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BOD > Intro to pathology > Flashcards

Intro to pathology Flashcards

1
Q

Pathology

A

Disturbance of hemostasis by cell death

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2
Q

Adaption to stress

A

increase in the size (Hypertrophy)
number (Hyperplasia) of individual cells

cell atrophy-cell volume diminishes as cytoplasm digested by proteosome and autophagy where lysososymes fuse and digest

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3
Q

Apoptosis

A

Controlled cell death (metabolism)
Cells shrink
membranes bleb and bud
Critical proteins cleaved by caspases
Expose signals for phagocytosis on surface

Intrinsic-caspase
Extrinsic-T cell Fas ligand

Development needs apoptosis, spaces between hands

Hayflick limit (telomere) not apoptosis

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4
Q

Necrosis

A

loss of cell volume
cellular swelling and rupture of internal and plasma membranes occurs
Intracellular contents leak
components are chemotactic for neutrophils
acute inflammatory reaction
Poorly controlled, spreads

Caused by something outside cell

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5
Q

Oxidative stress

A

reactive oxygen species (ROS),(NO), free radicals with unpaired electron
Made naturally by oxidative enzymes, also by radiation and xenobitoics

Damage DNA by strand scission
Disrupt protein folding
Damage fatty acid membranes

Used by neutrophils and macrophages

Made after periods of hypoxia, repurfusion injury

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6
Q

Impaired energy homeostasis

A

Loss of control of energy production due to e.g lack of oxygen
Na+/K+ pump stops, Na+ accumulates, water in, cell swells
Glycolysis increases, Lactic acid up, lower pH

Influx of Ca+ so increased activity of intracellular proteases, phospolipases,
endonucleases and ATPases

Ribosome detachment and loss of protein synthesis occurs

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7
Q

Heat shock

A

heat shock factors (HSFs), normally bound by heat schock proteins (hsp) and kept inactive
When heated, proteins unfold, hsp bind, HSF-1 becomes free to become a trimer and activate transcription of hsp and stops transcription of other proteins
Preconditioning

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8
Q

The unfolded protein response

A

cell protein concentration in the ER can reach 100mg/ml,
Proteins start to aggregate at too high conc

UPR activates signalling
cascades that increase synthesis of folding chaperones, enhance proteasomal protein
degradation by ubiquitin and slow down protein translation
Part of the response to injury

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9
Q

The stress kinase pathways

A

osmotic stress, oxidative stress, heat, UV,
DNA cleavage

activate heterodimeric transcription factors (e.g. AP1)

Jun N-terminal Kinase (JNK)/stress-activated protein kinase pathway (SAPK)
pathway

P38 kinase pathway

Pathways make AP-1, which causes inflammation, apoptosis, repair, adaption etc

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10
Q

Intracellular and extracellular infection

A

Extracellular- COmplement
Phagocytosis, Antibodies
anitmocorbials, antibodies
IgA

Intracellualr, viruses mainly chlamydia,Protozoa
NK cells, cytotoxic T cell, they also activate macrophages

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11
Q

Innate and Adaptive Immunity

A

Innate (natural) immunity.
This is in place before infection occurs and is poised to react immediately.

Adaptive (acquired) immunity.
This system takes time to develop and helps deal with infections that the innate system may
be unable to eliminate.
The adaptive response is highly specific, tailored to fit each particular pathogen
4-5 days

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12
Q

acute inflammatory response

A

Response to injury
eliminate the initial cause of cell injury, to remove damaged
(necrotic) tissue
initiate
repair of the damage tissue

PAMPs recognised by PRR on macrophages/mast cells,
Chemicals like histamine released, causes vasodilatation so neutrophils can enter

Calour (heat)- from increased blood flow
Dolor (pain)- stimulation of nerve endings,protsoglandin
Rubor (redness)- increased circulation/vasodilation
Tumour (swelling)- increased fluid in the tissues, increased permeability
tight junctions disrupted

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13
Q

Epithelial barriers

A

Tight junctions between squamous epithelial cells of the skin and mucosal glandular epithelia of the gastrointestinal and respiratory tract prevent access to tissues.
Additional modifications such as cilia (respiratory tract) and keratin (skin) function as
added barriers.

