Iid - Introduction And Innate Immunity

Front 1

What are cytokines?

Back 1

Small secreted proteins that bind to specific receptors on immune cells and trigger a variety of responses.

Front 2

What are chemokines?

Back 2

A subset of cytokines that signal movement of cells to the site of chemokine production (up the concentration gradient) - usually the site of infection.

Front 3

What are macrophages?

Back 3

Professional phagocytes that patrol the tissues looking for evidence of "danger". When activated, they produce a wide array of toxic factors and chemokines. Collaborate with helper T cells to contain/eliminate mycobacterial infections.

Front 4

What are dendritic cells?

Back 4

The scouts of the adaptive immune response. Like macrophages, they patrol the tissues and are also superb sensors of "danger". When they enter a site of infection, they acquire pieces of the infecting organism and then take them to the lymph node and display those antigens to the millions of naive T cells that percolate through the lymph node. Eventually the lymphocytes and their products flood out of the lymph node to attack the invader.

Front 5

What are natural killer (NK) cells?

Back 5

5-20% of the mononuclear cells in blood. They recognize infected and stressed cells in a variety of ways and kill them. Though cytokine production they participate in innate responses.

Front 6

What are B cells?

Back 6

Producers of antibody molecules which come in billions of variations. One B cell, however, expresses only one variant which is expressed at the cell surface and also secreted after activation. When activated a B cell undergoes several rounds of division and some of the progeny go on to become plasma cells - antibody producing factories. Others go on to become memory B cells, ensuring that greater numbers of cells will be able to respond at the outset should the same or a similar organism infect again.

Front 7

What are CD4+ ("Helper") T cells?

Back 7

Producers of many factors that guide and potentiate the effector immune response. Like B cells, they expand upon activation with some traveling to the site of infection to participate in the "effector" response and others going on to become memory T cells. Based upon the cytokines that they produce, can be "Type 1" or "Type 2" CD4+ T cells.

Front 8

What are CD8+ ("cytotoxic") T cells?

Back 8

Best known for their ability to kill cells that have been infected by viruses and intracellular bacteria (Listeria, Mycobacteria). They have several ways of delivering the lethal hit. They cannot clear an infection but can substantially limit the spread by killing the the cell before new progeny are produced. They also produce a variety of cytokines upon infection. As with B cells and CD4+ T cells, memory CD8+ cells persist following resolution of the infection.

Front 9

What are examples of antibacterial and antifungal peptides?

Back 9

Cryptdins or alpha-defensins in the lower GI tract

Beta-defensins in other epithelia (respiratory and urogenital tracts, skin, tongue)

Front 10

What are the 3 triggers for apoptosis caused by acute viral infection?

Back 10

1. Perturbation of mitochondrial function leading to activation of the intrinsic (caspase-9-mediated) pathway

2. Activation of the p53 transcription factor which activates both the intrinsic and extrinsic pathways

3. "ER Stress" - Large quantities of viral glycoproteins produced in the endoplasmic reticulum trigger the cell to undergo a poorly defined apoptotic program.

Front 11

Describe the RNA helicase PAMP receptor.

Back 11

Cytoplasmic sensors of viral infection that preferentially bind viral RNA species; members include RIG-1 and MDA-5

Activation of transcription factors IRF3 (interferon regulatory factor 3) and IRF7 which dimerize and induce production of type I interferons (IFN-alpha and IFN-beta)

Front 12

Describe the PKR PAMP receptor.

Back 12

Double stranded RNA dependent protein kinase. Senses minute quantities of double stranded RNA (a hallmark of many viral infections).

dsRNA binding to PKR triggers autophosphorylation leading to a global block in translation via phosphorylation of the initiation factor eIF2a and programmed cell death via caspase 8 activation.

Front 13

Describe Toll-Like Receptors.

Back 13

A set of ten different membrane bound proteins that play key roles in defense against bacteria, fungi and viruses. Expressed most prominently by monocytes/macrophages and dendritic cells.

Like the NODs, triggering TLRs leads to NFkB activation and, consequently, cellular activation and release of many cytokines and chemokines

Front 14

NOD1

Back 14

Bacterial cytoplasmic sensor.

Binds g-glutamyl diaminopimelic acid, a breakdown product of Gram-negative bacterial proteoglycans.

Leads to NFkB activation, resulting in cellular activation and the production of an array of factors

Front 15

NOD2

Back 15

Bacterial cytoplasmic sensor.

Binds muramyl dipeptide, a component of both Gram-positive and Gram-negative proteogylcans.

Leads to NFkB activation, resulting in cellular activation and the production of an array of factors.

Front 16

TLR-1:TLR-2

Back 16

Heterodimer that recognizes triacyl lipopeptides

Located at the plasma membrane

Front 17

TLR-6:TLR-2

Back 17

Heterodimer recognizes diacyl lipopeptides

Located at the plasma membrane

Front 18

TLR-4

Back 18

Recognizes lipopolysaccharide - the major component within the outer membrane of gram-negative bacteria

Located at the plasma membrane

Front 19

TLR-5

Back 19

Recognizes flagellin

Located at the plasma membrane

Front 20

TLR-3

Back 20

Recognizes double stranded RNA, a hallmark of most viral infections

Located in the endosome

Front 21

TLR-7

Back 21

Recognizes single stranded RNA, also a feature of many viruses

Located in the endosome

Front 22

TLR-9

Back 22

Recognizes unmethylated CpG DNA, a hallmark of bacterial DNA

Located in the endosome

Front 23

What are the immediate cellular activations following NFkB signaling?

