Immunobiology Week 1-10 Flashcards
(343 cards)
1
Q
Innate immunity
A
This is the non-specific, unchanging lines of defenses. physical and chemical barriers to pathogens
2
Q
Adaptive immunity
A
where immunological memory is made after initial response to new pathogen, leading to an enhanced response to future exposre
3
Q
Cytokine
A
plasma proteins. a group of secreted, low molecular weight molecules that regulate immune responses. Actions are mediated through specific cytokine receptors on surface of target cells. Can deliver positive or negative signal for immune activation. A messenger that reglates immune responses
4
Q
chemokines
A
secreted low molecular weight molecules that mediate chemotaxis (movement of cells) for leukocytes and regulate expression of adhesion molecules
5
Q
components of immune system
A
epithelial barriers, cells in circulation and tissues, molecules (such as cytokines)
6
Q
cells in circulation and tissues
A
phagocytes and exocytes
7
Q
phagocytes (2) types
A
neutrophils and macrophages
8
Q
exocytes (3 + purpose)
A
eosinophils, mast cells, basophils. Purpose is to release active mediators from granules
9
Q
immune cells in blood
A
white blood cells, neutrophils, eosinophils, basophils, lymphocytes, monocytes
10
Q
how do immunologists identify immune cells?
A
through cell morphology and expression of surface molecules
11
Q
Cluster of differentiation (CD)
A
groups of antibodies that recognize the same molecule = ‘cluster’
12
Q
CD nomenclature
A
a system for naming and classifying cell surface molecules. established by the Human Leukocyte Differentiation Antigens (HLDA). There are regular workshops to designate CD numbers. Includes CD1 to CD371
13
Q
myeloid cells
A
granulocytes and phagocytes
14
Q
mast cell (maturation and where they are)
A
enter tissues as immature mast cell progenitors. They mature and have different functions in tissue. The function depends on where they mature. Mature mast cells are in peripheral tissues that are exposed to the environment (i.e. skin, lung, gut). They are long lived.
15
Q
mast cell purpose
A
secrete or degranualte to release soluble mediators (i.e. cytokines, histamines, etc). Contain preformed cytoplasmic granules filled w inflammatory and antimicrobial mediators
16
Q
eosinophils
A
derived from bone marrow. Similar to mast cells in which they have cytoplasmic granules filled with inflammatory and antimicrobial mediators. Their granules are special because they have enzymes that are harmful to cell walls of parasites and helminths. they can also damage host tissues. they can participate as effector cells in adaptive immunity as well (specifically humoral and anitbody responses)
17
Q
eosinophil location
A
some are found in peripheral tissues such as mucosla linings of repiratory and GI tracks.
18
Q
eosinophils during inflammation
A
their numbers increase by recruitment from the blood.
19
Q
basophils
A
derived from bone marrow. They are less than 1% of blood leukocytes. They have many structural and functional similarities to mast cells (such as cytoplasmic granules with inflammatory and antimicrobial mediators). They have been shown to place supporting role in adaptive immunity
20
Q
basophils location
A
NOT in pheripheral tissue
21
Q
basophils during inflammation
A
increase by recruitment.
22
Q
neutrophils
A
derived from bone marrow common myeloid progenitors. Short lived, usually no more than a few hours. Infiltrate inflamed peripheral sites. Potent antibacterial functions.
23
Q
neutrophil inflammation
A
signals are sent to bone marrow to increase neutrophil production during inflammation. They also secrete cytokines to further promote inflammation and reruitment of other cells. They promote phagocytosis by macrophages.
24
Q
neutrophils location
A
not usually found in tissues.
25
NETs
neutrophils can kill bacteria by entrapping them in extracellular structures. (this could also be a mechanism that helps tumours grow when gone wrong)
26
monocytes and macrophages
derived from bone marrow common myeloid progentiros. Monocyotes in blood migrate to inflamed tissues and become macrophages. Macrophases may be found as resident cells in tissues. They have potent antibacterial functions. They are long lived and secrete cytokines (TNFalpha, IL1,IL6,IL8 and IL12. they might also be involved in tumor growth (TAMs)
27
Antigen presenting cells (APC)
specialised at capturing microbes and other foreign materials. Some are tissue resident cells and others are recruited during inflammatory events. Others are found in secondary lymphoid tissues (such as B cells and FDC)
28
Dendritic cells
peripheral tissues contain types of dendritic cells in specific locations with different functions. They are strategiacally located to maximize 1st encounter changes. DC at peripheral sites allow them to detect microbial pattersn or PAMPs and trigger inflammatory cytokines. DCs are 'professional antigen presenting cells' because they initiate adaptive immune responses and are the bridge between innate and adaptive immunity.
29
Innate lymphoid cells (ILCs)
lymphocyte-like cells. Live in epithelial tissues and produce cytokines that perform similar to T cells. They provide early defense against infections and interact with adaptive immunity (to guide T cell responses)
30
ILC groups (5)
NK cells, ILC1(defence against viruses), ILC2(allergic reactions), ILC3 - intestinal barrier function, Ltis
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Natural Killer cells
a class of innate lymphcutes that recognize infected and stressed cells. They kill these cells by secreting the cytokine. Component of innate immunity. They are important in anti-viral immunity
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if microbes breach epithelia and enter tissues or circulation they are attacked by…
phagocytes, plasma proteins, and natural killer cells
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lymphocytes
unique to adaptive immune system. Have specific receptors. Two classes: B cells and T cells
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antigens
substance that induces an immune response
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immune cells originate from where
bone marrow stem cells. Most mature there, others will leave and mature in other sites.
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primary (central) lymphoid tissues
bone marrow, thymus, generative lymphoid organs.
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secondary (peripheral) lymphoid tissues
lymph nodes, spleen, mucoasa associated lymphoid tissues.
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all circulated blood cells arise from what
bone marrow. This process is called hematopoiesis
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bone marrow development
at birth, all bones. In adults, mainly flat bones.
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Bone marrow
site of B cell maturation. Can also be a site of initiationg lymphocyte reponses.
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thymus
T cell university. Site of T cell maturation.
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cortex of thymus
contains dense T cells
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medulla of thymus
T cells, DCs and macrophages
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spleen
vascularised abdomical organ. Blood entering flows through network of channels (sinusoids) and blood borne atigens are trapped. Spleen contains phagocytes that ingest and destroy microbes in blood.
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red pulp spleen
blood-filled cascular sinusoids
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white pulp spleen
rich in lymphcytes
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marginal zone of spleen
the transit zone. It is where cells move from blood to WP. Cell movement is controlled carefully. There are several resident cells and two layers of macrophages.
48
lymphatic system
fluid is always leaking out of blood vessels. This fluid is called lymph. Lymph is drained by lymphatic vessels from the tissues to the lymph nodes (and then eventually back into blood). As the lymph passes through the lymph nodes, APCs sample microbial antigens that may have entered into tissues.
49
lymph nodes facts
they are secondary lymphoid organs. They are important for initation of adaptive immune responses. There are around 500 in the human body strategicaly located. They are connected by lymphatics, they merge to form the thoracic duct, which drains into superior vena cava.
