Myeloid Differentiation Flashcards
1
Q
what is an epigenetic landscape?
A
where chromatin regulates which genes are turned on and off via transcription factors (TFs)
- TFs guide cell fate lineages
2
Q
what do MEPs generate?
A
- megakaryocytes –> platelets
- erythrocytes
3
Q
what do GMPs generate?
A
granulocytes
monocytes –> macrophages
4
Q
what factors drive cell fate decisions?
A
extrinsic factors - molecules that are provided by other cells e.g. cytokines
intrinsic factors - transcription factors within cells
5
Q
what is a cytokine?
A
class of soluble protein or peptides which act as humoral regulators by stimulating cell signalling and promoting developmental processes and cell maturation.
- can be pro or anti-inflammatory
- guide cell fate decisions
- highly potent - only nano-picomolars needed in concentration
6
Q
what are the different classifications of cytokines?
A
interleukins - target leukocytes
chemokines - induce chemotaxis of cells
interferons - anti-viral immune responses
colony-stimulating factors - induce growth of lineage colonies
7
Q
what are colony stimulating factors?
A
– induces growth of colonies in semi- solid methylcellulose medium – individual cells in solid matrix, but cannot diffuse, so proliferation forms a colony
- Granulocyte colony is dense and small
- Macrophage colony is looser and disperses
8
Q
what are examples of colony stimulating factors?
A
Macrophage CSF (M-CSF) induces macrophages from progenitors
Addition of granulocyte CSF early enough will change progenitor cell fate from macrophage to granulocyte
9
Q
what are examples of extrinsic signals for each cell fate lineage?
A
IL-3 = proliferation in all lineages, not specific
specific signals:
- TPO for platelets
- EPO for erythrocytes
- M-CSF for macrophages
- GM-CSF for GMP stage
- G-CSF for granulocytes
10
Q
what are the producers and targets of stem cell factor (SCF)
A
producer: Bone marrow stromal cells
Targets: HSCs - maturation of haematopoietic lineages
11
Q
what are the producers and targets of GM-CSF?
A
producers: T cells, macrophages, fibroblasts, endothelial cells
targets: Immature and committed progenitors, macrophages; granulocyte and monocyte differentiation, activation of macrophages
12
Q
what are the producers and targets of M-CSF?
A
Producers: monocytes, endothelial cells, fibroblasts, mesangial cells
Targets: monocytes, macrophages
13
Q
what are the producers and targets of IL-3?
A
producers: T cells
targets: immature progenitors - proliferation/maturation of all lineages
14
Q
what are the producers and targets of IL-6?
A
producers: macrophages, endothelial cells, T cells
targets: proliferation of progenitors, neutrophils
15
Q
what are the producers and targets of TPO?
A
producers: BM stromal cells, liver
targets: maturation of megakaryocytes and platelets
16
Q
what are the producers and targets of EPO?
A
producers: eptihelial-like cells in renal cortex under hypoxic stress
targets: maturation of erythrocytes
17
Q
what are examples of type 1 cytokines?
A
IL-3, IL-5, IL-6, GM-CSF, G-CSF
18
Q
how do type 1 cytokines signal?
A
- Cytokine receptor at PM
- When engaged with cytokine, phosphorylation of tyrosine with JAK kinase
- STATs activated by JAK enter nucleus and bind DNA motifs to promote expression of target genes involved in survival, proliferation, activation
Feedback loop to inactivate this pathway, ready for next round of activation
19
Q
what are intrinsic signals of cell fate?
A
nuclear regulators: transcription factors (TFs)
- bind specific sequences of DNA (promoters or regulatory elements/enhancers)
- can bind alone or in complex with TFs
- induce co-activators and remodelling of chromatin to change transcriptional program
- most are activators some can be repressors
20
Q
why does chromatin need to be remodelled? how does this happen?
A
Chromatin is wound around nucleosomes, so needs to be unwound and opened for TF access
- Promoters have multiple binding sites for multiple TFs – more specificity and activation
- remodelling complexes use ATP to remove nucleosome and enable access of 150 bp for TF binding
21
Q
what intrinsic TFs are important for myeloid differentiation?
A
PU1 and GATA1 antagonise each other in the CMP progenitor
- GATA1 induces erythrocyte and megakaryocyte
- PU1 induces granulocyte/monocyte lineage
cEBP important for neutrophil development
GFli1 has inhibitory function
22
Q
how do TFs guide lineage specification?
