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I&I Clodicle > Innate Immunity > Flashcards

Innate Immunity Flashcards

1
Q

Briefly describe platelets

A

No nucleus but have granules which secrete substances which control clotting and the breakdown of the blood clot
The platelets themselves Dom a part of the blood clot
They live for 8-12 days and are r over by the macrophages in the liver and the spleen

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2
Q

Briefly describe granulocytes

A

Neutrophils- live in the blood for a few hours and they migrate into the tissues where that can live for 4-5 days
They are phagocytic
Granules contain lysozyme and myeloperoxidase
Eosinophils- parasite infections
Basophils sentinel cells that alert for damage
Both are involved in allergies

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3
Q

Briefly describe monocytes

A

Can migrate into tissues from the blood and become macrophages
They are phagocytic

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4
Q

Briefly describe lymphocytes

A

T cells are early progenitor cells from the bone marrow but develop in thymus
B cells develop in the bone marrow and exit as naive cells
NK cells develop in the bone marrow

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5
Q

Describe the sites of haematopoiesis in development

A 
Yolk sac- 17 days-
Aorta-Gonad mesonephros- 2 months-
Placenta- 7 months
Foetal liver- 7 months
Bone marrow- 5-9 months
Infants- bone marrow in vitally every bone 
Adults- bone marrow in axial skeleton
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6
Q

Describe the haematopoiesis development tree

A

LT-HSC➡️ ST-HSC➡️ Multipotent progenitors (MPP)➡️➡️
➡️➡️common myeloid progenitor➡️ granulocyte-macrophage progenitor➡️ ➡️eosinophil, neutrophil, monocytes, basophils
➡️myeloid-erythroid progenitor➡️ erythrocytes, megokaryocytes
➡️➡️lymphoid➡️ T cell, B cell, NK cell

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7
Q

How would you measure haemoatopoiesis at different differentiation stages?

A

Identify by functional assay until they are committed precursor cells- immunotyping- CD34
Then identify with marrow staining- blasts

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8
Q

What are the factors that affect HSC differentiation?

A

Intrinsic factors- transcription factors

Extrinsic factors- the microenvironment- adhesion molecules, growth factor, receptors and surrounding cells

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9
Q

Name three growth factors that drive haemoatopoiesis down a particular route

A

EPO- MEP➡️ RBCs
TPO- MEP➡️ platelets
G-CSF- GMP➡️ neutrophils

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10
Q

Describe the neutrophil maturation stages

A

Myeloblast (large round nucleus, no granules)➡️ promyelocyte (large mostly found nucleus, some 1’ granules)➡️ myelocyte (smaller indeed enter nucleus, some 1’ and 2’ granules)➡️ meta myelocyte (smaller more indented nucleus and mostly 2’ granules)➡️ band (smaller horseshoe nucleus and 2nd granules)➡️ mature neutrophil (smaller lobulated nucleus and 2’ granules)

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11
Q

Briefly describe monocytes maturation

A

Monoblast➡️ pro monocytes➡️ monocytes

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12
Q

Describe erythropoiesis

A

Pronormoblast➡️erythroblast➡️ early➡️ intermediate➡️ late➡️ reticulocytes (extruded nucleus but still has RNA so it can make haemoglobin- erythrocytes cannot)

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13
Q

Which organ stimulates erythropoiesis?

A

The kidney has oxygen sensing perivascular interstitial cells that produce erythropoietin that upregulate RBC production

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14
Q

Describe platelet production

A

2000-3000 platelets per megakaryocyte
The cells enlarge due to nuclear division- endomitosis
4n-64n- more nuclei=more platelets
Regulated by TPO

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15
Q

What clinical techniques have we gained from our knowledge of haematopoiesis?

A

Erythrocytes transfusion- 1 month
Platelet transfusion- few days
HSC transplant- should last for whole life
Growth factors- EPO mainly used for end stage renal failure and in myelodysplasia, pre-autologous blood donation
G-CSF- prevention of infection in neutropenic patients
And mobilise stem cells into peripheral blood for stem cell harvest and transplantation

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16
Q

Give a brief description of haematological malignancies

A

Leukaemias- malignancies of haematopoietic cells which arise in the bone marrow and spread to involve blood, lymph nodes/spleen
Lymphomas- malignancies of lymphoid cells which arise in lymph nodes/spleen and spread to involve the bone marrow
Myelomas- malignancies of plasma cells in the marrow
Myeloproliferative disease and myelodysplasia- neoplastic chronic abnormal myeloid proliferation

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17
Q

What type of cells do you find in the blood?

A 
Erythrocytes
Platelets
Leucocytes
-Lymphoid- T cell, B cell, NK cells
-Myeloid cells- monocytes, granulocytes- eosinophils, basophils, neutrophils
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18
Q

What are PRRs and PAMPs?