50
secondary (peripheral) lymphoid tissue FUNCTIONS
drain lympth, collect antigens and APCs, provide meeting palce for T cells and DCs, site for B and T cell interactions
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what is included in innate immune system
neutrophils, basophils, eosinophils and monocytes
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innate immunity properties (5)
very rapid, short lived, repetive (same way every time microbe encountered), interacts with other innate cells and adaptive, non reactive to host.
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Cells that express Pattern Recognition Receptors (PRRs)
epithlial cells, endothelial cells, and resident immune cells
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Damage-associated molecular patterns(DAMPs)
when innate immune recognizes molecules released from damaged or necrotic cells
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binding of PAMPs and DAMPs to PRRs
triggers release of soluble mediators (i.e. cytokines) and recruits innate immune cells
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Toll like receptors (TLRs)
crucial role in the innate immune system. some are present on cell suface and recognize extracellular microbes while others are in edosomes and recognise ingested/phagocytosed microbes. Singlas generated by TLR engagement of PAMPs can activate gene encoding transcription factors.
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PRR locations
cell surface, endosomal membranes, cytosol
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binding of PAMPs to PRRs
triggers release of histamine and inflammtory cytokines, dilate blood vessls which allows for blood flow to area (redness) and fluid to come in (swelling), induces expression of adhecion molcules on veins (this attracts neutophils and monocytes to perfom phagocytosis, secrete more cytokines and extend extracullar traps)
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how do phagocytes recognise microbes
using pattern recognition receptors (PRRs). Recruited neurotphiles and macrophages have PRRs
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phagocytes
macrophages and neutrophils ingest microbes. May be triggered by binding to phagocyte receptors and PRRs. Binding of icrobe is followed by extension of phagocyte plasma membrane around particple. It closes up, pinches off, and microbe is internalized in a vesical called a phagosome. the phagosome fuses with lysosomes and forms a phagolysosome. the toxic substances in it kill microbes (NO and ROS kill it). then there is production of cytokines.
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intracellular bacteria
bacteria that has evolved to live and replicate intracellular vesicales. Innate immunity does not work to kill these. So phagocytes need to be activated by T cells which induce additional killing methods.
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antigen processing
captured proteins are broken down into pepdites and the peptide antigens then need to be loaded into special surface mulcules (MHCs) for T cells to see them.
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dendritic cell maturation
upregulation of molcultes that allow DC to activate naïve T cells
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dendritic cell migration
DC needs to find naïve T cells
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stratification purpose
stratification in epithelial adds cellular layers. Keratin hardens the upper layer.
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acidic pH
natural antiseptic. Stomach is pH2, vagina is pH4
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physical epithelial barriers
tight junctions
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molecular epithelial barrier
antimicrobial peptides (i.e. defensisns secreted OUT)
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alpha defensins
produced by speciailsed anti microbial cells, clears infection (i.e leukocytes) and is a physiological barrier (i.e. paneth cells)
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beta defensins
produced by mucosal epithelial cells, consitutive barrier function
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defensins general
hydrophobic pore-forming peptides. Cationic (positive) charged (bacteria tends to have negative charge)
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TLR structure
They are dimers, the top is a leucine rich repeat ectodomain. Middle is transmembrane domain, bottom is toll/interleukin-1 receptor (TIR) domain.
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TLR leucine rich repeat ectodomain
top. This is ligand binding area
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TLR transmembrane domain
this is kinda self explanatory
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TLR toll/interleukin-1 receptor (TIR) domain
key component in cytosolic signaling
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TLR 1, 2, 5, and 6
use adaptor protein MyD88 and activate transcritpion factor NFkB (induces inflammatory gene expression)
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NOD receptors
includes NLRA, NLRB, NLRC, NLRP
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NLRA
acidic transactivating domain
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NLRB
survival
80
NLRC
immune activation
81
NLRP
cell death
82
NOD-like receptors
cytoplasmic sensors, RIP2 is the central adaptor that activates NFkB
83
NOD1
the ligand is meso-DAP, gram-ve bacteria, expressed by gut epithlial
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NOD 2
the ligand is MDP, gram -ve and +ve, expressed by leukocytes and specifialized immune cells.
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key signalling pathway for inflammation
NFkB
86
complement system
system that has a circulating and cell membrane proteins that are important in host defence against microbes and in antibody-mediated tissue injury.
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complement system activation
sequential proteolytic cleavages of complement proteins lead to effector molecules that help in eliminating microbes. This cascade of complement protein activation is capable of amplification (early molecules produced in cascade can generate many many effector molecultes). Finally, activated complement proteins are covalently attached to cell surfaces and activation occurs.
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3 complement activation pathways
1. alternative pathway (initiatioon by microbes, no antibody) 2. lectin pathway (initiaion by microbes, no antibody) 3. classical pathway (isotypes of antibodies attached to antigens initiate it)
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all complement pathways rely on what
trigger from C3 (the most abundant complement protein in blood)
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all complement pathways do what to C3
convert it into active forms, C3b and C3a
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C3a
inflammation
92
C3b
opsonization and phagocytosis
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c5a
inflammation
94
C3 tick over
inactive (itact) C3 has hidden reactive thioester group. C3 is cleaved continuously at a low rate to create C3b. When it is cleaved, the thoiester domain flips and is exposed instead of hidden. If there is a microbe, a small amount of C3b can attach to the survace. if there is no microbe, then the thioester bond is hydrolysed and C3b becomes inactive
95
Alternate complement pathway (APC)
microbe bound C3b becomes a substrate for the binding of another protein, factor B. factor B is broken down by Factor D and becomes Bb fragement. The C3b-Bb breaks down more C3 and functions as the "alternative pathway C3 convertase." more are produced and bind to microbe or to each other creating C3b-Bb-C3b, which functions as C5.
96
classical complement pathway activation
requires an antibody and begins when C1 binds to antigen-antibody complexes. C1 is made up of C1q and a C1r and 2 C1 tetramer. The C1 complex binds to two or more Fc portions and this initiates the cascade.
97
classical complement pathway
triggered by IgM or IgG bind antigen. Activated C1 cleaves the next protein, C4 into C4b and C4a. C4b contains hidden tioester bond similar to C3b. C2 complexes with C4b and C1 cleaves it to create C2b and C2a. C2a creates complex with C4b. This C4b-2a is the classical pathway C3 convertase (cleaves C3 into C3b and C3a). more C3b molecules are made and attacch to the microbe (opsonisation). some C4b@a bind to C3b and create C4b-2a-C3b and this acts as C5.
98
antigen antibody complexes must be…
soluble, fixed on surface of cells or deposited on extracellular matrices.
