Watson leukocytes sem 1 Flashcards
What are selectins?
During the tethering/rolling stage of leukocyte migration fast moving leukocytes are tethered to vessel wall. They are guided by specific homing receptors and their ligands.
Selectins are lectin-like adhesion molecules which bind CHO structures weakly.
What selectins are constitutively present?
L-selectins, leukocytes.
P-selectins, platelets.
What selectins require de novo synthesis taking 2-6 hours?
E-selectin: endothelium.
What is L-selectin?
Expressed by leukocytes, binds weakly to CHO structures. Constitutively present.
Leukocyte activation leads to transient avidity increase, rapid shedding by proteolytic cleavage
How do P-selectin and L-selectin differ?
L+S = leukocytes P = Platelets and endothelium, stored in granules and constitutively present.
Rapidly translocated to the cell surface upon cell activation by thrombin, histamine etc.
What selectin is rapidly translocated to the cell surface upon cell activation by thrombin, histamine etc.?
P- selectin.
Why is E selectin slower to appear than P or L?
It is not constitutively expressed and requires de novo synthesis after induction via IL-1 and TNF.
Inhibited by GCs.
What is LADII?
Leukocyte adhesion deficiency II.
Patients will suffer recurrent infections with no pus produced.
Neutrophillia.
Severely impaired neutrophil accumulation in skin inflammation.
What is LADI?
Leukocyte adhesion deficiency I.
Patents suffer recurrent bacterial infections with no pus.
Leukocytes do not adhere to extracellular material or endothelium in vitro.
What are integrins?
Activated following signals from chemokines to endothelial surfaces.
Heterodimeric proteins expressed on surface of leukocytes and most other cells.
Leukocyte activation has what effect on integrins? [2]
- Conformational change - affinity.
2. Clustering of integrins - avidity.
What is the ligand for leukocyte bound integrins?
ICAM.
IntraCellular Adhesion Molecule.
ICAM-2 basally expressed.
ICAM-1 induced by IL-1, TNFa from bacteria/damaged cell or tissues.
Which ICAM is basally expressed?
ICAM-2 basally expressed.
ICAM-1 induced by IL-1, TNFa from bacteria/damaged cell or tissues.
What is VCAM1 and what binds to it?
Vascular adhesion molecule 1.
Integrin alpha4-beta1 binds to it.
Expression of VCAM1 induced by cytokines.
VCAM1 expression is induced by what?
Cytokines.
ICAM1 expression is induced by what?
IL-1/TNFa from bacteria or damaged cells and tissues.
Natalizumab was a treatment for MS.
How was it believed to work?
Monoclonal antibody against alpha-4 integrin which inhibits T lymphocyte interactions with brain endothelium, decreased trafficking of T-cells into the brain.
It led to progressive brain viral infection.
What is the process of chemotaxis?
Directed leukocyte movement stimulated by chemotaxins/chemoattractants.
The source of chemotaxins is the site of inflammation.
Chemotaxins attract leukocytes and activate them, causing integrin activity and avidity change + movement.
What is the difference between a chemokine and a chemotaxin?
All chemokines are chemotaxins but not all chemotaxins are chemokines.
Chemokines are SELECTIVE, most other chemotaxins such as LTB4, C£a, C5a and formylpeptides are not selective.
Which of the following is selective in its actions?
Chemokines
Chemotaxins.
Chemokines are SELECTIVE, most other chemotaxins such as LTB4, C£a, C5a and formylpeptides are not selective.
All chemokines are chemotaxins but not all chemotaxins are chemokines.
What is fMLP?
Bacterial product that is also a chemotaxin.
What lipids are chemotaxins?
LTB4
What are the common chemokines?
CXCL
CCL
What plasma proteins are chemotaxins?
C3a
C5a
What is the synovial fibroblast and what role do they play in RA?
They secrete lipid mediators such as PGE2, cytokines such as IL-6 and IL-8, enzymes and matrix materials.
They act to nurse T cells and may exhibit a malignant phenotype which contributes to synovial inflammation and degradation.
What are osteoclasts?
Inflammatory cells that drive tissue breakdown. T-cells and macrophages release IL-6, TNFa and IL1 etc which all contribute to the activation osteoclasts.
Osteoclasts break down bone via:
carbonic anhydrase,
MMPs,
Cysteine proteases.
Why are proteoglycans easily broken down in the progression of RA? What is the effect of this?
Proteoglycans have an open structure and are thus highly accessible and sensitive to breakdown by several proteinases.
This results in the loss of joint function and pain, impaired shock absorption ability.
How is collagen lost during RA?
More slowly than proteoglycans.
Native collagen is only susceptible to collagenases, after damage however other enzymes can continue to degrade collagen.
What are MMPs?
Matrix Metalloproteinases which breakdown collagen and other matrix proteins.
Active at neutral pH and contain/require Zn2+.
Inhibited by TIMPS: tissue inhibitors of metalloproteinases..
What are TIMPS? What are they involved in?
Tissue inhibitors of metallo-proteinases,
What types of drugs are used as MMPi’s and how do they work? [2]
Peptidomimetics, small hydroxamic acid based molecules.
Bind to Zn2+ and mimic the substrate collagen.
They lack specificity: Marimastat will thus act on most metalloenzymes.
Non-peptide hydroxamates: better selectivity, still Zn binding: Prinomastat.
Why are TIMPs not used therapeutically to reduce collagen degradation by MMPs in RA?
They can cause upregulation of the synthesis of MMPs and have limited selectivity.
Why are tetracycline derivatives used at sub-antibiotic doses in the treatment of RA?
They reduce MMP synthesis and activity.
Doxycycline (periostat) is used for treatment of periodontal and skin disease.
Neutrophil elastase, cathepsin G, kallikrein are all:
Serine and Cysteine proteases active at neutral pH which breakdown matrix proteins such as elastin, laminin, chondroitin sulfate and proteoglycans.
What are serpins?
SERine Protease INhibitors which are endogenous inhibitors readily deactivated by oxidation.
What is Marimastut?
MMPi.
Peptidomimetics, small hydroxamic acid based molecules.
Bind to Zn2+ and mimic the substrate collagen.
They lack specificity: Marimastat will thus act on most metalloenzymes.
What is the purpose of RONS?
Host defence.
What is Prinomastat?
Non-peptide hydroxamates: better selectivity, still Zn binding: Prinomastat.
What catalyses the formation of superoxide (02-)?
NADPH.
Why does Rheumatoid synovial tissue undergo oxidative stress?
Cycles of hypoxia and reperfusion leads to this oxidative stress.
What are the effects of RONS? [5]
DNA damage
Activation of inflammatory gene transcription, NFKB –> further inflammation.
Amino acid modifications, make host proteins immunogenic - autoimmunity –> inactivation of serpins.
Matrix modifications.
Cell apoptosis and necrosis.
