PCB3233 -- Exam 2

Tertiary Granules

Gelatinase granules -gelatinase -metal sequestering protease -- restricts bacteria from gaining access to iron

a spectrum of biological activity to coordinate body response to infection

Heat cyto kines alter energy mobilization to generate increase temperate by acting on hypothalamic temperature control sites, muscle, fat cells, this results in body temperate increase aka Fever done by pyrogens

IL1, IL6 and TNF alpha

Liver: acute phase proteins (C reactive protein, MBL) --> activation of complement opsonization Bone marrow endothelium: neutrophil mobilization --> phagocytosis Hypothalamus: increase body temp (decrease viral and bacterial replication) Fat, muscle: Protein and energy mobilization to generate increased body temp (decrease viral and bacterial replication)

Chromic Granulomatous Disease

NADPH oxidase is non-functional -no oxidative burst -pH isn't raised in phagolysosome means no activation of granular contents and no killing of pathogen -Infected neutrophils and macrophages are surrounded by other leukocytes (walling them off) to stop the spread of the pathogen and causes granuloma formation

Epithelial cells have PRR that recognize its infection so it tells NK cell by putting surface molecules up to say its virally infected so

NK cell scans on w activatory and inhibitory receptors to determine if infected.

If virus is in cell, we cant recognize it with

anything outside cell, cell has to recognize itself as infected and let other cells know

Macrophages receptors recognize the cell-surface carbohydrates of ____________ but not those of human cells

bacterial cells

Carbohydrate-binding proteins = lectins

bind to particular carbohydrates (not found on human cells), mannpse and glucan receptors are examples

Mannose Binding Lectin

binds mannose containing carbohydrate of bacteria and yeast -calcium dependent lectin -MBL molecule is similar in structure to C1q -15 to 18 potential binding sites to attach to the pathogen surface (even weak individual interactions with a carbohydrate structure can be developed into a high-avidity using multipoint attachments) Mannose containing carbohydrates on human cells do not bind MBL because their geometry does not permit multipoint attachment to MBL

CRP activates what complement pathway

clasical

MASP initiates

complement activation -lectin pathway of complement activation -MBL serves as an opsonin to facilitate bacteria uptake by monocytes in the blood -Monocytes do not express the macrophage mannose receptor but have receptors that can bind to MBL molecules coating a bacterial surface

NADPH oxidases superoxide radicals which are

converted to hydrogen peroxide by superoxide dismutase (the rxn causes increased consumption of hydrogen ions, raised pH and activation of primary and secondary granule contents

NOD-like receptors

cytoplasmic receptors for recognition of pathogens

Toxic Oxygen species produced during the respiratory burst can

diffuse out and damage host cells

Macrophages recognize pathogen

directly

Antibodies bind with C1q

globular heads (and the same sequence of complement rxns occurs whether c reactive protein or Abs interacts w/ pathogen and C1q binds)

Fevers

help the immune system fight off infection most bacterial and viral pathogens grow better t temps lower than body temp elevated temperature means bacterial/viral replication decreases Antigen processing increases human cells become more resistant to TNF-alpha deleterious effects

Opsonins

iC3b, C3b, CRP, and MBL, antibodies

CR3 and CR4 recognize...

iC3b, LPS (lipopolysaccharide-- a gram negative bacteria), lipophosphoglycan, filamentous hemagglutinin, cell-surface structures on yeast

IL-1Beta and TNFAlpha

induce blood vessel permeability, enables effector cells and fluid containing soluble effector molecules to enter the infected tissues

IL6

induces fat and muscles cells to metabolize, makes heat and raises temperature in infected tissue

Homing of neutrophils to infected tissue sis induced by

inflammatory mediators

Phagocytosis by macrophages is aided by receptors of

innate immunity that bind directly to microbial surfaces

All nucleated cells can secrete

interferon alpha and beta (tells NK cell there a viral infection and tells cells they need to be activated and die by apoptosis b/c of infection)

Inflammatory response

involves recuitment of cells and molecules of innate immunity to infection sites -Neutrophils=pus -Extracellular bacteria (ex: S. aureus --> superficial infections and abscesses nuetrophils attack in large #s) Pus forming=pyogenic bacteria

alternative pathway doesn't need to be activated b/c

its always working

MBL can acivate which complement pathway

lectin

to limit respiratory burst damage:

phagocytes synthesize enzymes to inactivate toxic oxygen species (for example: catalase degrades H2O2 to H2O + O2) and neutrophils replenish granule contents so they die

Neutrophils --> apoptosis -->

phagocytosed by macrophage

Scavenger receptors

preference for negatively charged molecules (nucleaic acids, phosphate-containing lipoteichoic acids which are gram positive and LPS which is gram negative)

Neutrophils are potent pathogen killers but are

programmed to die

Phagocytosis by macrohpages:

provides first line of defense against invading microorganisms

Acute phase response increases the supply of

recognition molecules of innate immunity and shows opsonization of pathogen by MBL and CRP