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lectin complement pathway
tripped by mannose binding lectin (MBL). It recognises terminal mannose resudules on microbial glycoproteins and glycolipids. It has a hexameric structure (similar to C1q). MBL initaties downstream steps identical to classical pathway. (side note, MASP1 and MASP2 are part of mannose binding lectin and have similar functions to C1r and C1s. See lecture 5, week 3, page 17 for more)
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late steps complement activation
this is initiated by binding of C5. proeolysis of C5 creates C5b and C5a. C5b stays bound to complement proteins on cell surface. C5b maintains capable of binding to C6 and C7. C7 component of C5b,6,7 complex is hydrophobic and can insert into lipid bilayer of cell membraine. it becomes receptor for C8. then when attached, C5b,6,7,8 complex (aka C5b-8) has limited ability to lyse cells. C9 polymerizes at this site and binds to C5b-8 to form Membrane Attack Complex (MAC) in pores in plasma membrane. this creates channels that allow movement of water and ions. this entry of water ruptrure the cell from osmotic swelling.
101
all 3 complement pathways result in…
C3b, C3a, C5b, C5a and MAC
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anaphylatoxins
potent stimulators of inflammation. C3a and C5a are anaphylatoxins
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membrane bound inhibitors
mammalian cells have regulatory proteins that inhibit complement activation. Microbes lack the regulatory proteins, which is why they are susceptible to complement pathways. DAF and MCP are two inhibators
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Decay accelerating factor (DAF)
membrane protein that disrupts binding of factor B to C3b or the binding of C4b2a to C3b. This terminates complement activation for both alternative and classical pathways
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Membrane cofactor protein (MCP)
cofactor for proteolysis of C3b into inactive fragements. It is mediated by a plasma ensyme called factor 1
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soluble inhibitors
C1 inhibitor (C1 INH) prevents assembly of C1 complex. Blocks classical pathway.
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C3 deficieny
associated with frequent pyogenic bacterial infections. It can be fatal because C3 is a central roll.
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C2 deficiency
most common complement deficiency. It resembles autoimmune lupus.
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C1 INH deficiency (hereditary angioneurotic edema)
excessive C1 activation leads to leakage of fluid in larynx and other tissues.
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DAF deficiency (paroxysmal nocturnal hemoglobinuria)
unregulated complement activation occurs leading to lysis of erythrocytes.
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B lymphocytes can see what
Lymphocyte that mediates adaptive imune responses. They are mediators of humoral immunity They are on cell membrane or in solution antigens. They influence the production of antibodies, neutralize and eliminate extracellular microbes and microbial toxins.
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T lymphocytes can see what
only peptide antigens associated with MHC
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maximizing change of antigen encounter
T cells patrol the body. Dendritic cells capture antigens and transport them to local lymphocytes
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antigen processing
capture proteins must be broken down into peptides (processing) Then they need to be transported to lymph node and loaded onto MHC for T cells to see them
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Epitopes
small parts of molecules from pathogens. T cells only recognizethese processed antigens.
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polymorphic MHC
class 1 and class 2 MHC genes are the most polymorphic (variation between individuals) genes encoded in mammals. They are co-dominantly expressed, meaning we get one from egg and 1 from sperm,, each are expressed equally. There are 3 associated with each class, HLA-A, HLA-B,HLA-C. so there are 6 on every dendritic cell.
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another name for MHC
HLA (in humans)
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MHC class 1 is expressed by…
all nucleated cells
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MHC class 2 is expressed by…
only on APCs
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chains in class 1 MHC
alpha 1 and aplha 2 create the CLOSED peptide binding cleft. Alpha 3 is invariant, it contains binding site for T cell co-receptor CD8 (NOT CD4). It anchors the MCH class 1 molecule to the membrane.
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chains in class 2 MHC
alpha and beta chains. Alpha 1 and beta 1 create the OPEN peptide binding cleft. It accommodates larget peptides than class 1. invariant beta 2 contains binding site for CD4 (NOT CD8). Aplha 2 and beta 2 anchor MHC 2 in the membrane of APCs
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CD8 MHC
class 1
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CD4 MHC
class 2
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DCs are capable of presenting antigen on what MHC class
both
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MHC class 1 pathway
proteins are sourced from cytoplasm. They are unfolded and tagged with ubiquitin for degradation. A Proteasome shreds the protein into peptides (inflammatory cytokins such as IL1 and TNF enhance this). Then peptides are moved by TAP into the endoplasmic reticulum (ER). the ER class 1 molcules are synthesided and the newly formed class 1 MHC binds to TAP via tapsin. Peptides are loaded into MHC cleft binding site. the MHC class 1 with peptide loaded exits into golgi apparatic to repsent to CD8 T lymphocytes.
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MHC class 2 pathway
extracellular antigens are recognized by PRR. They are then internalised by phagocyotsis into phagosomes/endosomes. The endosome fuses with lysosome and degrades proteins into peptides (now called phagolysosome). During this, the MHC 2 aplha and beta chains are synthesised in the ER. the invariant chain has CLIP in the cleft to prevent other peptides from binding. the class 2 molcule exits ER and goes into Golgi. then the vesicle it is in fuses with phagolysosome. CLIP is exchanged for the peptide antigen and then are transported to the cell membrane for CD4 presentation.
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non host resistance
when a plant is resistant to an antigen
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non adaptive pathogen
a pathogen that cannot infect a plant
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gene for gene hypothesis
for each gene reistant to the host, there is a specific gene conditionince avirulence in the pathogen. When capital AVR1 (avirulence in pathogen) and capital R1 (resistance in host) occur, defence related genes are activated.
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hostoria
can take nutrients from host cell and supplly it to pathogen
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infectors
avirlunce gene product. The pathogen sends this out and the plant ca recognize it and attack back. The plant will kill itself so that the rest of the cells are healthy and it does not spread.
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rust
pathogen that kills plants
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rust types
stem rust (100% losses) Leaf rust(50% losses), stripe rust (70% losses)
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approaches to control plant diseases
cultural practices, chemical control, resistance breeding
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resistance breeding
economical and enironmentally acceptable. The issue is that pathogens are variable so they could overcome resitsance through mutations But plants have also evolved resitance genes. (i.e. the stem rust restance gene, Sr, is now up to Sr67)
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resitance on a spectrum
not everything is 0 or 100% resistance. Not all resistance provides a level of protection that will prevent losses.
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plant resistance complexity
plant immune responses are very complex. Unline animals they don’t have mobile immune cells and an adaptive immune system. So they have a much bigger pathogen recognition repertoire
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humoral immunity
macromolecules in the 'humors' i.e. body fluids. Includes things like secreted antibodies, complement proteins, etc.
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what happens if you don't have B cells
you can't make any antibodies and are highly susceptible to infection. Often severe recurrent bacterial infections. You also have a poor response to vaccination.
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where are B lympocytes developed
bone marrow
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where are T lymphocytes developed
in the thymus
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B cell receptor (BCR)
this is wehre do antibodies come from .they start as a cell surface bound receptor, aka the B cell receptor (BCR)
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diverse antigen receptors
these are adaptive immune cells, such as B and T cells and can regonize MANY mpre antigens.
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antigen receptor - what does it look like
membrane bound. They have a constant region(purple in lecture 7 slides) and a variable region (other colors). They have ONE specificity. Each cell expresses thousands of one receptor on the surface. They have 2 identical heavy changes and 2 identical light chains. fab region is top, Fc recion is bottom.