A
To become erythroid, need erythroid TFs to regulate erythroid genes
To become myeloid, need myeloid TFs to induce myeloid genes
TFs guide differentiation to become erythroid or myeloid cell
23
Q
why must the extrinsic signals and TFs be balanced for myeloid differentiation?
A
There is overlap of what is required for different cell type
- Balance cytokines and TFs to guide cell fate decision
- Need to balance what cell types are produced as both populations are needed for survival – steady state
24
Q
how can lineage fates respond to a depletion in red blood cells or low oxygen levels?
A
Need signals to repair problem:
More EPO production – more erythroid differentiation to erythrocytes
25
how do myeloid and erythroid TF signals antagonise each other to induce cell fate?
Myeloid TFs
- Need to reduce erythroid signal and boost myeloid
- Myeloid TFs have positive feedback, whilst inhibited erythroid TF
Erythroid TF
- Need to reduce myeloid signal and boost erythroid
- Erythorid TFs have positive feedback of TFs, whilst inhibiting myeloid TFs
26
what is PU.1?
transcription factor of the Ets family, which bind the core DNA sequence GGA(A/T)
- expressed in myeloid and lymphoid cells
- opposes the Meg/E lineage by binding to GATA-1 and repressing GATA-1 bound genes
27
in what cells is PU.1 expressed?
On in B cells
High expression in granulocytic and monocytic cells
Turned off in erythroid cells
Turned off in T cells
28
how has PU.1 been implicated in disease?
- enhancer is an integration site for a virus which can increase PU.1 expression aberrantly --> erythroleukaemia
29
is PU.1 necessary for life?
yes - PU.1 K/O leads to mice dying as they lack myeloid, B and T cells
30
how can PU.1 expression be measured in cells?
- GFP (green fluorescent protein) knocked into exon 1 of the PU.1 gene, resulting in a PU.1 heterozygous mouse PU.1 +/GFP
- One allele is normal, other is tagged with GFP
- Flow cytometry to see how much is in cells
31
what is the expression of PU.1 in cells of the haematopoietic lineage
- LT-HSC and ST-HSC – some PU1
- Myeloid and lymphoid have PU1
- MEP lose PU1 as they mature – megakaryocyte and erythrocyte have no PU1 expression
- GMP gain PU1 – high in granulocyte and monocyte
- premature B cells maintain PU1 at low level, increases in mature B cells
- T cell loses PU1 as it matures
32
what is PU.1's effect on erythropoiesis?
acts negatively on erythropoiesis
- in PU.1 K/O mice there is a bias to erythroid phenotype - erythroid progenitors differentiate prematurely, leading to excessive apoptosis
- overexpression of PU.1 leads to anaemia due to a block of erythroid differentiation - accumulation of premature erythroblasts
33
how is PU.1 involved in regulating production of erythroid progenitors?
low PU.1 levels are important for proliferation of early erythroid progenitors
PU.1 must then be downregulated for terminal differentiation into red blood cells
34
what is the role of PU.1?
master regulator of myeloid differentation:
- Generation of monocytes and neutrophils is highly dependent on PU.1
- PU.1 is indispensible for CMPs differentiation to GMPs
35
how can PU.1 be studied in early differentiation stages from the from HSC progenitor?
induce PU.1 conditional knockout in bone marrow of adult mouse:
- leads to drop in HSC number
- loss of repopulation studies (bone marrow reconstitution assay)
- absence of CMPs and GMPs
- Controls have normal CMP and GMP,while PU1 K/O lacks these cells
36
how can PU.1 be studied in late differentiation stages from the from GMP progenitor?
Conditional K/O of PU.1 after GMP stage and sorted for CMPs or GMPs:
- colony forming potential of PU.1 deleted GMPs appears normal, however consists only of myeloblasts, no CD11b (maturation marker)
- colony forming potential of PU.1 deleted CMPs results in myeloblast colonies and MegE colonies
cells cant become granulocytes or monocytes anymore - CMPs redirect to myeloblasts or Meg/E cells
37
what TFs dictate if a GMP becomes a macrophage or neutrophil?
PU.1 and C/EBPa
- neutrophil: C/EBPa increases, PU1 stays constant, Gfi-1 expression goes up
- Macrophage: PU1 is increased, C/EBP stays constant, EGR and NAB increases
antagonism:
- G-fi1 inhibits EGR and Nab to promote neutrophil
- EGR and Nab inhibits G-fli1 to promote macrophage
38
what is C/EBPa?