Innate immune cell receptors

recognize pathogen/damaged/infected host cells

NOD 1

recognizes a degradation product of gram (-) peptidoglycan

NOD 2

recognizes a degradation product of most bacteria - muramyl dipeptide

IL12

recruits and activates NK cells that secrete cytokines that strengthens the macrophages response to infection

CXCL8

recruits neutrophils from the blood and guides them to infected tissie

TNF Alpha

released by macrophages (induces protection at local level)

Neutrophils

short lived dedicated killers circulate blood wait for the macrophage alarm to enter tissue (basically: dedicated phagocytes summoned to infection site)

Signaling

signaling after PRR binds to its PAMPS and the nucleus makes and secrete cytokines or PRR binds to PAMPS and causes phagocytosis

ligands

stress induced by virus inside cell, activating receptors bind to thw,

NK Cell Receptors recognize changes at the ______________________________________________________.

surface of human cells caused by viral infection

NK Cells

tells cell to die by apoptosis. Is innate lymphocyte. innate viral fighter. tells cancer cells to die.

Pathogen is engulfed by neutrophils, leads to degradative enzymes and the fusion of phagosomes w/neutrophil granules

the granules are modified lysosomes of hydrolytic degradative enzymes, NADPH-dependent oxidases and aplha-defensins

NK Cells can't recognize viruses directly, it recognizes

the infected cell as infected

Innate immunity

works immediately on pathogen confrontation -chemical weapons include reactive ions, peptides, kill pathogen directly -protease inhinitors, clotting cascade and kinin reactions (inhibit pathogen colonizing tissues and spreads infections) -complement (tags microbial surface proteins) -specific receptos (bind chemical parts of microbial macromolecules that are not a part of self) - all of these^^^ work to assist phagocytes in destroying invading pathogens

IL-1Beta

works with TNF alpha to activate endothelial cells and induce inflammation

Pathogen Invades then 1st Effector Cells (resident macrophages) come into play

1st Effector Cells: Resident in tissues, connective tissues (linings of GI, respiratory tract, lung. alveoli, liver), long lived phagocytic cells, involved in both innate and adpative immunity.

Neutrophil receptors

-Inflammatory mediators •C5a cleaved during complement activation •CXCL8 -secreted by activated macrophages •Peptides containing N-formylmethionine (not human) -Ligand binding to neutrophil surface receptor --changes in neutrophil adhesion molecules -Assist neutrophils in migrating out of blood capillaries •Extravasation

Acute Phase Proteins

-C Reactive Proteins (activate classical complement cascade) -Serum Amyloid A (binds to some TLR's leading to increased inflammation through increased cytokine release) -Mannose-Binding Lectin (activate lectin complement cascade and enhances complement fixation to pathogen surfaces) They are produced in response to inflammatory cytokines and produced by hepatocytes in the liver

-causes and consequences of TNK-Alpha w/local area

-Endothelium (venules)--> increase blood flow, increase permeability, endothelial adhesiveness for WBC and Plateletes -causes blood in venules to clot -prevents spread of infection to blood such as sepsis or septicemia

Phagocytosis by neutrophils

-Fc receptors -Complement receptors -Phagocytosis of complement opsonized pathogens -On availability of specific Abs •Opsonized with antibody and complement

Granulocytes

-Granules containing antimicrobials -Primary (azurophilic), secondary (specific) granules and tertiary (gelatinase) granules -Polymorphonuclear leukocytes •Variable and irregular shapes of their nuclei •Microphages •Smaller sized than macrophages •Most abundant wbc (50 billion in circulation) •Life span < 2 days •60% of hematopoietic activity of bone marrow •Large reserve kept in bone marrow

Neutrophils are excluded from healthy tissue

-Release of inflammatory mediators at infection sites is what attracts neutrophils -Become dominant phagocytic cells •3 X 109 neutrophils mouth and throat each day •Arrival of neutrophils is the 1st of a series of rxns -Inflammatory response

IL-12

-activates NK cells -lyphocytes of innaate immue system -nk cells secrete cytokines to maintain macrophage activity -protect against viral infection

TLR trigger a common pathway of intracellular signaling

-adaptor protein is MyD88 -interleukin 1 receptor associated kinase (IRAK) -Translocation of TF nuclear factor kB (NFkB) from cytoplasm to the nucleus -Directs the transcription of genes for inflammatory cytokines

Chemokine IL8

-attracts leukocytes (neutrophils) to site of tissue damage/infection (binds to CXCR1 and CXCR2 on neutrophil) -direct traffic of leukocytes during their development (small 60-140) -two major families (cysteine residues and CC or CXC) -cell attracted from blood to infection by the concentration gradient of chemokines produced by cells at the infection -chemokines interact w/target cells by binding specific cell surface receptors --> signal through associated GTP-binding protiens

Leukoctye adhesion molecules present on WBC

1.Selectins - are carbohydrate-binding lectins 2.Vascular addressins - contain carbohydrate groups to which selectins bind 3.Integrins - typically bind to Ig superfamily proteins 4.Immunoglobulin superfamily - e.g. ICAM-1

Toll Like Receptors

10 receptors, specificities for different microbial products, TLR-4 senses ligand LPS