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how many possible b cell receptors are there
10^11
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B cell receotir antigen recognition
recognize free antigens or antigens delivered by other cells. Linear and conformational epitopes. Can be protein, lipids, carbohydrates, neucelic acids
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T cell receptor antigen recognition
they recognize professed antigens presented by MHC molcules, linear epitopes, TCR binds to both peptide and MHC
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5 antibody classes
IgM, IgG, IgD, IgA, IgE
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what type of antibodies neutralize
IgM, IgG, IgA
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isotypes involved in opsination and pagocytosis
IgG and IgA
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antibody dependent cell mediated cytotoxicity (ADCC)
role for antibodies to fight intracellular pathogens. igG binds to foreign antigen on surface. NK cells engages with igGbound cell. Receptor mediated signals release graniles containing toxins.
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isotypes involved in ADCC
IgG
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helminth
parasitic worms that cannot be phagocysed
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clearance of heminths
IgE opsinises worms., induce eosinophil activation and release cytoplasmic granules that kill it.
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what isotype activates mast cells and bsophils
IgE
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what isotypes activate classical pathway
IgM and IgG
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B cell development
B cells start with DNA with two variable regions. Step 1, rearrange the gene segement through VDJ recombination. Step 2, Introduce junctional diveristy. Then go through positive and negative selection. Finally B cell maturation finishes in the spleen. Lastly, it is recirculated in the blood and lymph and looks to antigens.
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VDJ recomination
a random rearrangement of a V, D and J gene segment to create a single VDJ exon that will code for variable region of protein. It is ordered. D fuses to J and then V fuses to DJ. It is mediated by an enzyme that only is in immature B and T cells
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junctional diversity
introduce random nucelotides at the junctions between V D and J. this increases diversity of receptors produced.
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positive selection B cells
did the B cell make a productively rearranged recepture after VDJ and junction diversity. If not, there is not survival.
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negative selesction B cells
did the B cell make a receptor that binds strongly to self'antigen. If it is self'reactive, B cells rearrange in receptor editing. If this fails, it is deleted.
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B cell activation with BCR complex
since BCR cannot transduce singlas, it is associated with two proteins, Igalpha and IgBeta to form the BCR complex. BCR recognizes and binds with antigen. Cross linking with 2 or more BCRS triggers signalling. Then there is a T dependent or T indepenend response
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BCR complex
made of IgAlpha and IgBeta. They contain ITAMs
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ITAMs
these transduce signals inside the cells when phosphrylated by kinases
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T'independent B cell response
Where:B1 cells in the marigan zome B cells in the spleen. What: antigens that T cells cant respond to.
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T dependent response
T cells help B cells. T cells recognize the MHC in T cell zone and are activated. B cell recognises unprocessed antigen in B cell and is antigen. B and T cells migrate toward each other to respond to chemokine signals. They meet at the edge of primary follicle. B cell presents antigen to T cell. Then the T cell CD40 engages with B cell CD40 and activates the B cell. The T cells produce cytokinds that can provide differentiaion signals to B cells.
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T cell help can cause what
B cell proliferation, isotype switching
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Germinal center reaction
where cell proliferaton happens. After activation by T cells, some B cells move into the germinal center with T collicular helper cells. Here, somatic hypermutation occurs. Then it moves out and tests affinity of BCR for antigen. Then it repeats.
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Somatic hypermutation
mutatio of igC genes while proliferating. Tries to make variable region with higher affinity for pathogen.
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Plasma cells
Usually 2-3 weeks after immunisation with T dependent antigen, bne marrow beomes major site of antibody production. Plasma cells enter this bone marrow and continue to secreete antibodies for months or years after the antigen is no longer present. This causes immediate protection if the antigen is encountered again.
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what happens if you don’t have T cells
you are very susceptiable to viral, bacterial and fungal infections. You have SCID, which is severe combined immunodeficiecy. This causes a group of rare genetic disorders. Usually fatal within first 1-2 years of life unless cured by HSCT (a transplant) or gene therapy
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helpter T cells
CD4. produce cytokinds to direct immune responses. Usually intercellular viruses, bacteria, parasites, extracellular fungi and bacteria
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Cytotoxic T cells
CD8 directly kill infected cells. Intracellular viruses and bacteria
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Co receptors
CD4 and CD8. they restric the cell to seeing antigens that are relevant to their capabilities
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MHC1 presents what type of antigens to what type of co-receptor
intracellular pathogens to CD8
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MHC2 presents what type of antigens to what type of co-receptor
extracellular pathogens to CD4
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TCR complex
TCR can recognize peptide/MHC but it cant transduce a signal to activate the cell. It needs the TCR complex, which is TCR + Cd3 chains plus zeta chain.
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CD3 proteins
3 polypeptide chaind. Arranged in two heterodimers, conaitn 1 ITAM
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T cell development
occurs in thymus. It starts with DNA that has variable regions. There is VDJ recomination and junctional diversity. Then there are selection events of positive and negative selection. If the cells pass (only 2% do), then it leaves thymus and enters circulation and lymphoid organs to await encounter with antigen.
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positive selection T cells.
needs to answer 2 questions (double positve). 1. did it rearrange to useful TCR (will it bind to MHC) 2. will it bind to MHC1 or MHC 2 (aka is it CD4 or CD8). If it fails, it will die. 90-95% die. Death is caused by neglect.
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negative selection T cells
Question: did it rearrange with self-reactivity? (aka does it bind to MHC with too high affintiy?) if it does, it dies.
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central tolerance
self tolerance. Does react with self.
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mTEC
they test TCRs. They express tisue restricted antigens, allowing TCRs to be tested for relf reactivity. It ensures an all encompassing approach to central tolerace. Aire, which is in it, promotes transcirotions of genes that would normally be silenced so that mTECS can present it to DCs for presentation to TCRs and testing.
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CD8 killing mechanism
cytoplasmic graule toxins and perforin-granzyme mediated killing and FAS/FAS-L mediated killing. Triggers classical caspase dependent apoptosis. Main path is to eliminate self-reactice lymphoid cells. Also differentiatiates into memory cells
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CD4 killing mechanisms
they differentiate into effector subsets and produce cytokines to direct immune responses.
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convential T cells
presented by MHC molecules
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innate like (unconventialnal) T cells
recognize mostly non peptide antigens, presented by non-polymorphic antigen presenting molcules (not MHC 1 or 2)
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subsets of NK
glycolipids
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DC are placed where and why
pheriphery to maximise first change encounter. DC in periphery have high phagocytic capacity.
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where do DC acquire acntigens
from many different sources and they can activate both DC4 and CD8 T cells
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DC in periphery functions
PRRs recognize PAMPs, they have high phagocytic capacity, process antigens into MHC 1 and 2, migrade to T cell zones
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DC in lymph nodes
home to T cell zones, express required surface molcules to activate naïve T cells (MHC, cytokines, co-stimulatory molecules)
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cross presentation
activation of naïve CD8T cells by professional APCs (aka DC). There are 2 pathways. Cytosolic pathway or vacuolar pathway.