A

Pattern recognition receptors (greatest expression on sentinel cells of the innate immune system) recognise pathogen-associated molecular patterns (common microbial components) eg. LPS, flagellin, lipoteichoic acid, beta-glycans or nucleic acid

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19
Q

Describe TLRs

A

Toll-like receptors are surface expressed PRRs that recognise surface/secreted PAMPs
Eg. Viral coat proteins, LPS, lipoteichoic acid, beta-glycan
Can be endosome expressed- found in phagocytic immune cells recognise nucleic acids

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20
Q

Describe CLRs

A

C-type lectin receptors are PRRs found on macrophages and dendritic cells
They recognise sugars- mannose in bacteria, beta-glucan in fungi or fructose

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21
Q

Describe NLRs

A

NOD- like receptors are PRRs expressed in the cytoplasm of macrophages and dendritic cells
Recognise surface PAMPS

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22
Q

Describe RLRs

A

Rig-like receptors are cytosol expressed PRRs expressed by most cells
Rig1 recognises ssRNA and MDA5 recognises dsRNA from viruses

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23
Q

Describe DSRs

A

DNA sensing Receptors are cytosol expressed PRRs found in most cells
Recognise DNA from viruses and bacteria

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24
Q

What are the cellular responses to the activation of PRRs?

A

Recognition of PAMPs- eg. Lipoproteins causes the heterodimerisation of the intracellular domains of TLR1 and TLR2➡️ release of interferon, interleukins, cytokines and chemokines which triggers a response
Also activates the adaptive response
Acute inflammation causes capillaries to become more permeable to fluid and cells

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25
Q

What TLR mediated effector functions inhibit virus replication?

A

IFN-alpha and IFN-beta stimulates the expression of ribonucleases and protein kinases that degrade mRNA and inhibit protein synthesis

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26
Q

How do TLR-mediated effector functions promote an adaptive immune response?

A

Dendritic cells increase CD80/86 expression
Present peptide-MHC complex after antigen uptake
Produce costimulatory molecules after activation of PRR➡️ activation and migration to lymph node to trigger the maturation of specific T cells

27
Q

What is special about blisters?

A

Sterile inflammation
Cause by physical damage to cells- cel lysis
They release Damage Associated Molecular Patterns (DAMPs)
Extracellular components exposes following lysis eg. DNA, histones and ATP
DAMPs are ligands for some TLRs, CLRs, NLRs and trigger then production of NF-kappa-beta for inflammation

28
Q

Briefly describe opsonisation

A

Complement and immunoglobulin receptors cover antigens if bacteria- promote phagocytosis

29
Q

Briefly describe how NK cells recognise and kill virus infected cells

A

MHC1 on normal cells is recognised by inhibitory receptors that inhibit signals from activating receptors
If this signal is edited the killer activating signal prevails
NK cells can also recognise and kill antibody opsonised virus-infected cells following Fc receptor ligation via Antibody-Dependent Cell-mediated Cytotoxicity (ADCC)
NK cells kill virus-infected cells via the release of lyric granules containing perforin, granzyme and FasL which induced apoptosis

30
Q

What is complement?

A

The humoral components of the innate immune system
Present in high concs in plasma and tissue fluids- produced in the liver and local release by macrophages
Involved in opsonisation- coating the pathogen so it can be more readily taken up by phagocytes
Can kill pathogen directly, indirectly and induce inflammation

31
Q

Describe complement proteins

A

Pro-enzymes- become active after cleavage
Classical pathway- C(number)a/b proteins
Small fragment is the ‘a’ protein, larger fragment is the ‘b’ protein
A is a mediator of inflammation, b has an attachment site to bind to microbe surface and an enzyme site to active the next proenzyme in the cascade

32
Q

Describe opsonisation by complement proteins

A 
Eg. C3b,C4b bind to bacterium
Complement receptors (eg. CR1,2,3,4,Ig) on phagocytes trigger phagocytosis of complement coated pathogens
33
Q

Describe pathogen lysis by complement proteins

A

Formation of Membrane Attack Complex by C5b,6,7,8,9n

Punctures membrane of bacteria and viral envelops

34
Q

Describe the three pathways of complement initiation

A

Classical- C1q interacts with pathogen surface or with antibodies bound to surface➡️ C1q, C1r, C1s, C4, C2
Alternative- C3 undergoes spontaneous hydrolysis to C3(H2O) to initiate eventual deposition to C3 convertase on microbial surfaces➡️ factorD, factorB, properdin, C3
Lectin- mannose-binding lectin (MBL) and ficollins recognise and nibs carbohydrates on pathogen surface➡️ MBL, ficollin, MASP2, C4, C2

35
Q

Describe the outcome from the three possible initiation pathways for complement

A

All pathways generate a C3 convertase which cleaves C3 leaving C3b bound to the pathogen surface and releasing C3a➡️
➡️C3a and C3b recruit phagocytic cells to the site of infection and promote inflammation
➡️phagocytes with CR to C3b engulf and destroy the pathogens
➡️completion of the complement cascade leads to the formation of a membrane-attack complex which causes cell lysis

36
Q

What are acute phase proteins?

