Lecture 4: HSC-Derived Cells Flashcards
Blood components
- Plasma (serum, clotting factors)
- Platelets
- RBCs
- Leukocytes
Hematopoietic stem cells
HSCs are pluripotent progenitors of all blood cells
Diapedesis
Process by which leukocytes leave circulation and enter the CT
Types of diapedesis
- Paracellular extravasation
- Transcellular intravasation
Paracellular extravasation
Leukocytes transiently break junctional complexes to squeeze between endothelial cells and exit circulation
Transcellular intravasation
Leukocyte pierces the endothelial cell body (fenestration) and leaves blood via the donut hole. Most common in bone marrow.
Cytokines
Secreted small proteins that act as signals for HSC cells in CT
MSC-derived vs HSC-derived cells
MSC-derived cells are capable of forming an ECM; HSC-derived cells are not and are therefore motile. HSC-derived cells instead interact by transmembrane proteins.
Celsus tetrad of inflammation
- Calor (heat)
- Dolor (pain)
- Rubor (redness)
- Tumor (swelling)
How is swelling in inflammation mediated?
Swelling occurs when fluid plasma filtrate is added to the CT through local vessel dilation and endothelial leakage. It helps with cell motility.
Rolling adhesion
Process by which circulating leukocytes slow down and attach to endothelium for diapedesis. Mediated by selectin/ICAM proteins
Acute vs chronic inflammation
In acute inflammation, local leukocytes secrete cytokines. In chronic inflammation, stromal cells acquire/are entrained to this function and are less easily regulated.
Inflammatory cells
- Mast cells
- Basophils
- Eosinophils
Mast cells
Contain histamine and heparin granules. Found in CT, have mechanisms for compound exocytosis, and are activated via surface IgE
Histamine
Inflammatory protein
Heparin
Glycosaminoglycan anti-coagulant
Compound exocytosis
Process for rapid, simultaneous degranulation where granules dock with other granules at the membrane surface
Basophils
Have blood stream and CT roles in immune modulation; granules contain histamine and heparin
Eosinophils
Have granules containing cationic proteins e.g. major basic protein. Mediate allergy and anti-parasite responses. Eosinophil degranulation creates EC Charcot-Leyden crystals
Innate immune cells
- Macrophages
- Neutrophils
- Natural Killer cells
Macrophages
-Phagocytose unwanted material
-Derive from circulating monocytes (stored in spleen)
-Can form Langhans giant/foreign body giant cells (syncytia)
-Many tissue specific forms (MPS)
Mononuclear phagocytic system
Refers to the system of tissue specific/resident macrophages around the body. Many of these come from monocytes seeded in the fetal stage (e.g. brain to avoid BBB).
Neutrophils
-Kill phagocytosed microorganisms by respiratory burst
-Capable of chemotaxis and cytokine secretion
-Act by phagocytosis or EC granules
-Capable of NETosis
-Storage by adhering to vessel walls
Types of intracellular neutrophil granules and their contents
- Azurophilic (primary; lysozymes)
- Specific (secondary; antimicrobial)
- Tertiary (gelatinase, cathepsin, collagenase; migration)
In order of production
NETosis
Specialized cell suicide process used by neutrophils; chromatin is expelled to create toxic areas (“nets”)
NK cells
Lymphocyte that primarily functions in innate immunity
Adaptive immune cells
- T-lymphocytes
- B-lymphocytes
- Dendritic cells
Mucosal-Associated Lymphoid Tissue
MALT are large CT congregations of lymphocytes found under mucosal surfaces. Within, B cells colocalize into lymphoid follicles as areas of monoclonal expansion
B-lymphocyte
Antigen-specific antibody recognition and production. On antigen recognition, become plasma cells and undergo clonal expansion
T-lymphocyte
Recognize self vs non-self w/ MHC molecules and TCRs. Characterized by their cell surface proteins; e.g. CD4+ Th, CD8+ Tc
Lymphocyte development
Lymphocytes initially develop in hematopoietic areas (e.g. marrow) and then undergo immunocompetence training to prevent auto-reactivity; B-cells in h-poietic tissue and T-cells in the thymus
Dendritic cells
Motile professional APCs
Immune defenses other than cells
- Surface secretions (e.g. stomach acid, antimicrobial peptides in saliva/mucus)
- Barriers (e.g. junctional complexes, basement membranes, fiber matrices)
- Proteoglycans (ZIP codes)
Mexican hat plot of inflammation
Plot of spatial inflammation regulation. Pro-inflammatory mast cell activity in area surrounded by limiting eosinophil activity.
Rolling adhesion/diapedesis process
- Rolling adhesion via upregulated selectin (“lectin-like” Cell Adhesion Molecule)
- Tight binding to endothelium via ICAM-1 (intercell. AM) and CD31
- Diapedesis
- Migration
Leukocyte signaling by cell type
Each leukocyte responds to a unique but overlapping ligand constellation, enabling responses to be general or specific, local or widespread
Macrophage life cycle
- Born in marrow as monocyte
- Release to circulation or “reserve” pool stored in spleen
- Enter CT and become mature macrophage
Timeline of cellular infection/damage response
- Local macrophages respond to cytokines
- Neutrophil numbers peak around 24 hours in
- Circulating monocytes enter the CT space ~36-48 hours in
Neutrophil life cycle
- Born in marrow
- “Marginal pool” stored in marrow as adults or pre-mature band cells
- Released to circulation
- Enter tissue by rolling adhesion/diapedesis
- Activated then dies later
Lymphoid follicle structure
- Cortex (B-cell)
- Germinal center (plasma cells)
- Paracortex (T-cells)
