Lecture 5: Activation Of Innate Immunity Flashcards
Which two cytokines are considered “regulatory” cytokines because of their role in contracting the immune response as well as having anti-inflammatory properties?
TGF and IL-10
________ is a cytokine secreted by many types of cells; it allows for repair without regulatory immune cells in the vicinity
TGF-beta
______ is a cytokine secreted by macrophages, dendritic cells, and T regulatory cells and has anti-inflammatory properties
IL-10
What 3 cytokines are considered the endogenous pyrogens?
IL-1
IL-6
TNF-alpha
The endogenous pyrogenic cytokines are responsible for a state of ____________, which is the “wasting” stage in those with chronic inflammatory conditions
Cachexia
________ is the endogenous pyrogenic cytokine involved in SIRs, or the systemic inflammatory response that occurs prior to going into shock
TNF-alpha
What effect does IL-1, IL-6, and TNF-alpha have on the liver?
Increased production of APPs like CRP and mannose-binding protein which leads to activation of complement and opsonization
What effect does IL-1/IL-6/TNF-alpha have on the bone marrow and endothelium?
Neutrophil mobilization –> phagocytosis
What effect do IL-1/IL-6/TNF-alpha have on the hypothalamus?
Increased body temperature
What effect do IL-1/IL-6/TNF-alpha have on fat and muscle tissue?
Protein and energy mobilization to generate increased body temperature
IL-1/IL-6/TNF-alpha act on the hypothalamus, fat, and muscle tissue to increase body temperature. What does this do to enhance your immune response?
Decreases viral and bacterial replication
Increased antigen processing
Facilitates adaptive immune responses
What effect does TNF-alpha have on dendritic cells?
Stimulates macrophage migration and maturation in LNs –> initiation of adaptive immune response
_________ allows adaptive immunity to become more potent and makes human cells more resistant to the negative effects of TNF-alpha
Fever
__________ protein is one of several serum proteins that increases rapidly due to infection, injury, inflammation, or trauma to tissue.
It functions in opsonization and complement activation and can increase 100-1000x within 48 hours (removal of stimuli will bring numbers back down)
C-reactive
What is the most widely used indicator of acute inflammation?
C-reactive protein - can be used clinically to follow disease progress and response to treatment
Which cytokines act on the liver to upregulate acute phase proteins?
IL-1
IL-6
The complement system consists of serum proteins produced by ___________, that are not antigen specific.
It is considered a part of innate immunity and is activated ___________ in the presence of pathogens.
However, in some instances it is considered part of humoral immunity as antibody is required to activate complement proteins in the ___________ complement pathway.
Hepatocytes
Immediately
Classical
What are the 3 primary functions of the complement?
Stimulates inflammation
Facilitates antigen phagocytosis
Can lyse some cells directly
If the classical complement pathway is considered to be related to adaptive immunity, what are the 2 innate pathways?
Alternative pathway
Lectin pathway
What initiates the alternative complement pathway?
Spontaneous lysis of C3 into C3a and C3b when it binds a bacteria
What initiates the lectin pathway of complement?
Mannan binding lectin binds to CHO on bacteria
Which complement proteins are considered anaphylatoxins?
C3a
C4a
C5a
[anaphylatoxins are named as such because of their role in anaphylactic shock]
C3a, C4a, and C5a are soluble products that have inflammatory activity when they bind to complement receptors on several cell types.
They induce smooth muscle __________ and __________ of mast cells/basophils, causing release of inflammatory mediators ____________ and __________, which increase capillary permeability.
This allows for the movement of antibody, complement, phagocytes, lymphocytes, and fluid into the affected tissues.
Contraction
Degranulation
Histamine
Vasodilators
Of the anaphylotoxins C3a, C4a, and C5a, which one is the most potent?
C5a
In leukocyte recruitment, IL-1 and TNF increase the expression of ____ and ___________ on the endothelium within 1-2 hours, which facilitate the _________ of the leukocyte (end result is that they slow down).
P and E selectins
Rolling
In the recruitment of leukocytes, the slowing down on P and E selectins allows the cells to respond to _________ in the area that were produced in response to TNF and IL-1, which increases the affinity and clustering of __________ for ligand binding.