Back 23

Macrophages - increased phagocytosis and killing capabilities within the phagolysosome; internal production of reactive oxygen intermediates and nitric oxide (tissue damage is a byproduct of extensive activation).

Dendritic cells - stop phagocytosing and start migrating toward a regional lymph node, with a load of antigen. Express molecules at the cell surface that is critical for initiation of the adaptive response.

Front 24

Pathogen Associated Molecular Patterns (PAMPs)

Back 24

Microbial molecules that are the targets of innate immunity; they are shared by microbes of the same type.

Front 25

RIG-1

Back 25

RNA helicase cytoplasmic sensor of viral infection; preferentially binds viral RNA species

Ligation causes activation of transcription factors IRF3 and IRF7 which dimerize and induce production of type I interferons (IFN-alpha and IFN-beta)

Front 26

MDA-5

Back 26

RNA helicase cytoplasmic sensor of viral infection; preferentially binds viral RNA species

Ligation causes activation of transcription factors IRF3 and IRF7 which dimerize and induce production of type I interferons (IFN-alpha and IFN-beta)

Front 27

Describe type I interferon signaling

Back 27

There are at least 16 functional products of IFN-alpha from 23 genes but only one IFN-beta.

Contact with the receptor triggers the JAK/STAT cascade

Genes with interferon stimulated response elements:
- Mx1 protein expression inhibits replication of several RNA viruses
- Oligoadenylate synthetase casues activation of RNase L or F with cleaves viral and cellular RNA
- PKR senses dsRNA

Front 28

NFkB

Back 28

Activated by NOD1, NOD2, and TLRs.

Causes immediate cellular activation of macrophages and dendritic cells.

Signaling causes production of factors that act locally and systemically:
- TNF-alpha
- IL-1
- IL-6
- IL-8

Front 29

TNF-alpha

Back 29

Produced by macrophages and dendritic cells.

Induces changes in vascular endothelium that encourage cellular infiltration.

Modifies cell-cell junctions to increase fluid in tissues and local blood clotting.

Front 30

IL-1

Back 30

Produced by macrophages and keratinocytes.

Induces the release of acute phase protein secretion from the liver.

Front 31

IL-6

Back 31

Produced by macrophages and dendritic cells.

Induces the release of acute phase protein secretion from the liver.

Front 32

IL-8

Back 32

Also called CXLC8.

Produced by phagocytes.

Attracts more neutrophils to the area. These are the first cells to enter the site of infection following the immediate innate response.

Front 33

What is the complement system?

Back 33

A series of circulating and membrane-bound proteins that are poised to initiate responses against foreign invaders through a cascade of proteolytic and assembly reactions.

Front 34

What are the 3 general consequences of complement activation?

Back 34

1. Deposition of complement products on the surface of the pathogen that encourages uptake by phagocytes - a process termed "opsonization".

2. Release of products that attract neutrophils and monocytes to the site of infection.

3. The insertion of pores into the microbe that cause its demise.

Front 35

What are the 3 ways to activate complement?

Back 35

The "alternative" pathway - in essence, this pathway is initiated constantly at cell surfaces but on host cells the activation process is interrupted by host factors. On foreign cell surfaces (bacteria, most commonly) the reaction is sustained.

The lectin-dependent pathway - activated by terminal mannose residues that are displayed by many bacteria but not on mammalian cells.

The "classical" pathway - activated by binding of antibody to a cell surface.

Front 36

E and P selectin

Back 36

Expression on endothelium induced by TNF-alpha and IL-1beta.

Cause a low level adhesion of circulating neutrophils via selectin ligands on their surfaces to the endothelial cells. This adhesion alone does not cause the cells to stop and migrate but it slows them down.

Results in the "rolling" of the leukocytes on the endothelial surface.

Front 37

Mannose-binding lectin

Back 37

Acute phase protein - produced in the liver in response to IL-1beta

The trigger for the lectin-dependent complement pathway

Front 38

C-reactive protein (CRP)

Back 38

Acute phase protein - produced in the liver in response to IL-1beta

Binds to phosphorylcholine on microbes and targets them for phagocytosis by macrophages which express receptors for CRP.

Front 39

Integrins

Back 39

Expressed on the surface of leukocytes.

Chemokines produced by tissue macrophages and the activated endothelial cells bind to proteoglycans on the luminal walls of the endothelium.

These chemokines induce a change in the integrins so that the leukocytes now have a high affinity for the integrin ligands on the endothelial cells.

Front 40

Describe the characteristics of NK cells

Back 40

NK cells are bone marrow derived from common lymphoid progenitor.

Kill infected cells.

Activated by innate cytokines: type I interferons and IL-12

2 families of receptors: Killer lectin-like receptors (KLRs) and Killer cell immunoglobulin-like receptors (KIRs). Both families have members that are activating and inhibiting.

One know basis for NK cell activation is loss of MHC class I molecules from the cell surface.

Front 41

What are the 3 types of innate-like lymphocytes?

Back 41

Intraepithelial gamma-delta T cells

B1 cells

NK T cells

Front 42

Intraepithelial gamma-delta T cells

Back 42

Innate-like lymphocyte

Extremely limited receptor diversity.

Proposed to recognize self components that are altered as a result of infection (like some NK cells)

Front 43

B1 cells

Back 43

Innate-like lymphocyte

Limited receptor diversity

Found in pleural and peritoneal cavities.

Produce IgM antibodies autonomously.

Specificity to very common targets such as polysaccharides

Front 44

NK T cells

Back 44

Found in thymus and peripheral lymphoid organs.

Extremely limited receptor diversity.

Recognition of glycolipid antigens.

Rapid cytokine secretion: IL-4, IL-10, and IFN-delta