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cytosolic pathway of cross presentation
proteasome dependent (it degrades it) Role for ERAP1 and IRAP peptidases
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vacuolar pathway of cross presentation
resistant to proteasome inhibitors, independent of TAP, sensitive to inhibitors of lysosomal proteolysis.
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Cross presentation of internalised antigens
some DC have the ability to ingest infected cells and then cross present to CD8 T cells. Some DC can transport the antigens into the cytosolwhich allows antigens to be processed into MHC 1 or 2.
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DC in response to danger signals
can be activated and migrate away from periphery in minutes to draining lymph nodes
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immunological synapse
interface between APC and T cell
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T cell activation steps
1: TCR recognizes MHC-peptide. TCR binding to peptide-MHC is low affinity. TCR itself does not not transduce activation signals. 2 or more TCR must be engaged for several minutes to commence activation. 2: co-receptor binds. Stabalizes low affinity binding and ensures appropriate T cell type is activated. activation occurs via signalling through TCR complex. 3: adhesion molecules LFA-1 (a integrin molecule in T cell membrane) binds ICAM-1 (adhesion molevule on APC). adhesion molvesules increase binding affinity. 4: co-stimulation. T cells require additional signals (two signal hypothesis). singla 1 is the antigen recognition, signal 2 is the co-stimulatory signal from DC (B7 1 and 2 bind to CD28 (on the T cell) )
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inhibitory receptors of T cells
CTLA-4(binds to B7 on APC) and PD-1 (binds to PD on APC). both are induced in activated T cells and function to terminate responses of those cells.
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Ig superfamily
proteins that have Ig fold structure (two adjacent beta-pleated sheeds held together by disulfide bridge)
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some transcription factor examples
NFkB, AP1, NFAT. These all stimulate IL-2 expression, which is essential for promoting T cell proliferation and differentiation into effector T cell.
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how does the adaptive immune system combat different infections?
division of labor
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how do CD4 T cells combat different pathogens?
cellular immunity or humoral immunity
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type 2 interferon
a Th1 cytokine. Increases phagocytosis and killing of microbes in phagolysosomes by promoting fusion and acidification. Enhances antigen presentattion, induces anti-microbial intermediates.
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how is CD4 T cell decision making process regulated
distinct differentiated states of CD4 subpopulations are determined by set of transcription factors they express and genes they transcribe. In addition, cytokine environment plays a role in chaping decision making and effector function. Pathogen recognition by innate cells provides singlas for CD4T cell effector choice (Th1 or Th2)
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T-Bet
key transcription factor involved in commitment of Th cells to Th1 lineage development. Low level expression in naïve T cells but it is upregulated upon TCR stimulation. Overstimulation can cause competence to produce IFN2. increases IL-12 expression.
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GATA-3
only T cells express GATA3. Naïve CD4 T cells express GATA 3 at detectable levels. Controls thymocyte development and Th2 differentiation. Deletion of GATA3 preventions differentiation into Th2.
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Th1
influenced by IL12 and T bet. Functiond: macrophage activation, production of some antibody isotypes.
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Th2
influenced by IL4 and GATA 3. functions: IgE production, eosinophil activation, mucosal secretion.
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the Th effector T cell generated influences what
the outcome of the infection. i.e. Th1 is good for intracellular bacterial infections while Th2 is resistant to helminth infection
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why do we need killer lymphocytes
important in situations where cells cant destroy microbes that infect them. Two situations where this happens 1. viruses live and replicate cells that lack machinery for destroying micribes. Second, sometimes microbes escapre from the vesicles and live in cytosol where the mechanisms are ineffective. thus, killer lymphcytes are needed.
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killer lymphocytes
CD8, CD4, NK. They lyse their cellular targets by 2 mechanisms, cytoplasmic granule toxins and engagement of target cell death receptors
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major cytotoxic proteins in granules of cytotoxic lymphocytes
granzymes A, B C (these are serine proteases. B can actuvate cspases which induces apoptosis). Perforin (membrane pertubring molecule homologous to C9 complement. Function is to facilitate delivery of gransymes into cytosol.) CTL granulysin (NK granule that can alter permeability and membranes)
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CTL in target cell killing- why isn't CTL damaged
delivers lethal hit. Then CTL is released from target cell (often before cell dies). CTL is not injured because the granule exocytosis dilivers granule to target and away from CTL. CTL containes cathepsin B that goes to CTL surface and degrades any perforin molecules that are close to CTL membrane to prevent it from being damaged.
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NK
natural killer cells. Bone marrow derived. Oldest member of ILC. Circulate blood. Provide early defense against pathogens (mainly viruses and intracellular bacteria). They germline DNA encoded receptors to distinguish pathogen infected from healthy cells. they also recognize stressed cells and damaged host cells and elimate them. NK cells secrete IFN to activate macrophages. they have array of receotprs that allows them to detect targets (including inhibitory, activating, adhesion, and cytokine receptors).
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why don't NK cells kill healthy cells
they have inhibitory receptors
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how do NK recognize tumor cells
tumors have loss of MHC 1 expression. Thus, NK become activated. This is called 'missing self' of NK activation
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comparative immunology
investigate major differences in the immune system between different organisms. Usually distantly related. i.e. fish vs other animal
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why is comparative immunology importat
to see variation in immune mechanisms (aspects that might not be seen in humans or mice) and to understance the evolution of immune system
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marsupials and monotremes and eutherians
the approximate 150 million years of evolution between species means these mammals are ideal for comparative immunology studies
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anatomical comparative immunology
lymphoid tissues
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functional comparative immunology
presence/activity of immune cell populations
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molecular comparative immunology
immunogenetics
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anatomical differences in marsupial and monotreme
there are many studies on differences in 1900s on primary and secondary lymhoid tissues. Similar structure and complexity to humans. The key differences are thymus and timing of immune development
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monotremes deveopment of immune system
timing of development differs. Montremes are largely unknown.
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marsupials development of immune system
timing of development differs. Montremes are largely unknown. Marsupials have short gestation of 30 days and are orn at early developmental stage. They are immunonaive at birth and immune system develops within non-sterile pouch. during development the young is exposed to numerous pathogens within the pouch. Liver is haematopoietic tissue at birth (bone marrow in humans). lack of mature immune tissues causes a delay in adaptive immunity. thymus and bone marrow are around 1-2 months after birth, sleen and lymph node are 3-4 months after birth.
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marsupial protection in pouch
passive immunity via milk. This is similar to eutherians. Expansion of antimicrobial peptide genes. Target and ill bacteria and fungi. Expressed in pouch, milk, and PY skin.
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cytokine network in monotremes and marsupials
messengers crucial for immune response. Similar complexity to humans. Marsupial immune cells respond to cytokines in vitro. Indicates functional capactiy of marsupial and monotreme immune system.
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immune cell populations monotremes and marsupials
majority of antibodies ffor human/mouse markers are not cross-reactive (not able to bind to monotreme and marsupial immune markers). Cell markers differ slightly. Lack of specific antibody markers so there is ongoing limintation of research in this field.
