8+
MHC 2 = CD4+
Describe briefly the MHC 1 pathway
endogenous antigen
proteasome
TAP protein
present on MHC Class 1
Describe briefly the MHC 2 pathway
endogenous antigen engulfed endocytic route peptide presented on MHC 2 or exogenous antigen
What MHC do DC’s use and how?
exogenous antigen engulfed peptide presented on MHC class 1
What is the role of co-stimliatory molecules?
Which are the important ones to know?
- they provide a second signal
- CD80/86 is presented on APC’s which stimulate the T or B cell for activation
- CTLA-4 on dendritic cells events activation of Tcell
- useful for unnecessary activation which is underlying cause of autoimmunity
What is the role of cytokine signatures?
Give 2 examples
- they provide a third signal
- they are produced by APC/DC
- e.g. IFNgamma, TNF
- They help with Tcell differentiation
Where are T cells produced?
What is their main function?
What are they defined by?
- produced in the bone marrow but mature in the thymus
- circulate in the blood and lymph nodes to identify any antigen as part of surveillance
- defined by the receptor e.g. CD4 / CD8
Describe lymphocyte expression
- lymphocytes express CD4 and TCR
- when CD4 interacts with MHC2 on APC, its TCR can meet and become specific or the antigen being presented by the MHC2.
- depending on the cytokine environment this interaction polarises the T cell to become either a memory cell or one of a number of effecter cell phenotypes
What are 4 main effector T cells?
Th1
Th2
Th17
Treg
What are the stimulatory molecules required for the 4 main effector T cells?
IL-12 –> Th1
IL-4 –> Th2
IL-1, IL-6, TGFb –> Th17
TGFb –> Treg
What are the cytokines products of the 4 main effector Tcells?
Th1 –> IFNgamma
Th2 –> IL-4, IL-5, IL-13
Th17 –> IL-17, IL-21, IL-22
Treg –> TGFb, IL-10
What is the function of CD8 cells?
cytotoxic killing of virally infected cells
What is 4 main effector functions of T cells?
Th1 –> pro-inflammatory cell especially for intracellular bacteria killing
Th2 –> parasitic killing
Th17 –> mucosal immunity (gut) by producing IgA and anti-microbials such as defending
Treg - regulatory function
Where are B cells produced and mature?
bone marrow
What distinguished immature B cells for matures B cells?
Immature = expresses surface IgM and undergoes negative selection if strongly binds antigen Mature = expresses IgM and IgD an circulate to enter an immune response
-
-
natural antibodies - from breast milk
thymus independent - non-protein antigens
thymus dependent - protein antigens
What is the type of response produced by thymus independent mechanism?
What is this ineffective against?
poor response
ineffective against encapsulated bacteria
Describe T cell and B cell interaction
- T cell is primed by dendritic cell
- B cells present antigens via MHC II - for a CD4 T helper cell
- Primed T cell activates B cell via CD40-CD40L
- These B cells and T cells form a germinal centre
What two process occur in the germinal centre?
- isotope switching
- affinity maturation
Describe the sequence of events that occur in a lymph node
Naive B cell Clonal expansion Somatic hypermutation - disadvantageous mutation --> apoptosis - improved affinity --> selection --> class sweating --> memory b cell or plasma cell
What is the different between the dark and light zone of the lymph node
Dark zone = clonal expansion and somatic hypermutation Light zone = selection and class switching
What is class/isotope switching?
What T cell induces each antibody type?
Isotype switching is induced by differentiated T cells
- TH1 - IgG
- Th2 - IgE
- Th17 - IgA
Occurs via spacing of the constant regions beside the VDJ gene
What is the role of affinity maturation?
produces antibody highly specific to anti
What are the 4 functions of antibodies? Which antibodies are responsible for each?
- neurtralisation of microbe and toxins - IgG and IgA
- opsonisation and phagocytosis - IgE, IgG
- antibody dependent cellular cytotoxicity (ADCC) - IgG (IgG mediate viral killing with NK cells)
- complement activation - IgG, IgM
Describe the 4 stages of ADCC
- anybody binds to antigen on the surface of target cells
- Fc receptors (FcgammaRIII) on NK cells recognise bound antibody
- Cross-linking Fc receptors signals the NK cells to kill the target cell
- Target cell dies by apoptosis
Which antibody type mediates viral killing with NK cells?
IgG
What is the clinical application of autoimmunity?
- transplantation
- allergic disease
- inflammation in ageing
When/why does autoimmune disease occur?
occurs due to failure of tolerance
This is mainly peripheral T cell tolerance
What are the 3 aspects of peripheral T cell tolerance?
ignorance
cell anergy and death
suppression - Tregs
What is cell anergy?
When there is cross-talk between self-antigen and a foreign antigen
Describe the implications of loss of T-reg function
–> autoimmunity
- reduced T-reg population in the tissue
- defects in the CTLA-4 leads to uncontrolled T-cell activation
Loss of T cell tolerance leads to antibody production
What is SLE?
systemic lupus erythematous - defective clearance of immune complex; anti double stranded DNA
What is found in RA?
anti-RF and anti-CCP
What is the general approach to managing SLE and RA patients?
immunosuppression
What is haematology?
a study of blood cells both RBC, WBC and platelets
Where does haematopoiesis occur?
Occurs in the bone
In the presence of CD34+ stem cells which continuously divide
