IMMUNITY REVISION Flashcards
what causes the cardinal signs of inflammation
caused by histamine release from mast cells, basophils and platelets, binds to histamine receptors and leads to vasodilation and exudation
what are the cardinal signs of inflamamtion
rubor
calor
dolor
tumour
functio laesa
what are the different barrier defences
flow of air or fluid
enzymes
low pH
defensins
normal microbia
tissue resident immune cells
cilitated cell
goblet cells
epithelial tight junctions
flow of air or fluid
reduces the change of mucroorganisms attaching
enzymes
secretions contain antimicrobial enzymes
lysozyme in tears
low ph
restricts which oathogens can survive if ingested
defensins
antimicrobial peptides disrupt the clel membranes and virus envelopes
normal microbia
outcompete potentiall harmful rganisms
tissue resident immune cells
recognsie
engulf
phagocytose and ill pathogens
cilitated cells
move mucus along to flush out thepathogens
goblet cells
produce mucus which acts as a sticky barrier
epithelial cells tight junctions
restrict movement of microorganisms deep into the tissue
migration of neutrophils in inflmmation
- Margination: cells line up against the endothelium
- Rolling: close contact with and roll along the endothelium
- Adhesion: connecting to the endothelial wall
- Emigration: cells move through the vessel wall to the affected area
what happens when no microbes are present
- DAMPs/PAMPs bind to PRR’s
- Activate cells
- Induce inflammatory cytokine release
- Trigger inflammation
what are the different types of PRR’s
toll like receptors
phagocytic receptors
NOD and RIG like receptors
toll like receptors
external or endosomal
change gene transcription and cytokine release
which toll like receptors are on the plasma membrane
TLR4
TLR5
TLR2
TLR1/6
which toll like receptors are endosomal
TLR3
TLR7
TLR8
TLR9
what binds to TLR 4
LPS
what binds to TLR 5
flagellin
what binds to TLR2, 1 and 6
lipoproteins
what binds to TLR 3
dsRNA
wat inds to TLR 7 and 8
ssRNA
what binds to TLR9
CpG DNA
phagocytic receptors
external
induce the uptake of pathogens into the endosomes and killing of the pathogen
what are the different phagocytic receptor
complement
savenger
mannose
Fc
C type lectin
NOD and RIG like receptors
cytoplasmic
change gene transcription
and cytokine release
extracellular TLR signalling
- Binding of PAMP to PRR
- Signal to nucleus
- Adaptors containing TIR domains transmit message to cytoplasm
- NFKB assembles and binds to DNA
- Instructs cells to produce new proteins which initiate next stage
endosomal TLR signalling
- Recognition of a pathogen within the endosome
- Signal to the nucleus
- Adaptors containing TIR domains transmit message to cytoplasm
- Interferon response factors assemble and bind to DNA
- Instructs cells to produce new proteins: interferons which direct immune responses against viruses and intracellular bacteria
- IRF3: interferon B so antiviral response occurs
- IRF7: type 1 interferons so antiviral response occurs
NOD and RIG signalling
- Recognition of DAMP’s and PAMPs in the cytoplasm transmits signal to the nucleus
- NLR aggregate and form inflammasome
- Activates and causes release of pro-inflammatory cytokines
- RLR aggregate and activate transcription factors leading to production of new proteins including type 1 interferons
macrophages and pathogens
- Pathogen recognized by the PRR and macrophages activated
- Phagocytosis induced
- Pathogen is either internalized in a phagosome or activated macrophages make proinflammatory cytokines to attract other immune cells
- Pathogen is killed by oxidative burst and digested enzymes
how do immune cells find pathogens
where the concentration of the chemokine is the highest
neutrophil arrival
- Phagocytose similar to macrophages
- Microbes are phagocytosed into phagosomes
- Phagosomes fuse with the granules which contain antimicrobial enzymes, proteins and peptides
- Microbes killed by digestion and respiratory burst
- 3 types of granules: primary (azurophilic), secondary (specific) and tertiary (gelatinase)
- Apoptosis and netosis: respiratory burst by producing toxic oxygen species to kill the bacteria
- Netosis causes release of NETs: DNA covered in histone proteins and granule contents which trap the microbes
what happens if the pathogen isnt cleared
- Release pro-inflammatory cytokines
- Damaged blood vessels will produce bradykinins to increase vascular permeability and stimulate nerves causing pain
- Then resolves in adaptive immunity
exampels of some acute phase proteins
Acute phase proteins: serum amyloid, C-reactive, fibrinogen, mannose binding lectin
complement pathway
howdo cells recognsie intracellular moleucles
- Damage caused can be recognized by PRRs
