Chp. 2 Neutrophil Arrival and Function & Macrophages Flashcards
What are the steps of neutrophil arrival? (7 steps)
The steps are as follows:
- Margination
- Rolling
- Adhesion
- Transmigration (Diapedesis) & Chemotaxis
- Phagocytosis
- Destruction of Phagocytosed Material
- Resolution
The first step in neutrophil arrival is margination. Describe what happens.
Background: In a blood vessel with laminar flow, everything flows in the very center of the vessel.
With margination, the point is to get the immune cells from the center of the vessel to the periphery. IT BEGINS WITH VASODILATION.
Vasodilation slows blood flow in POSTCAPILLARY VENULES. The blood slowing down allows neutrophils to “settle” on the periphery of the vessel
(Remember, vascular permeability means that things can leak or escape out, so all the fluid and immune cells will leave the vessel at this location.)
Describe “rolling”. What molecule on endothelial cells is upregulated. What do these molecules bind with?
Rolling is the process where immune cells, i.e. nuetrophils are rolling along the vessel wall toward the post capillary venule.
The molecules upregulated on endothelial cells are Selectin “speed bumps”. There are two types of Selectins:
P selectins are released from Weibel-Palade Bodies. These bodies also release Von Wildebrand Factor
E Selectins are released in response to TNF and IL-1 release.
Selectins bind Sialyl Lewis X on LEUKOCYTES (neuts and macros)
What binds to Sialyl Lewis X bodies? Where is this molecule located?
It binds selectins, and is found on leukocytes
The 3rd step in neutrophil arrival is adhesion. Describe the process, what molecules are involved, and what disease process results from a deficiency in this process.
Cellular adhesion molecules (CAM) are upregulated on ENDOTHELIAL CELLS in response to TNF & IL-1.
At the same time, INTEGRINS are upregulated on leukocytes by C5a & LTB4.
CAMs and Integrins interact and cause the leukocyte to become firmly adhered to the vessel wall.
Disease is LAD
Describe Leukocyte Adhesion Deficiency and what are the clinical features
It is an AR defect of the CD18 SUBUNIT ON INTEGRINS on the neutrophil.
Clinical features are delayed separation of umbilical cord, extremely high levels of circulating neutrophils (6-10x normal), and recurrent bacterial infections W/O PUS FORMATION
Common infections are Omphalitis, Pneumonia, Gingivitis, Peritonits
Describe the process of transmigration and chemotaxis
Leukocytes travel twd the post capillary venule and diapedese out of the vessel into the interstitium. It is then attracted by chemoattractants to the source of infection.
Chemoattractants for Neutrophils are:
Kalikrein, LTB4, C5a, IL-8, and bacterial products
Describe the process of phagocytosis by the neutrophil. What is phagocytosis enhanced by? What is the disease involved with defective phagocytosis?
Phagocytosis is for consumption of pathogens or necrotic tissue. Phagocytosis is enhanced by opsonins C3b and IgG which act as “post it” notes that tags what is supposed to be eaten by the neutrophil
Pseudopods from the leukocyte extend out like arms and grabs the material to be consumed. Once the material is inside, its a phagosome. The vacuole holding the material merges with lysosome. Now its a PHAGOLYSOSOME.
The disease is Chediak Higashi syndrome
What is Chediak-Higashi Syndrome?
It is a protein trafficking defect (AR) that has IMPAIRED PHAGOLYSOSOME FORMATION.
Clinical Presentations:
Increased risk of pyogenic infections
Neutropenia bc the cells can’t divide to form new cells
Giant Granules in leukocytes (these are granules that can’t be transported out of the cell so they are all stuck at the Golgi forming these large granules
Defective Primary Hemostasis (bc of dense granules in platelets so the clotting factors can’t be delivered to the surface so blood can’t clot)
Albinism (melanin can’t be delivered t/o skin cells)
Peripheral Neuropathy (nerves are long and bc of trafficking defect, proteins can’t be delivered to the very bottom of the nerve so it begins to starve
How is the phagocytosed material destroyed?
The material is destroyed via O2 dependent killing which is the most effective way
Describe the process of O2 dependent killing
An Oxidative Burst makes Bleach and it is the end product that is used to kill the pathogen.
O2–>O2- via NADPH oxidase (OXIDATIVE BURST)
O2- —>H2O2 via Superoxide Dismutase
H2O2–>HOCl via MPO (myeloperoxidase)
What disease process is associated with defective O2 dependent killing? What is the defect exactly? What test tests for this deficiency?
Chronic Granulomatous Disease. It is due to a NADPH Oxidase Deficiency (X-Linked or AR)
W/o this enzyme, can’t create the oxidative burst. No H2O2 can be formed. But most bacteria make a little H2O2 (those that are catalase - can’t get rid of it). So the infected cell can “steal” the bacteria’s H2O2 and use it for the final step in the reaction to make bleach.
But…with catalase + bugs, they get rid of their H2O2 so people with this deficiency has an issue with these bacteria. They are the following:
S. Aureas Pseudomonas Cepacia Serratia Marcesans Nocardia Aspergillus
The test is the Nitroblue Tetrazolium test. Leuks are incubated with this dye. If they can make NADPH Oxidase (meaning it can turn O2 to O2-) then the dye will turn BLUE. If no NADPH then the dye will remain COLORLESS IF NO NADPH OXIDASE
What is the respiratory burst?
Conversion of O2 to H2O2
What is MPO deficiency? Is the NBT normal? What are these patients at risk for?
An MPO deficiency is an inability to convert H2O2 to bleach (HOCl).
The NBT is normal bc their NADPH Oxidase is normal. Meaning they can make H2O2 just fine from O2.
Though these patients are asymptomatic, they are at increased risk for Candida infections.
Which is more effective, O2 dependent or independent killing?
O2 dependent killing bc independent uses enzymes in secondary granules that are less effective than bleach. O2 independent is used by macrophages (lysozyme) and eosinophils (major basic protein)