This binding leads to firm attachment of leukocytes to the endothelium, followed by reorganization of the cytoskeleton. Chemokines then stimulate migration through the endothelium in a process called ________
Chemokines (IL-8)
Integrins
Diapedesis
________ is an integrin found on leukocytes that binds to its ligand ICAM-1 on the endothelium in order to stop the rolling and begin diapedesis
LFA-1
What is the chemoattractant for neutrophils that is especially important for diapedesis?
IL-8
Macrophages have the integrin _________ which binds to endothelial ligand VCAM-1. The most important chemoattractant/chemoreceptor pair for macrophages is ________-________
VLA-4
CCR2-CCL2
The acute inflammatory response occurs immediately after trauma or infection to prevent the spread of pathogens, minimize further damage, and enhance repair and healing.
What are the 3 key processes involved in the acute inflammatory response?
Vasodilation (histamine, cytokines, prostaglandins)
Increased vascular permeability (leakage of mediators/plasma proteins/complement/Abs)
Emigration of leukocytes from blood into damaged areas
Inflammatory exudate involves the formation of _______, which brings plasma proteins into intimate contact with the damaged area
Edema
What are the 4 primary proteins in the inflammatory exudate?
Clotting proteins
Complement
Kinin
Fibrinolytic protein
What is the end result of the kinin cascade in the formation of inflammatory exudate?
Vasodilation and increase in permeability of blood vessels
Also stimulation of pain receptors
What is the purpose of the fibrinolytic protein involved in inflammatory exudate?
Degrades the clot when the wound has healed
What condition might present as the following:
Normal WBC distribution, absolute count for each WBC abnormally high
Normal T cell distribution. Serum Abs and Complement in normal limits.
No white cells on Rebuck skin window test. T cell proliferation was slightly depressed. No CD11a expression was found.
Leukocyte Adhesion Deficiency (LAD type I)
Why is a lack of CD11a expression indicative of LAD type I?
CD11a makes up an integral chain of LFA-1, which is needed for adhesion and diapedesis of leukocytes
What is the only treatment for LAD type I?
Bone marrow transplant (after treatment with immunosuppressive therapy)
After a patient with LAD type I receives a bone marrow transplant, they are expected to express _______ and have a normalized white cell count
Chimerism
LAD types I and III are defects in what function?
Adhesion
LAD type II is a defect in what function?
Rolling (so it is a defect in selectin receptor)
LAD type I may result from one of the following:
____ chain of integrins deficient
Defective ______ (CD11a/CD18)
Defective _______ (CD11b/CD18) - affects T cells
Defective ________ (CD11c/CD18)
Beta-2
LFA-1
Mac-1
gp 150/95
What is the inheritance pattern of LAD?
Autosomal recessive
Compare the levels of CD18 expression in severe vs. moderate LAD
Severe: <2% expression
Moderate: 2-30% expression
Clinically, LAD may present as:
Delayed separation of the umbilical cord and ___________.
Recurrent bacterial infections, primarily localized to the _____ and ______ tissues.
Absent _____ formation
Omphalitis
Skin; mucosal
Pus
[other symptoms may include leukocytosis, periodontitis, and impaired wound healing]
Various pathogenic species have ways of evading the innate immune system. How might a pathogen like pneumococcus resist phagocytosis?
Capsular polysaccharide inhibits phagocytosis
Various pathogenic species have ways of evading the innate immune system. How might a pathogen like staphylococcus resist ROS intermediates in phagocytes?
Production of catalase, which breaks down reactive oxygen intermediates
Various pathogenic species have ways of evading the innate immune system. How might a pathogen like Neisseria meningitidis resist alternative complement activation?
Sialic acid expression by the pathogen (typical of healthy cells) inhibits C3 and C5 convertases
Various pathogenic species have ways of evading the innate immune system. How might a pathogen like streptococcus resist alternative complement activation?
M protein blocks C3 binding to organism and C3b binding to complement receptors
Various pathogenic species have ways of evading the innate immune system. How might a pathogen like pseudomonas resist antimicrobial peptide antibiotics?
Synthesis of modified LPS that resists the action of peptide antibiotics
What is considered the “bridge to adaptive immunity”?
Antigen capture and presentation to lymphocytes