- PAMPs released from cells can also activate innate immune cells
- Phagocyte will try and kill the bacteria by acidification and enzymatic digestion
- Some thrive and survive
- Others will penetrate cell from outside or escape from phagosomes into the cytoplasm
- When in the cytoplasm the bacterial products can be recognsied by internal PRRs
- Cytokines released to activate NK cells and adaptive immune cells
interferons
increase viral defences and reduce viral replication
tpye 1 interferons
Type 1: IFN alpha and beta, made by infected cells which increase anti-viral defence mechanisms in nearby cells
- IFNa and b bind to IFNa receptor
- Activation of genes which degrade viral RNA and stop protein synthesis needed to make viral capsues
- Recruit and activate NK cells
- NK cells kill by apoptosis: granules containing perforin and granzyme by recognizing altered self cells
type 2 interferons
Type 2: IFN gamma released by adaptive immune cells
type 3 interferons
Type 3: anti-viral and anti-fungal responses
naive CD4 secreting IL-12 and IFN gamma
autoimmunity
intracellular pathogens
T helper 1 with T bet transcription factor
then T helper 1 will secrete IFN gamma and TNF
naive CD4 secreting IL-2 and IL-4
extracellular pathogens, allergy and asthma
GATA 2 transcription factor to TH2
Th2 secretes IL4,5,13
naive CD4 secreting TGF beta and IL-4
allergy, asthma, helminthes
TH9 by PU.1 and IRF4
secretes IL-9
naive CD4 secreting IL-6 and 21
B cell help in the germinal centre
Bcl-6 will transcribe Tfh
which will secrete IL-21, 4 and IFN gamma
naive CD4 secreting IL-1 and 23
extracellular bacteria, fungi and autoimmunity
RORyt will transcribe Th17
which will secrete IL-17 and IL-22
naive CD4 secreting TGF beta and IL-2
immune tolerance, lymphocyte homeostasis
FOXp3 will transcribe Treg cells
which secrete TGF beta and IL-10
naive CD4 secreting TNF and IL-6
autoimmunity
AHR will transcribe TH22
which secretes Il-22 and TNF alpha
t celsl
cytotoxicity, help of other immune cells, regulation, originate in the bone marrow and mature in the thymus, express T cell receptors (heterodimeric) and will recognize peptides presented to it
b cells
antibodies
memory T and B cells
long-lived, trigger quicker and more effective immune response on second infection with the same pathogen
professional APC’s
macrophages, B cells and dendritic cells
dendriticc cells
- Have MHC class 1 and 2 so can activate both CD8 and CD4
- Migrate to secondary lymphoid tissue
- Mature when stimulated by PAMP’s and DAMP’s
cytotoxic T cells
- MHC class 1, which presents antigens on all body cells, ecode for HLA A,B and C antigens
- CD8 co receptor
- kill virus infected cells directly
T helper cells
- MHC class 2, presents antigens only on professional antigen presenting cells, encode for HLA-DP, DQ and DR
- CD4 co receptor
- Produces cytokines to activate other immune cells and express surface molecules to affect other cell types
MHC class 1 presentation
- Infection of the body cell by the virus
- Virus is chopped up by the proteosome
- New viral particles are synthesized in the ER
- Antigens loaded onto the MHC class 1 in the ER
- Activates CD8 cytotoxic t cells
MHC class 2 presentation
- Phagocytosis of the pathogen by APC
- Pathogen chopped up by phagolysosomes
- Antigens loaded onto MHC class 2 in phagolysosome
- Activates CD4 T helper cells
3 signals for naive T cells to be activated
- Antigen binding to the T cell receptor: peptide- MHC to the TCR, an immune synapse will form if recognition occurs
- Co-stimulation: B7 molecules (CD80 and 86) on the APC binds to CD28 on the T cell
- Cytokines: APC produces cytokines that instruct the T cell to differentiate into the correct type of effector T cell
what are the 2 cytotoxic T cell killing mechanisms
perforin/granzyme
Fas:FasL interaction
perforin/ granzyme
- Exocytosis of the lytic granules at the immune synapse
- Perforins polymerise forming cylindrical pores in the target cells
- Triggers the caspase cascade
Fas:FasL interaciton
- FasL is expressed by the cytotoxic T cells
- Fas by the target cells
- Activates FADD and then pro-caspase 8
- Caspases are activated
- Resulting in orderly destruction of the target cell
how can a CD4 T cell activate a CD8 t cell
- Activated CD4 T cell expresses CD40L and upregulates IL-2
- This enhances APC survival and cross primes CD8 cytotoxic by enhancing APC activation
- Increases B7 expression and CD70
- Increases APC production of IL-12
b cells activation
- Antigen activates the B cell via the BCR, taken up, processed and presented on MHC class 2 to a specialized CD4 helper T cell
- B cell will co-stimulate with CD4 helper T cell with CD40: CD40L respectively
- CD4 helper T cell will instruct the B cell to produce a certain antibody type