TF which binds CCAAT enhancer
- Expressed lowly in HSCs, then upregulated in granulocytes and monocytes
- C/EBPα -/- knockout mice die few hours after birth due to hepatic hypoglycemia
- Conditional C/EBPα -/- mice showed that the knockout blocks the transition from CMPs to GMPs
- C/EBPα and PU.1 levels determine the cell fate choice into macrophages or neutrophils
39
what is the network that drives macrophage vs neutrophil specification?
balance between PU.1 and C/EBPα determines the lineage fate
Secondary factors (Egr/Nab or Gfi-1) are reinforcing the establishment of each lineage
40
what is a PUER cell?
cell line generated from PU1 K/O mice – not viable but live during embryonic stage, CMPs in foetal liver can be obtained
PU.1-eostrogen receptor TF bound to ligand binding domain
- if nothing bound, it is in cytoplasm
- if bound to tamoxifen, it enters nucleus and becomes active to drive gene transcription and differentiation to macrophage or neutrophil
41
how do IL-3 and G-CSF affect macrophage/neutrophil differentiation via PU.1?
IL-3 induces proliferation of macrophages under PU.1 transcription
G-CSF skews towards neutrophils over macrophages, despite PU.1
- G-CSF enhances C/EBPa
extrinsic factor G-CSF and intrinsic PU.1 dictate final differentiation step between macrophage or neutrophil
42
how do extrinsic and intrinsic factors overlap in cell fate decisions?
cytokines modulate cell fate decisions by regulating lineage determining TFs
43
what is GATA1?
member of the GATA trancription factor family, which binds the DNA sequence GATA
- erythroid master regulator
- lowly expressed in HSCs and CMPs
- essential for the development of erythrocytes and megakaryocytes
- GATA-1 knockout mice die during the embryonic stage E10.5 and E11.5 due to anemia
- regulator of the α- and β-globin genes, GATA-1 itself, Epo and EpoR (receptor)
- antagonizes PU.1 by displacing the co-activator c-Jun at its Ets domain
44
what complex does GATA1 recruit when it binds DNA?
GATA1 binds DNA and forms larger complex, SCL, E2A, Lmo2 bridging factor
– binds many specific DNA sites
– both elements needed for transcription
– more specificity
45
what are the interacting partners of GATA1?
GFI-1b
FOG-1
KLF-1
TAL-1/SCL
these complex with GATA1 to induce erythroid genes and stimulate erythrocyte proliferation
46
what is GFI-1b?
- repressor function in concert with LSD1-CoREST (demethylation of H3K4me and H3K9me)
- repression of cell proliferation genes, e.g. myc and myb
47
what is FOG-1?
- interacts with MeCP1, a large, methylated DNA binding complex, including NuRD which promotes histone deacetylation
- repressor function of genes maintaining the multipotential state and alternative lineage priming genes
48
what is KLF1?
krueppel-like-factor 1
- Exclusively expressed in erythrocytes and their precursors
- KLF-1-/- mice die at E14.5 due to severe anemia
- KLF-1 acts primarily as an transcriptional activator
- Important for α- and β-globin synthesis as well as for heme synthesis and iron procurement
- Survival and proliferation of red blood cells
49
what is TAL-1/SCL?
pentameric complex with LMO2, LBD1 and E2A
Activation of erythroid genes
50
what does a master regulator mean?
- Essential for specific lineage differentiation (k.o. models – lineage not produced or differentiation block)
- Repress other potential lineage programs – antagonise each other
- Able to direct or even change a specific cell program when introduced into cells
51
how can conversion between cell lineages be studied?
Made library of TFs in retroviral construct which would infect T cells (marked with human CD4 tagged with GFP)
- Sequenced to see which viruses led to conversion of T cells into macrophages
- It was C/EBPa-positive viruses that did this
52
why does lineage differentiation need to be so well regulated?
for example: LOF mutation in TF
- Block in differentiaton, so cells accumulate mutations which drive proliferation --> leukaemia
- Common in progenitor stages which proliferate often to produce many mature cells
- Mutation that stops differentiation in these stages will easily promote accumulation of progenitors
53
what is the AML-ETO subtype of AML?