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functional differences monotreme and marsupials
overall, similar to eutherians (tissue, cell type, antibody production, immune cell activation). Level of response differes between the species. Peripheral immune cell response to antigens in vitro.
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genome era
genomes have become essential tool for immunogenetics. They provide information about number, type, and expression of receptors/antibodies/signalling molecules
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marsupial and monotreme T cell receptors
fith TCR chain unique to marsupials and monotremes. Ancient TCR gene lost in eutherians and non-mammals. 2 isoforms in marsupials, only one in montremes
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marsupial and monotreme toll like receptors
same as eutherians except TLR1 and TLR6 could not be identified. Unique TLR1/6-like TLRs that are not found in eutherians. Ancestral gene duplicated and evolved into TLR1 and TLR6
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MHC marsupial and monotreme
3 classes of genes, 2 involved in antigen presentation. Most variable region of the geneome- it is always evolving. The complexity and number are similar to eutherians. There are a number of unique MHC genes. Organization of MHC genes differs to eutherians- it reflects ancestral mammalian MHC and is more similar to birds.
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immunoglobulins marsupial and monotreme
two heavy and two light chanes. Eutherians and montremes have 5 classes. Marsupials differ- they don’t have IgD and only a single subtype of IgA and IgG rather than multiple. Eutherians have high diversity within variable region. Marsupials and echidna have limited heavy chain diveristy, light chain compnsates. platypus has limited heavy and light chain diversity.
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T cells all express what
CD3
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memory B cells- T independent
IgM secretion is greatest when antigens are multivalent. Many bacteria have polysaccharide rish capsules. Early IgM production is important. IgM response to proteins is poor. IgM activates elimination mechanisms.
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memory B cells - T dependent
trigger CD4 T cell help to B cells. Protein antigens elicit poor IgM response. They require T cell help.
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how do Th and B cells get together
naïve CD4 Th cells bind foreign peptide-MHC class 2 displayed by professional APC in T cell zone of lymph nodes. Activation requires costimulation (signal 1 and signal 2). Result of T cell activation: proliferation, differentiation, migration. Some effector T cells migrate toward B cell follicles.
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B cell migration
follicular B cells newly activated migrate toward T cell zone. They change chemkine receptors expressed on surface. This allows them to follow T cell zone chemokine gradients, stopping them from re-circulating between B cell follicles.
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Receiving T cell help
t and b cells are specific for same anitgen. If T cell recognizes the peptide MHC 2 complex it will receive a signal through immunological synapse. It becomes reactivated and sends a signal to the B cell by engaging its CD40L with CD40 on B cells. T cell will also produce cytokines and send additional signals to B cell. leads to activation of B cells by CD40
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T cell-B cell interaction is called
cross talk, cooperation, or collabration.
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class switching
in response to non-protein antigens B cells produce IgM antibodies. Heavy chain isotype switching is induced by a comination of CD40L- mediated signals and cytokines
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why does class switching happen
different antibody isotypes perform different functions. Isotype switching braodens functional capabilities of humoral immune response. Different cells have different Fc receptors that bind specific heavy chains.
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Macrophage Fc receptor
Fcy, binds to IgG
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eosinophil and mast cell Fc receptor
Fce for binding IgE
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somatic hypermutation
mutations in variable genes increases the affinity of an anitbody for its antigen. Affinity increases over time with repeated antigen exposure. Occurs in B cells that return to and poliferate rapidly in germinal centres.
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Germinal center- dark zone
part of germinal centre. Does not contain any FDC or t cells. Densely packed with rapibdly proliferating B cells. Doubling time of B cells in germinal centrea (aka centroblasts) is 6-12 hours. Progeny of the proliferating B cells in germinal center are smaller (aka centrocytes)which undergo differentiation and selesction in the light zone
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light zone
site of selection of events. Small non dividing progeny of B cells migrate to adjacent light zone. There they come into close contact with processes of abundant FDCs. They also form intimate contacts with T follicular helpfer cells.
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Follicular dendritic cells (FDC)
only found in lymphoid follicles. Not like dendritic cells (do not present antigen on MHC to T cells). FDCs provide source of antigen for Germinal Centre B cells. Involved in displaying anitgens for selection of germinal centre B cells. FDC test B cells by presenting antigen bound antibody complexes.
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memory phase
some B cells activated in germinal centre acquire ability to survive for long periods. Memory B cells make rapid responses to subsequent antigen re-exposure. Some memory B cells remain in lymphoid organ where they were generated. Others exit and recirculate. production of large amounts of isotype switched, high affinitiy antibodies is greatly accelerated after second exposure
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effective vaccines induce what
both affinity maturation and memory B cell formation
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memory phase response
IgG responds higher after second exposure. Secondary response is faster, greater magnitude, and better quality.
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subsets of memory CD8 T cells
central memory, effector memory, resident memory.
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central and effector memory
largely definied on basis of circulation. CM circulates through lymphoid, EM circulates through non-lymphoid tissue. Functional differences- CM highly proliferative, EM enhanced effector functions
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resident memory
do not circulate in blood. Often positioned at sites of possible antigen encoutner.
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cytokine production
not usually stored as preformed molecules. Cutokines are synthesized and released rapidly after cellular sitmulation. Cytokine gene transcriptional activation is transient and most of cytokine mRNA are unsatble (to ensure cytokine synthesis is brief and self-limiting). one cell can simulatneously produce multiple cytokines.
