Immunology Test 1 Ch. 3

Activated macrophages release cytokines that promote inflammation

-Cytokines are small soluble proteins secreted by cells that influence other cells by binding to a specific surface receptor --Interleukin (IL) is a generic term used for many cytokines made by leukocytes --Cytokines have both local and systemic effects -Macrophage (pro-) inflammatory cytokines --Interleukin-1b (IL-1b), IL-6, IL-12, CXCL8, & Tumor Necrosis Factor-a (TNF-a) --Combined effect is to induce a state of inflammation ---redness, heat, pain, swelling ---vasodilation and vascular permeability ---movement of fluid, plasma proteins (e.g. Abs and complement) and WBCs (especially neutrophils) to the infected site

Toll-like Receptors (TLRs)

-Family of 10 Signaling Receptors that sense infection and are present on many types of innate cells, including macrophages, dendritic cells, and neutrophils (receptors are different than phagocytic receptors - different function) -Expressed on the cell surface and within cells (e.g. on endosomal membranes). Have recognitionand cytoplasmic signaling domains. -Each type of TLR is specific for a different pathogencomponent. Examples - bacterial LPS and flagellin, unique bacterial andviral DNA and RNA not found in humans. -Signaling through TLRs usually leads to the production of inflammatory cytokines Promotes innate responses and inflammation Promotes the adaptive immune response

Macrophages Toll-like Receptor 4 (TLR4) recognizes LPS and leads to the production of cytokines, adhesion molecules and other proteins necessary for inflammation

-Involves a complex of TLR4, MD2, and CD14 -LPS binds CD14 (co-receptor) -TLR4 with MD2 protein bind CD14/LPS -Cytoplasmic domain of TLR4 generates an intracellular signal that leads to inflammatory cytokine production --Signaling involves adapter proteins and protein kinases that lead to activation of transcription factor called nuclear factor kB (NFkB) --NFkB initiates transcription of cytokine genes ---Note that NFkB functions in other signaling pathways of the innate/adaptive systems.

Innate Immunity: the induced response to infection

-Mechanism that require ~4 hours to 4 days to develop -Involves soluble and cellular receptors that detect infection, the synthesis of new molecules, and the recruitment of leukocytes to do something about it

All tissues contain resistant macrophages that express numerous Phagocytic and Signaling receptors

-Phagocytic Receptors primarily recognize bacterial carbohydrates and lipids and trigger macrophage phagocytosis -Examples --Lectin Receptors recognize carbohydrates ---For example, the Mannose Receptor recognizes specific terminal sugars on molecules like bacterial lipopolysaccharide (LPS) and polysaccharides --Scavenger Receptors (SR) and LPS Receptor (CD14) recognize LPS and other specific structures on microbes. --Some Complement Receptors (CR3 and CR4) recognize LPS and polysaccharides on a variety of pathogens.

Septic Shock (Sepsis)

-Presence of gram negative bacteria in the blood which express LPS (aka endotoxin) -Extensive numbers of macrophages in spleen and liver become activated via TLR-4 and secrete significant amount of TNF-a systemically into the bloodstream -Causes a massive leakage of fluid from vessels into tissues which in turn causes a drop in blood pressure (shock). Elevated TNF-a also causes fever, diarrhea, and widespread clotting. -Poor blood flow leads to failure of major organs such as kidney, heart, lungs and the liver. -High mortality - In US, afflicts ~1 million/year; 28-50% die -Cost of treating patients in US - >20 billion/year

Cell-surface receptors of innate cells that detect pathogens distinguish between 'self' and 'non-self'

-Receptors are able to distinguish microbial proteins, carbohydrates, lipids, and nucleic acids -Each receptor can recognize multiple pathogenic species. ->100 different innate receptors

Infants with X-linked Ectodermal Dysplasia and Immunodeficiency lack a subunit of Inhibitor of kB Kinase (IKK)

-Without IKK, NFkB does not get activated, no gene transcription -Kids (mostly boys, gene is on X chromosome) are susceptible to bacterial infections because macrophages are not activated by TLR4 -Other physical defects are seen due to the importance of NFkB

TLR4 homodimer

-chromosome 9 -ligands: lipopolysaccharide -microorganisms recognized: gram negative bacteria -cells carrying receptor: macrophages, dendritic cells, mast cells, eosinophils -cellular location of receptor: plasma membrane

IL-1Beta

Induce blood vessels to become more permeable, enabling effector cells and fluid containing soluble effector molecules to enter the infected tissues.

TNF-alpha

Induce blood vessels to become more permeable, enabling effector cells and fluid containing soluble effector molecules to enter the infected tissues. TNF-a action on endothelium (e.g. increased blood vessel diameter and adhesion molecules for leukocytes; blood clotting) can be beneficial for a local acute infection. However, if a gram neg. bacterial infection spreads systemically, it can cause widespread production of TNF-a with fatal consequences.

IL-6

induces fat and muscle cells to metabolize, make heat and raise the temperature in the infected tissue.

CXCL8

is an example of a chemoattractant cytokine called a chemokine. One of many. Recruits neutrophils from the blood and guides them to the infected tissues.

IL-12

recruits and activates natural killer (NK) cells that in turn secrete cytokines that strengthen the macrophages' response to infection.