Translocation mutation between chr 8 and 10, induces fusion protein between DNA binding RUNX1 (AML1) and co-repressor ETO
- Interference with normal RUNX1 regulation leading to a block of granulopoiesis
- Second hit leads to transformation and high myeloblast counts
- Decrease of C/EBPα and PU.1 levels
54
what is RUNX1?
TF which regulates C/EBPa and PU.1
55
how can AML-ETO phenotype be rescued?
add C/EBPa back in using estrodial so it enters nucleus
- induces macrophage differentiation from the myeloid leukaemia cells
56
what TF is commonly mutated in AML?
C/EBPa:
- Incomplete loss of function of C/EBPa
- frame-shift mutations, truncated products
Leucine zipper enables dimerisation for activation – mutations found here
Interestingly, C/EBPα knockouts don’t lead to leukaemia: aberrant C/EBPα contributes to transformation in leukaemia.
57
what disease is a decrease of PU.1 associated with?
Association of decreased PU.1 levels with myelodysplasia and AML
PU.1 has many enhancers
- If enhancer is lost, 30% reduction in PU.1 there is accumulation of immature cells,
- cells likely to develop into AML due to lack of differentiation stop and aberrant proliferation
- Mice with K/D of PU.1 have lower survival
58
what happens to PU.1 levels in myelodysplastic syndrome? how is this overcome?
Reduced PU.1 levels in myelodysplastic syndrome (MDS)
- Methylation of CpG promoter inactivates PU1
- Demethylation increases expression of PU1
Combined demethylation and G-CSF causes shift from immature cells to more differentiated, mature cells to treat MDS patients and force cell maturation
- Chromatin is more accessible as DNA is no longer methylated
59
what is innate immunity?
- present at birth
- induced by myeloid cells
- not affected by prior contact - no memory
- rapid response
- recognises PAMPs via PRRs
- limited diversity - germline encoded
60
what is adaptive immunity?
- developed over lifetime based on pathogen exposure
- induced by T and B cells
- generates memory
- slower response - needs time to develop antibodies
- antigen receptors with high specificity
- highly diverse - somatic recombination - unlimited
61
what are the general stages of an immune response?
- site of microbe entry lined with macrophages
- recognition and production of pro-inflammatory cytokines
- recruitment of neutrophils/macrophages from bloodstream to engulf and kill pathogen
- DCs/macrophages act as APCs to lymphocytes
- soluble proteins like complement combat infection
- macrophages induce tissue repair
62
what are neutrophils?
- most abundant
- short-lived - 6 hrs
- contains granules to digest pathogens
- lysozyme, collagenase, elastase proteases
63
what are mononuclear phagocytes?
- granular cytoplasm with lysosomes and phagocytic vacuoles
- broad range of PAMP recognition via PRRs
- many subtypes
- long-lived
- can proliferate at site of infection
64
what are the types of mononuclear phagocytes?
1. monocytes - circulate in blood and can differentiate to inflammatory mature macrophages
2. tissue-resident macrophages e.g. microglia, Kupffer cells
65
what are the functions of phagocytes?
- engulf microbes and apoptotic host cells
- produce cytokines to instruct immune system
- act as APC to T cells via MHCII presentation
- tissue repair by stimulating angiogenesis
66
what are mast cells?
- found at skin and mucosal epithelia
- FcyR for IgE
- release granules containing cytokines and histamine once bound to antigen
- defence against parasites
- involved in allergy
67
what are basophils?
- circulate in blood
- similar to mast cells
- low in number
- granular
68
what are eosinophils?
- increase in number upon inflammation
- usually low numbers in peripheral tissues
- granules contain enzymes to damage large parasites
69
which cells are the main antigen presenting cells?
dendritic cells
macrophages
B cells
70
How do APCs stimulate T cells?
- migrate to lymph node and stimulate T cells with 3 signals:
1. present antigen-MHCII to TCR
2. co-stim via CD80/86 to CD28 on T cell
3. release cytokines to induce T cell differentiation
71
what are dendritic cells?
- main APC
- phagocytic cell
- recognise PAMPs via PRRs
- conventional DCs migrate to lymph node to present antigen to T cells
- plasmacytoid DC respond to viral infection via type 1 interferon production
72
what are follicular dendritic cells?
- present in germinal centres of lymph nodes, spleen and mucosal lymphoid tissues
- present native antigens to B cells undergoing GC reaction
73
how do leukocytes reach sites of inflammation/infection?
Interaction of leukocytes with the endothelial layer in the capillaries: adhesion molecules
also chemotactic gradients
74
what adhesion molecules are involved in recruiting leukocytes from blood into tissues?