- B cell is activated, proliferates and differentiates into plasma cells and memory cells
- IgM is the first antibody class to be made
variable regions
detemrine antigen specificity
constant region
determines antibody class
binds to Fc eceptors
5 types of antibodeis
IgG
IgE
IgA
IgD
IgM
IgG
high affinity and crosses the placenta
IgE
parasite repsosnesand allergies
IgD
basophils
IgA
secreted at mucosal sites
IgM
made on first encounter with an antigen
5 functions of antibodies
neutralisation
opsonisation
complement activation
NK cell sensitisation
mast cell, eosinophil and basophil sensitisation
neutralisation
bind bacterial toxins and virus particles, stop them binding receptors on the host cells, prevent tissue damage, IgA and IgG
opsonization
antibodies that bind to pathogens, phagocytes recognize bound antibody via Fc receptor, trigger phagocytosis and killing, IgG
complement activation
antibodies that bind pathogens and activate complement pathway, trigger formation of membrane attack complex and killing of pathogen, IgM and IgG
NK cell sensitisation
antibodies against their viral proteins, may bind their target on surface of infected host cells, NK cells recognize bound antibody via Fc receptor and kill cells, IgG
mast cell, eosinophil and basophil sensitisation
cross linking causes mast cell degranulation and releases mediators, eosinophils recognize IgE bound to parasites and release granules to kill parasite, basophils recognize IgD activating anti-microbial and pro-inflammatory mechanisms
what is a primary lymphoid organ
site where T and B cells are made and matured
exampels of primary lymphoid organs
bone marrow
thymus
secondary lymphood organs
site where B and T cells can recognise antigen and beome activated to fight infeciton or cancer
examples of secondary lymphoid organs
lymph nodes
spleen
MALT’s
spleen in immunity
- Foreign antigen carried into the spleen from the splenic artery
- Into the marginal zone
- Captured by dendritic cells
- Dendritic cells and T cells move to the PALS from the splenic artery
- In the PALS dendritic cells activate helper T cells
- Activate B cells and activated B cells and helper T cells move to the primary follicles in the marginal zone
- Leads to production of secondary follicle in the germinal centre
lymph nodes in immuntiy
- Antigen and APC from the tissue travel to the lymph node in the lymphatic fluid
- Antigens are processed by the resident dendritic cells in the paracortex
- Dendritic cells and B cells activate antigen specific helper T cells
- B cells also activated in the paracortex by antigen directly via the BCR and helper T cells
- Activated B and helper T cells form foci with proliferating B cells
- B cells and helper T cells migrate to primary follicles of the cortex and interact with the follicular dendritic cells
- Leads to production of a secondary follicle with a germinal centre and production of antibody producing plasma cell
germinal centres
- In the secondary lymphoid follicles
- B cells proliferate and undergo somatic hypermutation to make better antibodies
- Proliferating B cells seen in the centre, light and dark zones
- Inactive B cells pushed towards the edge to form the mantle zone
- B cells surrounded by a cuff of T helper cells
wehat happens in the dark zone of a germinal centre
b cells mutate their genes
what happens in the light zone of a germinal centre
b cells present to follicular t helper cells
somatic hypermutation
immunoglobulin gene sequences are further mutated after rearrangement and binding to their antigen, V sequences are mutated resulting in more diversity and higher affinity
affinity maturation
selection of B cells with the highest affinity BCR through interaction of follicular T helper cells
what occurs after somatic hypermutation and affinity maturation
- B cells move into the light zone
- Receive a second signal from a T helper cell
- Causes differentiation into either plasma cell or memory B cell
- Can induce class switching of antibody
class switching
make different types of isotypes with different constant regions
2 types of MALT’s
BALTs: bronchus
GALTS: gut
inductive sites
where B and T celsl are primed by antigen and differentiate into the effector cell
effector site
where B and T cells migrate to carry out effector funcitons to clear pathogens
microfold cells
- Inductive sites
- Broad processes in contact with the lumen
- Deep invagination in basal membrane
- Filled with clusters of B, T, dendritic cells and macrophages
- Antigen is phagocytosed by the M cell
- Transported and released into the basolateral pocket of the cell
- Antigen taken up by the dendritic cells leading to activation or tolerization of T and B cells in the lamina propria
what do plasma cells secrete
IgA and IgD