TLR-4

-expressed on macrophages -detects LPS and sends signal to nucleus of the macrophage to make/secrete inflammatory cytokines and cytokines that activate innate immune responses

changes in blood capillaries

-increase diameter (dilation) -- reduction in the rate of blood flow leads to increased permeability to blood vessel wall, leads to increased blood supply, means redness and heat -increased blood vessel permeability leads to movement of fluid, plasma proteins and WBC (mainly neutrophils) from the blood capillaries into the tissue causes the swelling and pain -translocation of NFkB to macrophage nucleaus initiates transcription of proinflammatory cytokines --> IL1, IL6, CXCL8, IL12 and TNF-alpha

Neutrophil process of phagocytosis is similar to that of macrophafes but

-less range of particulate engulfed - Less microbicidals -3 types of granules -devoted to storage & delivery of antimicrobial weaponry

LPS

-major gram-negative bacteria component -endotoxin responsible for septic shock

Primary Neutrophil Granules

Azurophilic granules Lysozyme, defensins, myeloperoxidase, neutral proteases, elastase, proteinase 3

C reactive protein binds with

C1q (stalks)

MASP 2 cleaves

C4 and C2

Cr1 and C4b recognized by what complement receptor

CR1

Macrophages can use

CR1, PRR, Opsonins, Cr3, Cr4 to recognize opsonins on surface to bring in pathogen and destroy by phagocytosis

iC3b recognized by what complement receptor

CR3, CR4

Soluble molecules

CRP and MBL (act as opsonins). MBL activates lectin pathway. CRP activates classical pathway

USE MCH CLASS II

Dendritic cells (only ones that can actiavte T cells), macrophages ( monocyte and macro--need to be activated by CD 4 cells) and B cells (Need to be activated by CD4 cells)

USE MHC CLASS I

all nucleated cells

Macrophages produce cytokines:

IL6 Il1 and TNF alpha (theyre all pyrogens)

The homing of neutrophils to infected tissues is induced by inflammatory mediators (cytokines)

Inflammatory mediators (Cytokines) secreted by macrophages change the ligand expression for the neutrophil receptors on the surface of endothelial cells near the site of infection .•This allows the neutrophils to exit the blood near the site of infection = Extravasation 4 steps

MBL activates a proteolytic enzyme complex:

MBL associates serine protease (MASP)

All nucleated cells can use

MHC Class I (presents intracellular pathogenic peptides)

CD4 recognizes

MHC Class II (CD4=T Helper Cell) Remember Help 4 You Too

C3b is ligand for

Macrophage CR1

Cells that use receptors to recognize self from non-self

Macrophages and NK Cells

Induce Innate Immune System

Once pathogens breach physical barriers and outrun initial response, Induced Innate response occurs: Inflammation happens, leukocytes called into the site of infection, and soluble molecules make and secrete into blood, and are then brought to infection site

Nucleated cells are virus targets and have

PRR's inside to recognize that they've been infected

C Reactive Proteins

Pentamer of identical subunits (pentraxin family) -- binds to phosphorylcholine component of LPS of bacterial and fungal cell walls but not to phosphorylcholine in human cells. it acts as opsonin, and can bind to C1q to initiate classical pathway of complement fixation in absence of Abs

Secondary Neutrophil Granules

Specific granules Lactoferrin -metal sequestering protease -lysozyme -NADPH oxidase granules

Step 1

Step 1 --> cytokines/inflammatory mediators induce selectin expression on vascular endothelium to bind neutrophilsTransient interaction between neutrophil (sialyl-Lewis X) and selectin on the endothelium

Step 2

Step 2 -->Rolling adhesion tight binding --> migration to infection site Interactions between LFA-1 to ICAM-1.Strong interaction is induced by CXCL8 held on ECM proteoglycans--> chemokine attraction-->neutrophil squeezes between endothelial cells

NETs (neutrophil extracellular traps)

The neutrophil's nucleus swells and leads to the cell bursting (netosis) leaving behind all the antimicrobial components of the granules as well as DNA and histones that serve to trap the pathogen.

Respiratory Burst

Transient increase in oxygen consumption = purpose is to raise the pH of the phagosome so the granule contents can become active to kill pathogen lysozyme releases contents that lower pH and continue destruction of engulfed enzymes

Netosis

a way neutrophils die that leads to capture and destruction of the pathogen

Surface components are characteristic of pathogens but

absent from human cells

IL6

acts on local muscle to increase temp. (signal to liver to make acute phase reactants) MBL and Creactive protein)

C3b

ligand for macrophage CR1

There are _________________________ for recognition but because many pathogens have same surface molecules this limited diversity works well

limited innate receptors (Ex: Gram negative bacteria have LPS in their outer membrane so it doesn't matter what genus it is it will still be recognized by an LPS receptor on a macrophage)

Inflammation in tissue causes

local accumulation of fluid, swelling, redness, heat and pain

Macrophages

long lives reside in tissues work as infection begins (raise alarm)

All nucleated cells can present viral pepetides

on their surface for CBAT cells to recognize

Macrophages have receptors/sensors for

pathogen components that signal macrophages to make and secrete cytokines (Toll-Like Receptors)