1. P- and E- selectins expressed by active endothelium - bind to glycoproteins on leukocytes
- L-selectin expressed on leukocytes - bind to sialomucin on endothelium
- low affinity adhesion
2. Integrins - cell-cell or cell-ECM adhesion for cytoskeletal signalling
- LFA-1 and VLA-4 on leukocytes
- ICAM-1 expressed on activated endothelial cells can bind MAC-1 on monocytes
- high affinity
75
how does valency control leukocyte docking onto endothelium?
Valency regulated by grouping of receptors on cell surface for improved docking site
76
what are chemokines?
Family of structurally homologous cytokines (human: 50) which instruct movement of leukocytes
- produced by leukocytes, endothelial and epithelial cells, fibroblasts
- Chemokine secretion induced by microbe recognition and inflammatory cytokines
- induces cytoskeletal changes in cells for migration
77
what are chemokine receptors?
Chemokine receptors are G-protein coupled receptors expressed on all leukocytes
- Signals transmit cytoskeletal changes and increase integrin affinity
- regulate traffic of leukocytes through lymphoid tissues
- guidance of DCs from site of infection to the draining lymph nodes
78
what is the process of leukocyte migration from blood to tissue?
Cell in blood and rolls on endothelial cells
- Selectins and ligands cause cell to slow down and arrest
- more interactions with integrins to cause flattening – increases adhesion
- cells will migrate through endothelial wall into underlying tissue
79
what are the 2 ways in which leukocytes can pass through the endothelium to enter tissues?
Between two cells – paracellular
Transcellular – cell makes hole through endothelial cell, membrane gives way – not known if this truly happens
80
what are PAMPs?
Pathogen-associated molecular patterns
- recognition of specific molecular structures of microbes that are highly conserved
- but number of recognized PAMPs limited
81
what are DAMPs?
Damage-associated molecular patterns
- produced by cells damaged due to infection
- any injury to cells, e.g. chemicals, burns, trauma
82
give examples of PAMPs in different pathogens:
bacteria:
- flagellin
- LPS (gram-negative)
- mannans
- CpG
fungi:
- dectin
- mannans
virus:
- ssRNA
83
give examples of DAMPs:
heat shock proteins
HMGB1 - nuclear protein
histones
84
how are PAMPs/DAMPs recognised?
Pattern recognition receptors (PRRs):
- germline encoded
- expressed by macrophages and neutrophils, DCs, epithelial and endothelial cells (barrier between the environment and the body) - these are likely to come into contact with pathogen
- can be extracellular or intracellular (cytosolic and endosomal)
85
what are Toll-like receptors?
type of PRR:
- mostly on cell surface
- can be endosomal
- different TLR has different specificity
e.g. TLR4 = LPS, TLR3 = ssRNA
86
What is the structure of TLRs?
- leucine-rich repeats in PAMP-binding domain
- TIR domains dimerise to induce signalling
- depend on adaptors and co-receptors to form dimer
87
what are the main adaptors and downstream effectors of TLRs?
- Myd88 for all (except TLR3)
- TRIF for all
- induces MAPK pathway, IRF3
- activates NF-KB to induce gene transcription and activate pro-inflammatory genes
88
what do NF-kB and AP-1 induce?
Expression of inflammatory genes:
- cytokines (TNF, IL-1, IL-6)
- chemokines
- Endothelial adhesion molecules
- co-stimulatory molecules
induce acute inflammation
89
what do interferon response factors (IRFs) induce?
Expression of type I interferon (IFNα/β) genes:
- secretion of IFNα/β
induce antiviral state
90
what are cytosolic PRRs?
cytoplasmic PRRs detect infection in the cytoplasm where some bacteria escape to and viral particle assembly happens
e.g. NOD-like receptors, RIG-I-like receptors
91
what are NOD-like receptors?
- NLR-C: recognise bacterial cell wall components and toxins
- signalling of NF-KB activation via RIP2 --> inflammation
- NLR-P: activated by microbial products and cytoplasmic changes - inflammasome complex and secretion of IL-1b for inflammation
92
what are the RIG-I-like receptors?
- recognize ss and dsRNA
- distinguish between viral RNA and cellular RNA
- different specificities depending mostly on the length of dsRNA
- binding of RNA results in activation of IRF3 and IRF7 or NF-κB depending on adapter molecules
- induces antiviral state via type 1 interferons
92
what is complement?