A

Free floating soluble PRR
MBL (mannose-binding lectin) -sugars and CRP (C-Reactive protein)- phospholipids
Levels significantly increase during inflammation
They don’t bind to your own cells- initiators of the complement cascade

37
Q

What are complement inhibitors?

A

A check system that prevents C3b from binding to self
Eg. Surface bound- CR1, MCP, DAF, CD59
Plasma- C4BP, factor H, factor I
Block factor B binding to C3b, degrade C3b and degrade C3 convertase

38
Q

What else does C3b do in terms of the amplification of complement?

A

Activate C5 convertase that cleaves C5 to yield C5a and C5b that mediates inflammation and binds to pathogen surfaces
C5b forms a membrane attack complex

39
Q

What are the actions of C3a and C5a?

A

Activate tissue mast cells
Activate endothelial cells
Attract innate immune cells from the blood to the infection site

40
Q

Briefly describe the increased susceptibility of individuals with complement deficiencies to infections

A

Early pathway proteins (MBL, C1q, C2,3,4 and C3 convertases)- encapsulated pathogen infections eg. Strep pneumoniae and Haemophilus influenzae
Late pathway proteins (C5,6,7,8,9- formation of MAC)- infections with Neisseria spp
Early classical pathway proteins (C1q, C2,3,4 and C3 convertase)- autoimmune disease (SLE-like syndrome)

41
Q

What is the role of the macrophage in acute inflammation?

A

PRR respond to PAMPs and DAMPs induce transcription of cytokines (IL-1beta, IL-6 and TNFalpha) and chemokines (CXCL(IL-8)

42
Q

What is the role of mast cells in acute inflammation?

A

C3a, PAMPs and DAMPs stimulate mast cell release of inflammatory mediators
Early phase- granules
Granules contain vasoactive peptides (histamine), cytokines (TNFalpha) and chemokines (IL8)
Late phase- de novo synthesis
Arachidonic acid➡️ leukotrines (LTB4) or prostaglandins (PGD2)
Increase blood flow and permeability

43
Q

What opsonic receptors do phagocytes have?

A 
Complement receptors (CRs)
Antibody receptors (FcR)
44
Q

What is NADPH?

A

A large multi-subunit enzyme complex whose assembly in the phagosome membrane is triggered by a phagocytic stimulus
Gp91 and p21- granule membrane components
P47 and p67- cytosolic components
It helps to generate chemicals used in the digestion of pathogens

45
Q

Describe the oxidising agents used by neutrophils to kill microbes

A

O2➡️ (NADPH Oxidase) O2- Superoxide anions
➡️ (superoxide dismuatse (SOD)) H2O2
➡️ (Myeloperoxidase (MPO) HOCl (hypochlorous acid)
OH- by-products (hydroxyl free radical)

46
Q

Describe the generation of oxides of nitrogen in the killing of bacteria in phogocytes

A

L-arginine + O2➡️ (inducible nitric oxide synthase (iNOS)) citrilline + NO- (nitric oxide)➡️
NO- + O2-➡️ ONOO- (peroxynitrite)
Peroxynitrite- lipid perioxidation, protein oxidation, protein nitrification, inactivation of enzymes

47
Q

What are the contents of neutrophil granules?

A

Cationic peptides- permeabilisation
Phospholipase A2- phospholipid cleavage
Lysozyme- peptidoglycan cleavage
Lactoferrin- iron binding
Peroxidase- generation of hypohalites
Neutral proteases- digest many cell wall proteins
Acid hydrolases- digest many cell wall constituents

48
Q

What happens to neutrophils after phagocytosis?

A

Apoptosis
ACAMPs- Apoptotic Cell Associated Molecular Patterns
Eat me signals to macrophages
If not removed they degenerate into secondary necrosis

49
Q

Describe NETosis

A

Activated neutrophils can release strands of nuclear DNA- an active form of cell death
Neutrophil Extracellular Traps (NETs) contain histones coated in antimicrobial proteins, proteases and lysozyme
Is ROS dependent CGD and MPO deficient cells fail to undergo NETosis

50
Q

How is the generation of diversity for B and T cell receptors generated?