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cytokine receptors
all receptors consist of one or more transmembrane proteins (receptor subunit or chain): extracellular domains for cytokine binding, cytoplasmic tails for initiating signaling pathway
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cytokine types
interleukins (IL), interferons(IFN), Tumor necrosis factors (TNF) and growth factors (GM-CSF)
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lymphokines
cytokines produced by lymphocytes
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monokines
cytokines with monocytes/macrophages as cellular source
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cytokine receptor families
type 1 cytokine receptor, type 2 cytokine receptor, TNF receptor, IL-1 receptor, G-protein coupled receptors
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regulation of cytokine activity
3 mechanisms that prevent cytokines from activating cells in non-specific way during immune response: 1 regulated cytokine receptor expression 2 short half lives 3 cytokines and target cells need to be in close proximity
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pleiotropic
cytokines are pleiotropic meaning they act on different target cells
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antagonistsic
cytokines are antagonistic meaning inhibition of one cytokine effects by another
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redundant
cytokines are redundant meaning mulciple cytokines have same effect
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synergistic
cytokines are synergistic meaning cooperative effect of multiple cytokines
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3 functional categories of cytokines
1. mediators and regulators of INNATE immunity. 2. mediators and regulators of ADAPTIVE immunity. 3 stimulators of hematopoiesis
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major pro-inflammatory cytokines of innate immunity
IL12, TNF, IL1, IL6, IFN type 1
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major effector cytokines of adaptive immunity
IFN type 2 and IL4
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interferons
they were discovered based on their ability to interfere with viral infection. Now they are recognized as a family of pleoitropic cytokines that play essential role in controlling viral, intracellular bacterial and parasitic pathogens. There are 3 major families, IFN 1, IFN2, IFN 3
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IFN 1 and 3
produced by tissue cells and innate immune cells. Essential for anti-viral immunity. Type 1( α, β, ε, κ, and ω) type 3 is IFN λ
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IFN 2 (IFN y)
produced predominately by activated lymphocytes. Imporant for control intracellular bacterial and parasitic infection
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Type 1 IFN biologic actions
mediate early innate immune response to viral infection. Most potent stimuli for type 1 are viral nucleic acids. Antiviral action of type 1 is primarily paracrine action in that a cirally infected cell secretes IFNs to act on and protect neighboring cells that are not yet infected
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type 2 IFN biologic actions
IFN y is only type. Mainly produced by activated lymphocytes. It is a major phagocyte activating cytokine. Upreculating MHC 1 and 2 molecules. Induces antimicrobial substances
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tumor necrosis factor (TNF)
main mediator of acute inflammation in response to bacteria and other agents. Large amounts of TNF can be produced in response to gram+ and gran- bacteria. LPS is most potent stimulus for TNF production. TNF is produced by macrophages, DCs, Th1 cells and other cell types. preformed TNF is quickly released from mast cells. IFNy is produced by T cells and NK cells augment TNF prduction by LPS activated macrophages
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local inflammation of TNF
stimulates recruitment of neutrophils and monocytes to sites of infection and to activate cells to eradicate microbes. Induces endothelial cells (ECs) to adhesion molecules, more adhesive for leukocytes. Stimulated Ecs and macrophages to secrete chemokines enhance affinity of leuocyte integrins for their ligands. acts on mononuclear phagocytes to stimulate IL-1 which functions much like TNF. induces DC migration to lymph nodes
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system protective effects TNF
severe infections- TNF produced in large amounts and causes system effects. Large amounts can enter bloodstream and act at distant sites as endocrine hormone. Can also act of hypothalamus to induce fever, liver t increase synthesis of serum proteins, and prolonged production of TNF causes wasting of muscle and fact cells
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pahtogenic effect (septic shock) TNF
high concentrations of TNF cause septic shock, reduction in myocardial contractility, organ failue and hypoglecemia
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chemokines
divided into 4 families (CC, CXC, C and CX3C). CC and CXC subfamilies are produced by leukocytes and tissue cells. All induced by microbial products and cytokines. Receptors are expressed on all leukocytes and they exhibit overlapping specificity for chemokines within each family. pattern of cellular expression of the receptors determines which cell types respond to which chemokines
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biological functions of chemokines
interaction of chemokine and its receptors stimulate cyroskeletal changes leading to increased cell motility. Critical in development of lymphoid organs. Reguired for migration of dendritic cells. Essential for recruiting leukocytes from blood vessels into extravascular sites, partly through enhancing integrin affinity. CCR5 and CXCR4 are co-receptors for HIV
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integrin activation by chemokines
integrins respond intracellular signals such as chemokines by rapidly increasing their affinity to their ligans. They mediate adhesion of cells to other cells or extracellular matrix. Essential for recruitment of leukocytes into sites of infection or injury
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integrins
heterodimeric cell surface protein composed 2 polypeptides
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leukocyte endothelial interactions and leukocyte recruitment into tissues
leukocyte recruitment from blood into tissues requires adhesion of leukocytes to endothelial lining of postcapillary veules and then movement throough endothelium and vessel wall into extravascular tissue. This is a multistep process orchestrated by different adhesion molecules and chemokines. Includes 1 selectin mediated rolling of leukocytes on endothelium 2 chemokine mediated increase in affinity of integrins 3 stable integrin mediated arrest of leukocytes on endothelium 4 transmigration of leukocytes through endothelium
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why is leukocyte migration important
deliver cells to tissue or site of infection, myeloid cells from blood to tissues, lymphocytes from primary lympod organs to secondary lymphoid organs, secondary lymphoid tissues to site of infection, immune response initated at one site and delivered at another.
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homing
blood goes to specific site
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migration or recruitment meaning
general leukocyte movement from blood into tissues
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adhesion molecules defintion
mediate adhesion of leukocytes to vascular endothelial cells. Expression varies between different leukocytes
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two classes of adhesion molecules
1. selectins and selectin ligands 2. integrins and integrin ligands
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selectin and selecting ligands
expressed on plasma membranes. They are carbohydrate binding adhesion molecules. Mediated initial stpe of low-affinity binding to endothelial cells. Expression can be induced by cytokines.
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integrin and integrin ligands
heterodimeric surface proteins. 15 types of alpha chains and 7 types of beta chains. There are 30 different integrins. Integrate signals between extracellular ligands and cellular function associated with cytoskeleton-dependent motility/shape/phagocytosis. they increase their affinity for ligands upon intracellular signals
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how do leukocytes know where to go
tissue resident cells promote inflammation. TNF and IL-1 stimulate endothelial cells to rapidly express two adhesion molecules (E-selectin and P-selectin). Circulating phagocytes express surface carbohydrates that bind weakly to the E selectin and P selectin- causes the cell to roll along the endothelium
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leukocytes entering peripheral site of inflammation
leukocytes express integrins that are adhesion molveules. At the site of infection, resident cells produce chemokines which stimulate rapid increase in affinity of leukocyte integrins for their ligans on endothelium. This directs migration of cells. The firm binding of integrins to their ligands arrests leukocyte rolling. the cytoskeleon of the leuocyte is reorganized and the cell spreads out on the endothelial surface. firm adhesion is quickly followed by extravasation into inflamed tissue. chemokine directed migration tells the leukoctytes where to go.
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High endothelial venules (HEVs)
found in secondary lyphoid organs except spleen. Postcapillary veules adapted for lymphocyte trafficking. Endothelial cells have a cuboidal morphology. espress addressins.
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how do naïve T cells find their way into lymph nodes
naïve T cells express specific homing receptors that allow them to recirculat between lymphoid tissue (i.e. L-selectic , CCR7, LFA-1, ICAM-1). Naïve t cells that have homed into lymph nodes but fail to recognise antigen and become activated will eventually return to blood stream.
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naïve T cells return to blood
blood provides naïve T cells with another change to enter secondary lymphoid tissues and search for antigens they recognize. Route of re-entry: 1. through efferent lymphatics (i.e. through other lymph nodes in same chain), through lymphatic vasculature to thoracic or right lymphatic duct, and finally into superior vena cava or right subclavian vein
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how do naïve T cells know when to return to blood
They need to be given time to inspect. Recently arrived ones express low levels of S1PR1 . If they do not engage after several hours they will re-express S1PR1 on their surface and allow them to return to blood.