Proteolytic cascade of proteases activating downstream proteases thereby multiplying the effects of opsonizing and sometimes killing the microbe
- Serum proteins which complement innate immunity
- flags cells or bacteria to immune system or kill directly
93
how does complement work?
Proteases C2, C3 and C4 are cleaved into two fragments
- Those fragments are the active components which start the pathway
- In all pathways, C3 needs to be cleaved
- C3a and C3B generated
- C5 is cleaved next, forms C5a C5b-9
94
what are the activities of complement?
C3a and C5a act as chemoattractants for phagocyte recruitment
C3b induce opsonisation – phagocytes have C3 receptors to engulf an opsonised pathogen
C5b forms complex with other complement proteins to form MAC - forms pore in bacterium to induce cell lysis
95
which cytokines can induce acute inflammation?
TNF
IL-1
IL-6
96
what is TNF?
Tumour necrosis factor:
- produced by macrophages, DCs and others
- binds as trimer to a trimeric receptor
- cell signaling dependent of the IC domain of receptor, which induces apoptosis and cell death
activation of NF-κB and AP1 for inflammation
97
what is IL-1?
Interleukin-1:
- produced by macrophages, neutrophils,
epithelial and endothelial cells
- binds IL-1 receptor (TIR domain)
- activation of NF-κB and AP1 - acute inflammation
- TLR and NOD signaling leads to IL-1 precursor synthesis
- NLRP3 inflammasome induces
maturation to active IL-1
98
what is IL-6?
Interleukin-6:
- Produced by PAMP activated macrophages,
fibroblast, endothelial cells
- binds IL-6 receptor which signals via STAT3
- Stimulation of neutrophil generation in the BM for fast turnover
99
what are the outcomes when TNF, IL-1 and IL-6 combine in function?
TNF and IL-1:
Activate endothelial cells by increasing their selectin and integrin expression
TNF, IL-1 and IL-6:
induction of acute phase proteins in the liver (C-type lectin, mannose-binding-protein, complement), fever
100
what is IL-12?
cytokine which provides link to adaptive immune system:
- produced by macrophages and DCs
- stimulates IFN-γ production by NK cells and T cells
- enhances NK cell and cytotoxic T cell cytotoxicity
- promotes Th1 (T helper) cells differentiation
- acute inflammation to stimulate T cells
101
what cytokines induce TH1 or TH17 CD4 differentiation?
APC produces different cytokines which induces differentiation of T cell subsets:
IL12 = TH1
TGFB, IL-6 = TH17, produces IL-17
102
what are the two types of macrophage?
M1 - inflammatory
M2 - anti-inflammatory
103
how are M1 macrophages induced?
IFNy and TLR ligands
104
how are M2 macrophages induced?
IL-4, IL-13
105
what are the functions of M1 macrophages?
destruction via ROS, NO, lysosomal enzymes - enhanced microbe killing via phagocytosis
- tissue damage
also induces acute inflammation via IL-1, IL-6 and IL-12
- anti-tumour immunity
106
what are the functions of M2 macrophages?
anti-inflammatory response via IL-10 and TGFb - can aid tumour persistance
Fibrosis, tissue remodelling and angiogenesis
- produces proline polyamines, TGFb and VEGF
107
how can innate immunity be regulated?
Negative feedback:
- TLR and cytokine signalling inhibitors
- IL-10 inhibits production of other cytokines IL-1, IL-12, TNF
- Autophagy genes to digest inflammasomes – reduces IL-1 response
- IL-1R agonist inhibits IL-1R
- Decoy receptors which mop up and sequester cytokines without downstream signalling
108
how can inflammation be bad?
severe acute inflammation can cause septic shock:
Sepsis: when cytokines produced due to severe infection enter the blood stream and act systemic they cause organ damage and ultimately failure
109
how can antibodies be involved in autoimmune diseases?
Autoimmune antibodies recognize host cells or tissue
→ activated leukocytes produce inflammation state and tissue damage
110
what are examples of antibody-mediated autoimmune diseases?
autoimmune haemolytic anaemia
- targets erythocyte membrane proteins --> phagocytosis and lysis of red blood cells
Autoimmune thrombocytopenic purpura
- targets platelet membrane proteins
- opsonisation/ phagocytosis of platelets
Acute rheumatic fever:
- crossreaction of antibody from streptooccus to myocardial antigen
- inflammation