Secretions
* Mucous covers all glandular surface
* Stomach acid (low pH)
* Antimicrobial peptides (defensins, cathelicidins) damage microbe membranes
* Enzymes in tears and saliva (lysozyme) or stomach (pepsin)

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14
Q

Phagocytic/Cellular Barriers: Cells of the immune system

A

leukocytes made in bone marrow by hematopoiesis

Hematopoietic stem cell
lymphoid precursor- B cells and NK/T cell precursor

Myeloid precursor-
monocyte- macrophage/dendrite

granulocyte precursor- neutrophil, eosinophil, baso
mast cells unknown precurse

Megakaryocyte/erthroid precursor

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15
Q

Neutrophils

A

most abundant, not in tissue

Use chemotaxis with C5a and fMLF

Phagocytose

Short half life

Degranulate releasing antibacterial proteins

Extrude their DNA forming neutrophil extracellular traps
(NETs) to trap microbes (PUS)

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16
Q

Macrophages

A

Large phagocytic cells, in tissue

M1-macrophages secrete
cytokines and pro-inflammatory mediators that stimulate the acute inflammatory response

M2 or alternatively activated macrophages are associated with tissue repair and parasite
killing and expulsion

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17
Q

Mast Cells

A

In tissue

Cause inflammation quickly with histamine in secretory vesicles
Histamine acts on vascular endothelium, vasodilatation

degranulate within seconds

Triggered by allergens,IgE
PAMPs,DAMPs,
complement

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18
Q

Eosinophils

A

Parasite/worm defence
degranulates
pink biolabel

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19
Q

Basophil

A

Anti parasitic
Very little in blood
Release IL-4 which promotes TH2 response which delas with helminths

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20
Q

Dendritic cells

A

Bridge between innate and adaptive
Recognise pathogens and take them up to lymph nodes to activate T cells

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21
Q

Patter recogntition receptor

A

Stimulate phagocytosis
GUide cells
produce effectors

Toll-like recptor, TLR4-LPS
important for gram-ve detection
NOD-recognises multiple, peptidoglycan from bacteria
C-type lectin-fungal
RIG-I-like-viral RNA

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22
Q

PAMP
Pattern associated molecular patter

A

Essential for an organism, conserved
Should always be present
Not in host

Bacteria- + lopteichoic acid LTA
-ve lipopolysaccharide LPS
peptidoglycan PGN
DNA
flagellin
lipoproteins

Virus
COat protein
dsRNA

Parasite
GP1 anchor

Yeast
zymosan
beta-glucan

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23
Q

DAMP

A

Released during necrosis
ATP
DNA
RNA(less stable so less present)
CHromatin proteins
Cholesterol crystals

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24
Q

NK cells

A

Natural Killer
Healthy cells inhibitory signals from MHC class 1

MHC class 1 presents molecules inside cell as peptides, if infected, pathogen presented, death so

Some virus remove MHC class 1 no inhibitory signal, Missing self response

When infected express activating ligands, Induced self response

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25
Q

Viral infected cells

A

PRoduce IFN alpha
IFN beta

Causes resistance to viral replication
Increase expression of ligands recognised by NK
Activate NK cells

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26
Q

NK effector

A

Release perforin to form pores in membrane
Releas granzymes to induce apoptosis

Antibody Dependent Cell Cytotoxicity
(ADCC)
Recognise Fc part of antibodies, needs multiple antibodies

Macrophage activation
Make CXCL8, IL-12 & IL-15 which activates
NK cells make IFNgamma which increase killing capactity of macrohphage

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27
Q

Innate Lymphoid Cells

A

amplify signals produced
during innate recognition

ILC1s protect against viruses and intracellular pathogens

ILC2s assist mucosal and barrier immunity against parasite and helminths infection