A

Somatic gene segment recombination
Gamma and kappa light-chain locus contains around 30 and 38 V (variable) segments and 4 and 5 J (joining) segments
Heavy chain locus contains ~40 V segments, ~23 D (diversity) segments and 6 J segments
Immunoglobulin isotypes by the range of heavy chain C region gene segments
Recombination by recombinase activating genes (RAG1 and RAG2)
Further diversity introduced at the joining regions by terminal deoxynucleotidyl transferase (tdt)
Hyper mutation in B cells will further increase diversity

51
Q

What is allelic exclusion?

A

Prevents gene rearrangement and expression from both maternal and paternal chromosomes
Heavy gene, kappa, gene, gamma gene

52
Q

What is clonal selection theory?

A

Single progenitor cell gives rise to many varying lymphocytes
Removal of potentially self-reactive immature lymphocytes by clonal deletion leaving a pool of mature naive lymphocytes
Proliferation and differentiation of activated specific lymphocyte to form a clone of effector cells

53
Q

What is a Major histocompatibility complex?

A

MHC or human Leukocyte antigen (HLA)
MHC1= HLA A, B, C
MHC2= HLA DR, DP, DQ

54
Q

Describe MHC1

A

If a cell is infected with a virus interferon is released which increased production of the LMP1/2 subunit which cause proteosomes which degrade viral proteins to produces larger peptides suitable for antigen presentation
Interferons also turn of cytoplasmic proteases which might degrade these peptides
MHCs being synthesised in the ER are stabilised in the absence of peptide binding by calnexin and calreticulin
Tapasin holds the MHC near a TAP
Peptides enter through TAP and bind to the MHC molecule, if it fits there is a conformation change and MHC disassociates with the chaperone proteins and is transported to the surface of the cell for CD8+ T cells to kill the cell.

55
Q

How can viruses interfere with antigen processing?

A

HIV can interfere with MHC production
EBV has a way of preventing viral protein degradation and therefore peptide-antigen production
Adenovirus- competitively inhibit tapasin and cause the retention of MHC1 in ER
Herpes simplex virus1 and human cytomegalovirus (HCMV) blocks peptide entry to ER by interfering with TAP
Adenovirus and Ebola can stop the transformation of the proteosome

56
Q

What is the significance of HLA-E?

A

It’s function is to bind to leader peptides cleaved from other MHC molecules during their synthesis
NK cells activation is inhibited by HLA-E activity
If a viral infection leads to decreased MHC synthesis then fewer leader peptides will be available to bind HLA-E so it’s expression at the cell membrane will decrease and the inhibition of NK cells will stop and the cell will be killed by the release of cytotoxic products from the NK cell

57
Q

Describe MHC class 2

A

Peptides presented are derived for proteins taken up by an antigen processing cell by surface Ig on B cells or pinocytosis
Forms an antigen processing compartment with MHC2 molecules complexed with invariant chain until proteins are processed by proteosomes into compatible peptides
The MHC-peptide complexes are transported to the cell surface to activate the T-cell antigen receptor on the T cell

58
Q

What the differences between MHC class 1 and 2?

A

Class 1 recognised by CD8 cytotoxic T cells which kill target cells
Class 2 recognised by CD4 helper T cells which secretes and proliferates
Different subunits class 1- alpha 1,2,3 and beta2
Class2- alpha 1&2, beta 1&2
Class1 binds short peptides
Class2 binds longer peptides

59
Q

Describe peptide binding to MHC1

A

8-10 amino acids
Anchored at the ends into MHC1
Number and sequence of amino acids in the peptides between anchor residues can vary

60
Q

Describe peptide binding to MHC2

A

Peptides may be up to 30 amino acids
Anchor residues are not localised at the termini
The ends of the peptide are in extended conformation and be trimmed
Motifs are less clear than in class 1 binding peptides

61
Q

Describe polymorphism in MHCs

A

Affects peptide antigen binding
Expression is co-dominant
A diverse range is expressed I each person with high polymorphisms as each locus have many alleles
As a consequence some MHC molecules are in effective Witt done pathogens allowing rapidly mutating pathogens to escape
HLA-B27 and B57 bind in relatively conserved regions of the virus
Virus Escobar occurs because good B27 epitope do contain Arg at 2nd position which the virus mutates to a Lys

62
Q

Describe some consequences of polymorphism in MHC

A

HLA-A1 no HIV epitope a found so far
HLA-B53 reduced risk of malaria in Africa
HLA-B7 and B14 Ebola virus survivors
HLA-B67 and B15 Ebola virus deaths
HLA-DR2 associated with leprosy in India
Zhka-DR4 associated with rheumatoid arthritis

63
Q

Can lipids be presented to T cells?

A

Yes
Dendritic cells and monocytes express CD1 that is structurally similar to MHC that can bind a range of lipid molecules from mycobacteria
They can be recognised by a subset of Y cells that express neither CD4 or 8
This activate macrophages to kill the source of lipid

I&I Clodicle (5 decks)

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