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evolution immune system- general info
immune cells evolve repeatedly during lifetime. Within weeks they evolve and adapt. How? Food played a key role in shaping immune system
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why do we need specialized cells to fight
physiological functions (such as nutrient intake, waste excretion, etc.) and defense mechanisms (such as mucus secretion and triggering cell death)
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fixed immunity cells in gut
epithelial cells
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mobile immunity cells in gut
leukocytes
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how do worms protect themselves
epithelial cells only, no blood. Short lifespan because its best to avoid infection instead of fight. Three types of PRRs, melanisation, anti-microbial proteins
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how do flies protect themselves
partial TLR system, blood equivalent is hemolymph. Longer lifespan, bigger body and complexity. Fat body is liver which produces circulating AMPs. They have 3 types of leukocytes
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plasmatocytes
the phagocytes of flies
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crystal cells
melanisation and clotting of flies
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lamellocytes
encapsulation of flies
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phagocytes in different organisms
different names in different organisms. Phagocytic abilities are present even in unicellular and primitive multipcellular organisms. All are able to discriminate between self and non-self and perform effector functions
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why are phagocytes important
surveillance (PRRs, lectins, complement receptors etc), containment (phagosome and autophagosome) and destruction of pathogens (anti-microbial peptides, acidification, etc)
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granules
content defines cell types. Deployed by fusion into phagosomes or exocytosed out of cytoplasm. Contain dicrect acting antimicrobial peptides and enzymes. Highly toxic to bystanders.
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how do jawed vertebrates protect themselves
immune cells are more specialized. They all share a common innate immune system.
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heterophils
comprable to neutrophils but cytoplasmic granules are cidophilic or eosinophilic. Mainly same antimicrobial granule proteins. Present in birds, some repiles, some mammals.
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immunological big bang
big bang for adaptive immunity. Development of lymphocytes, special organs, key immune cells (T cells and B cells), and key immune molecules
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MHC gene cassette
evolution of key molecule for adaptive immunity. A self ligand for immune recogntition. Based around Ig Super Family domains
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variable lymphocyte receptors
evolution of key molecule for adaptive immunity. Ig super gamily domains. New class of receptors, variable domain.
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Recombination activating genes (RAG)
able to direct site-specific recombination. RAG1+RAG2=VDJ recombinase. Catalyses recombination of DNA and core to shared vertebrate adaptive immunity.
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tasmanian devils are what species
marsupials. Theyre the worlds largest remaining carnivore marsupial. Extinct on the mainland around 3000 years ago. They are restriced to tasmania and experience a number of historical unexplainined population crashes.
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devil facial tumour disease (DFTD)
spread over 80% of tasmania. Up to 95% local poplulation decline. It is restriced to devils and is a contagious cancer. It is transmitted as an allograft through biting. Primary lesions around mouth and face. Very limited evidence of natural recovery or immunity. no diagnositic test.
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clonal cell line
tumors from different individuals have similar karyotype which differs to the host. Are identical at genetic markers. DFTD chromosomes have undergone significant rearrangement and continue to evolve
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orgin of DFTD
arose from a schwann cell in a female devil. Highly expressed genes, myelination pathway. stain positive for periaxin (shwann specific stain). Female- ID genes nronally found on X chromosone, no male-determining SRY gene (y chromosome)
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hypothesis (2) of why tasmanian devil immune system doesn't reject DFTD
1. DFTD is seen as self because devils lack diversity at MHC genes 2. DFTD evades the immune system by down-regulating MHC expression
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DFTD hypothesis 1
DFTD is similar to skin graft. Donor and recipent matched at MHC genes for successful transplant. Cheetah study (low MHC diversity individuals with same MHC type allografts accepted. Immune system functioning but it doesn’t recognise MHC differences between individuals. cheetah poplulation grash loss of MHC diversity)- is something similar happening in devils? there is a limited pool of MHC alleles in devils and many share same MHC type as tumour. devils don't recogize tumour cells as foreign and therefore don't mount an immune response.
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when did devils loose MHC diversity?
3 popluation crashes since european arrival. Devil MHC diversity has been low for thousands of years though. This might explain the history of desease susceptibility.
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DFTD northwest
DFTD is not present in north west tip of tasmania. MHC types are different in east vs. northwest devils. Northwest devils have more diversity in MHC types. A small number had antibodies to DFTD Could this be why they are resistant to DFTD?
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cedric vs clinky
cedric devils (MHC disparate) produced antibodies 3 weeks after whereas clinkly devils (MHC similar to DFTD) developed tumours after 12 weeks.
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genome wide association study tasmanian devils
millions of polymorphic (higlyh diverse) sites differed between groups of devils that succummend to DFTD and those that didn't. some of these were contained within genes involved in angiogenisis. Highly diverse may disruspt angiogensisis which would hinder tumour growth, metastasis and limit access to blood supply and nutrients.
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DFTD hypothesis 1 conclusion
deviles do have low MHC diversity BUT if transmission is due to low MHC diversity alone, devils should be able to accept tissue transplants
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skin graft study devils
2 devils with almost identical MHC types. Allograft and autograft. The allograft was rejected even though MHC of 2 devils was almost identical. Thus while devils have low MHC diversity they have functional MHC diversity and can distinguish self from non-self
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lymphocyte infiltration
immune activation and rejection of foreign cells
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hypotheses 2 DFTD
MHCI and genes essential for antigen loading and presentation show low/no expression in DFTD. Functional MHCI is not expressed on surface of DFTD cells. DFTD changes the way DNA is packaged preventing transcritpion of B2m, Tap1 and Tap2. DFTD antigens can't enter ER, MHCI retained and degraded within ER. DFTD effectively 'hidden' from the immune system.
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age and DFTD
older devils are first to succumb to disease. IgM and IgG decline with age. deviles with higher IGM/IgG ratio had lower DFTD prevalence. Lymphocutes also decline with age and there is a shift in immune system toward Th2 response. TCR diversity and expression of cytokines involved in T lymphocute activation declines with age
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NK cells DFTD
altered MHCI expression on tumour cells should trigger NK anti-tumour response. But devil NK cells showed no response. Are their NK cells functional? Maybe devil NK cells may require anti-DFTD antibodies for activation of NK response.
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how are tasmanian devils not extinct?
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DFTD evolution
constantly evolving. About 9-12 strains. DFT2 is a second cancer now.
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holobiont
assemblage of host and meany other specieies living in or around it which together form a discrete ecological unitethrough symbiosis
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when is there no disease (Avr1,avr1; R1,r1)
Avr1 and R1. all others are compatigon and there is disease
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effector triggered immunity
pathogen to effector to protein
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plant resistance protein structure
most are nucleotide-binding leucine rich repeat proteins (NLR) and share structual similarity with proteins involved in animal immunity.
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plant NLR effector regonition strategies
1. direct recognition (effector directly binds ) 2. indirect recognition (effector triggers target protein which) 3. integrated decoy (effector binds to integrated decoy)
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pattern triggered immunity
for broad resistance against conserved pathogen derived motifs. Activated upon PAMP binding to PRRs( i.e RLK or RLP). efense response to pathogen.
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Receptor like kinase (RLK) structure
LRR (leuchine rich repeate) outside domaine and kinase domain inside.
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Receptor like protein (RLP) structure
LRR (leuchine rich repeate) outside domaine
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how do plants defend themselves from surrounding pathogens
by two layers of plant immune recognition systems (PTI and ETI). It is at every cell due to lack of mobile immune cells in plants. Extensive physiological defense response of phytohormones, callose deposition, MAPK cascase, etc.