ILC3s protect against extracellular bacteria and fungi

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28
Q

Cytokines

A

Secreted soluble proteins
BInd to recptors to conteol activity of immune cells

Autocrine,paracrine,endocrin

Redundancy, several different cytokines may have the same function
* Pleiotropism, a single cytokine may have a variety of different effects
* Antagonism, one cytokine blocks the action of another
* Synergy, multiple cytokines work together to achieve an effect that is greater than
the additive effect of each alone

Use JAK/STAT pathway

Interluekins
INterferons
TNF-Tumour necrosis factor

29
Q

Acute phase proteins

A

IL-6 stimulates hepatocytes to release acute phase proteins

C-reactive protein
(opsonin and complement activation) and Fibrinogen (fibrin clot formation)

Denfensins disrupt microbe membranes

Pentraxins bind to pathogens and phagocytes liek antibody

30
Q

Arachidonic acid metabolites

A

potent inflammatory mediators such as prostaglandins
and leukotrienes

Prostoglandins
vascular permeability
vascular dilation
neutrophil chemotaxis

leukotrienes
back up for histamine, longer stronger response
bronchial smooth muscle
contraction
neutrophil chemotaxis
Slow Reacting Substance
of Anaphylaxis (SRS-A)

31
Q

Chemokines

A

cells move towrads it down gradient
CXCL8

32
Q

Kinin system
made in liver

A

Bradykinin which increases vascular permeability, vasodilatation
Activates complement

33
Q

Inflammasome

A

Nod like recpeote NLRP3 forms inflammsome

Recognise peptideoglycan, bacterial DNA, ATP,
toxins, ds-RNA

induce inflammation by causing caspase-1 to activate IL-1b

34
Q

Inflammatory Exudate

A

dilate blood vessels to increase blood flow.
* increase permeability of the vessel wall to allow a protein rich fluid into the tissues. A
fibrin web forms and complement and CRP are recruited.

Recruit neutrophils and others like monocytes-macrophages
lymphocyte, eosinophil

35
Q

endogenous pyrogens

A

Induce fever

IL-1beta
TNF-alpha
IL-6

Secreted by activated macrophages

36
Q

Recruitment of leukocytes

A

Selectins like P/E selectin bind to glycoprotein ligands present on the neutrophil

integrin family adhesion
molecules (LFA-1) on cell bind Intercellular Adhesion
Molecules) on the endothelium tightly

Diapedesis, squeeze through the gaps between endothelial cells (extravasation)
elastase to degrade membrane

Migration using CXCL8 grad

LFA-1 deficiency stops neutrophil recruitment
Leukocyte adhesion deficiency (LAD)

Monocytes are recruited later because the endothelial adhesion molecule (VCAM-1)
is made slower

37
Q

Sepsis

A

Sepsis occurs when pathogens enter the
blood stream.
TNF=alpha secreted by macrophages
vasodilation and movement of fluid into the tissues
causes loss of blood pressure
Septic shock

Also triggers clotting in small vessels
disseminated intravascular
coagulation)

38
Q

Stopping Inflammation

A

Short half lives and degrade quickly

When apoptic neutrophils engulfed by macrophage,
anti-inflammatory lipoxin made
Makes anti inflammatory cytokines such as IL-10 and TGF-b to stop inflam

39
Q

Repair And Healing: Granulation Tissue

A

repair is called granulation tissue
recruitment of
endothelial cells to form new blood vessels and fibroblasts to lay down extracellular matrix (ECM)

Macrophages
phagocytose debris
kill microbes with ROS
recruit fibroblasts FGF
recruit endothelial cells VEGF
secrete metalloproteinases to allow remodelling of ECM

40
Q

Angiogenesis

A

stimulated by cytokines produced by macrophages (e.g. VEGF).

drives preexisting vessels to send out capillary sprouts into the area of damage.

