Innate Immunity- Induced Response Flashcards
What is the pattern of microbial molecules recognized by cells of the innate immune system? Through what receptor?
Pathogen Associated Molecular Patterns (PAMPs); Through Pattern Recognition Receptors
What are the two types of Pattern Recognition Receptors?
Phagocytic receptors and signaling receptors
To what molecules do macrophage CR3/CR4 receptors bind?
iC3b and LPS
What are the pattern-recognition signaling receptors in the macrophage?
Toll-like receptors
What is the general structure of a functional Toll-like receptor? On which membrane can it be found?
Functional receptors are either homo- or hetero-dimers; can be on internal or external membranes
With what other subunit does TLR4 solely form dimers with? What does the receptor detect?
TLR4; gram negative bacteria
How is lipopolysaccharide recognized by macrophages?
When LPS is released from the bacterial surfaces, it is bound by CD14 on the macrophage surface, which acts as a co-receptor to TLR4. The TLR4 dimer associates with MD2 to form a complex with CD14 and LPS
What downstream transcription factor is activated through the binding of LPS to CD14 and TLR4?
NF-kB
What two cytokine responses can be elicited via signaling through TLRs?
Inflammatory cytokine production (IL-6, TNF-a, etc.) or IFN- alpha and beta
What is the result of a MyD88 deficiency?
Severe infections by pyogenic bacteria without an development of high fever
How does NEMO deficiency present?
Increased susceptibility to pus-inducing bacteria and abnormalities in ectoderm-derived tissues
What are the major cytokines secreted by activated macrophages?
IL-1b, IL-6, IL-12, CXCL8, and TNF-a
What are the functions of IL-1b and TNF-a secreted by activated macrophages?
Induction of vasodilation and decreased blood flow
What is the function of CXCL8?
Chemoattractant that attracts neutrophils to the site of infection
What is the function of IL-12?
Induces NK cells to proliferate and secrete cytokines that sustain macrophage activation
What is the function of IL-6?
Acts on local muscle and adipose to adjust their metabolism and generate more heat
What are the immediate effects of Type I interferon?
Interference with viral replication, signal to neighboring cells that they too should prepare to resist viral infection, and alert immune cells that infection is about and to make virus-infected cells more vulnerable to attack by killer lymphocyte
What toll-like receptor mediates the interferon response?
TLR3
How is viral RNA detected within host cells? With what molecule do these detectors interact?
RIG-1 like receptors (RLRs): RIG-1 and MDA-5; mitochondrial antiviral signaling protein (MAVS)
What is the interferon response?
A series of reactions initiated by the binding of interferon to its receptor
What is involved in the interferon response?
Induced resistance to viral replication in all cells, increased expression of ligands for NK cell receptors, and activation of NK cells to kill virally infected cells
What are the consequences of a TLR3/TRIF deficiency?
Recurrent HSV encephalitis in early childhood
What are the 5 cardinal signs of inflammation?
Heat, redness, swelling, pain, loss of function
What causes the swelling associated with inflammation?
INcrease in vascular permeability, leakage of fluid from the blood vessels, accumulation of fluid in the tissue, and extravasation of leukocytes
What cytokines prompt the synthesis of acute phase proteins?
IL-1/ IL-6/ TNF-a
How do inflammatory cytokines raise body temperature?
Cytokines act on temperature-control sites in the hypothalamus and on muscle and adipose to alter their energy metabolsim and generate more heat
How does COX-2 contribute to pyrogen-induced fever?
Production of prostaglandin E2 which acts on the hypothalamus causing an increase in heat production and decrease in heat loss by vasoconstriction
What can wide-spread secretion of TNF-a lead to?
TNF-a causes increased blood flow, vascular permeability, and endothelial adhesiveness to WBCs and platelets leading to blood clots and disseminated intravascular coagulation
What is the first population of effector cells recruited to infected tissue?
Neutrophils
What is the most abundant white blood cell?
Neutrophils
How do neutrophils recognize their targets?
Multiple receptors such as Fc(gamma) and C3b receptors
What determines the movement of leukocytes between blood and tissue?
Interactions between complementary pairs of adhesion molecules
What are Weibel-Palade bodies?
P-selectin granules in vascular endothelial cells that are activated by inflammatory mediators (leukotriene, C5a, histamine) and are transported to the cell surface
What endothelial adhesion molecule is activated by LPS or TNF-a?
E-selectin
With what neutrophil surface molecule do selectins interact?
Sialyl-lewis carbohydrate groups of glycoproteins
What is the process by which leukocytes squeeze between neighboring endothelial cells to enter tissue?
Diapedesis/extravasation
True or False: the range of particulate material that neutrophils engulf is greater than that tackled by macrophages?
True
What is contained in the azurophilic granules of neutrophils?
Lysozyme, defensins, myeloperoxidase, proteases, and elastase
What is contained in the secondary granules of neutrophils? Tertiary?
Lactoferin, lysozyme, and NADPH oxidase; Gelatinase
How does neutrophilic granular content come into contact with pathogens?
Phagosomes containing recently captured microorganisms are fused with preformed granules
What is the function of neutrophilic NADPH oxidase?
It produces superoxide radicals that are converted into hydrogen peroxide and raise the phagosome pH to 8, activating antimicrobial peptides to attack
What is the respiratory burst?
A transient increase in oxygen consumption that occurs in activated neutrophils that can kill bacteria and fungi
What is the neutrophil extracellular trap?
When neutrophils die via netosis, the nucleus swells and bursts, and the chromatin is extruded in a network of decondensed DNA with histones and proteins that traps and kills pathogens
What is severe congenital neutropenia?
A deficiency of neutrophils at birth or soon afterward that results in life-threatening pyogenic infections, acute gingivostomatitis and chronic parodontal disease
How does Leukocyte Adhesion Deficiency present? What is the underlying cause?
Recurrent skin infections, internal infections, periodontal disease, delayed wound healing, candidiasis, and leukocytosis; mutations of integrin beta chains
What causes chronic granulomatous disease?
Mutations in the NADPH oxidase enzyme complex
What are the two distinctive NK cell functions in the innate immune response to viral infections?
1) Kill virus infected cells and 2) maintain and increase inflammatory state
True or False: NK cells contribute to defense against both intracellular and extracellular pathogens
True
What is the key cytokine secreted by NK cells?
Interferon gamma