41
Q

Chronic Inflammation

A

causative agent is
endogenous: e.g. stomach acid (peptic ulcer)
non-degradable: e.g. silica
evade host defences: e.g. tuberculosis
autoimmunity): e.g. rheumatoid arthritis

42
Q

granuloma

A

multinucleate giant cell
area of necrosis
Surrounded by T cells
walled off as can’t remove infectous agent

43
Q

Complement

A

Activation of inflammation
Opsonisation of microbes
Lysis of target cells

C3 has an internal thioester bond.
When cleaved to C3a and C3b, C3b can bind to phagocyte surfaces

C3a anaphylatoxin and stimulates local
inflammation by activating mast cells

44
Q

Complement Receptors
(CRs)

A

CR1 binds directly to C3b
and once C5a binds trigger phagocytosis

C3b is an opsonin

45
Q

Alternate pathway of complement activation

A

C3 spontaneously reacts with H20
C3H20 bind factor B and factor D cleaves B into Ba which leaves and Bb
C3H20Bb fluid phase C3 convertase

Cleaves C3 into C3b and C3a
similarly surface bound C3b bind factor B and D so

C3bBb alternative pathway C3 convertase cleaves even more C3 so more C3b binds

46
Q

membrane attack complex

A

C3bBb binds C3b to form
(C3b)2Bb the alternative C5 convertase
cleaves
C5 into C5a and C5b

C5b binds C6 which binds C7
C7 inserts into membrane
C8 binds and causes polymerisation of C9 to form a membrane pore

47
Q

The Lectin pathway of complement activation

A

Mannose binding lectin
(MBL) is a PRR that binds f mannose residues that are found on microbial surfaces

MBL is bound to MASP 1 and 2 MBL-associated serine protease
which when MBL binds cleaves C4 into C4b and C4a
C4b binds to pathogen surface
C2 binds and is cleaved into C2a/b, C2a binds to C4b

C4bC2a, the Classical C3 Convertase cleaves C3

48
Q

The Classical pathway of complement activation

A

antibody or C-reactive protein (CRP) made in liver due to Il-6 release by macrophage

C1q can bind multiple antibodies or CRP

C1s then cleaves C4 so C4b binds then like lectin C2 binds, C2a remains forming C4bC2a which cleaves C3

C4bC2aC3b can form a classical pathway C5 convertase.

49
Q

Regulatory proteins control complement activity

A

Short half life
Properdin (Factor P) stabilises C3bBb and the C5 convertase complex

Factor I degrades C3b and C4b

Membrane cofactor protein (MCP) on host cells breaks down C3 convertases
Also cleaves C3b/C4b with factor I

Factor H attaches to sialic
acid present on host membranes but not bacteria
and causes dissociation of C3bBb and cleavage by I

Decay accelerating factor (DAF) dissociates C3 convertases

Protectin stops C9 recruitment

50
Q

Complement deficiencies

A

C1, C2, C4
Immune-complex disease, infection

C3
Infection with encapsulated bacteria as C3 important opsonin

C5-C9 Susceptibility to Neisseria infections as complement mediated lysis is best defence

Factor D,Properdin
Susceptibility to pyogenic bactera

Factor I, Factor H
uncontrolled AP activation resulting in C3 depletion,
Susceptibility to infection with pyogenic bacteria

DAF, Protectin
Autoimmune-like conditions as red blood cells are lysed

51
Q

Complement evasion strategies

A

Staphylococcus aureus.

polysaccharide capsule
Staphylococcus Complement Inhibitor (SCIN) on surface to inactivate C3

secretes proteins that bind or degrade and inactivate C3

protein A binds the Fc region of IgG blocking complement
recruitment and activation.

Clumping factor A recruits factor I to the bacterial surface

Chemotaxis Inhibitory Protein blocks the C5a chemotactic receptor on neutrophils
limiting recruitment to sites of infection.

52
Q

Antibodies

A

Bind small epitopes on antigens
variable regions that interact with antigen
COnstant region that recurits effector

Neutralization- binding toxin to stop it from binding

Opsonisation- IgG bind to Fcg recptors on macrophages and neutrophil to enchance phagocytosis

Complement activation
classical pathway by C1q

53
Q

T cell

A

cytotoxic T cells
CD8
MHC class 1
kill virus/tumour cells

T helper
CD4
MHC class II
Activate B cells, macrophages and cytotoxic T cells

MHC class II found on professional antigen presenters like dendritic, macrophage, b cells

54
Q

MHC

A

MHC I
oresents peptides from inside of cell

MHC II
presents peptides from molcules that enter via the endocytic pathway. Survey external environ

55
Q

Activating naive T cells

A

dendritic cell PRR binds PAMP
becomes professional antigen presenting cell (pAPC)

Presents on MHC I and II

Signal 1 from recognition of MHC and peptide

Need costimulation from B7 on dendrite to bind CD28 on T cell, Both signal needed
Cytokines can change which T helper cell

Cytotoxic T cells need both signals but also somtimes need TH1 to make IL-2

56
Q

T helper cell

A

TH1 cells help activate macrophages
IL-12 and IFN-g

TH2 helps parasite infections
IL-4

TH17 cells help promote neutrophil control of extracellular bacterial and
fungal infections
.IL-6, TGF-b and IL-23

TFH cells help B cells become activated
IL-6 and IL-21

Treg cells suppress the activity of other effector T-cell populations
TGF-b

57
Q

Lymph node

A

dendritic cells enter and activate T cell

follicular dendritic cells (FDCs) trap peptide fro long times so B cell with highest affinity matures
Affinity maturation

58
Q

Antibody structure

A

pairs of heavy and light chains held together by covalent (disulphide bridges)

Variable region and contstant region
IgA, IgD, IgE, IgG and IgM depends on heavy constant region
Has hinge to be flexible

antigen binding site is formed by interaction between heavy and light chain variable domains

complementarity determining regions
with CDR3 most variable

59
Q

Generation of antibody diversity

A

VDJ- variable, diversity, junctional gene segment

DJ first the V joins DJ for heavy chain
2 copies of VDj from parents so 2 tries for rearrangement

Light chains no D, diversity segment only VJ
Make K chain first then lamda so 4 tries

RAG1 and RAG2 recombinase

Further junctional diversity by addtition or loss of nucleotides by P or N addition

60
Q

Somatic hypermutation

A

deamination of cytosine to uracil by the enzyme Activation Induced
(Cytidine) Deaminase or AID to add point mutation

Antibodies with increased affinity are selected by affinity
maturation

61
Q

Isotype switching

A

Can swap from IgM and IgD to
IgG, IgA or IgE

62
Q

FC receptors

A

low and high affinity and bind single or mutliple to give different levels of antigen senstivity

63
Q

Antibody functions

A

Can cause degranulation of eosinophils

MAst cells have prebound antiobodies
bind to antigen to cause degranulation

IgA in gut protects mucosla surfaces, in breast milk

IgG moves across placenta

Antibody immune complexes can bind BCR and terminate them to stop response

64
Q

Affinity and avidity

A

Affinity is the strength of 1 anitbody binding site

Antibodies have multiple binding sites
IgG has 10 so though low affinity high avidity

65
Q

MHC

A

Class I
all cells except red blood cells
alpha 1 and 2
Beta 1 and 2
alpha 1, beta 1 peptide binding

Class II
Alpha 1,2,3
Beta 2 recognised by CD4

alpha 1,2 peptide binding

Bind a broad range of peptides

66
Q

Human Leukocyte Antigens (HLA)

A

Human MHC
3 copies A,B,C from each parent so 6 total

High polymorphism

Inherited together and codominantly expressed.

Variability in peptide binding and T cell receptor binding part

Depedning on the amino acid in important anchor position in the peptide binding region changes what is bound

67
Q

MHC polymorphism is pathogen driven

A

Chicken only 1 MHC
either fastidious binds few peptides or promiscuous binds many

After infection promiscuous favoured

68
Q

MHC class I antigen processing pathway

A

Protein into peptide by proteosome
Transporter associated with Antigen Processing (TAP) sends peptide into ER

Loaded onto MHC class I and sent by golgi to surface

69
Q

MHC class II antigen processing pathway

A

class II will bind peptide in cell when in ER so to avoid this it has an invariant chain to block peptide groove

class II is sen into a vesicle where it fuses with an endosome containing antigens and is loaded with the help of HLA-DM

BOD (5 decks)

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