lymph system inflammation

  1. Lymphatic tissues and organs
    • lymph vessels, nodes, nodules
    • thymus
    • spleen
    • bone marrow
    • tonsils
    • mucosa associated loose CT aka MALT (in gut)
  2. Lymph vessels
    • no basal lamina of endothelia and few smooth muscle cells (super thin)
    • largest is thoracic duct
    • moves by gravity and milking and intrathoracic pressure
    • stratified deep and superficial
  3. Abdominal aortic/IVC plexus lymph
    • afferent from abdominal organs
    • deep abdominal wall lymph
    • deep inguinal nodes
  4. Thoracic duct
    • connects abdominal aortic/IVC plexus lymph to internal jugular/subclavian veins via broncho-mediastinal trunk
    • afferent from posterior intercostal lymph (deep thoracic)
    • begins at diaphragm with cysterna chyli
  5. Jugular/subclavian veins
    • afferent from head and neck lymph (jugular trunk)
    • axillary nodes via subclavian trunk
    • heart/lung lymph
    • bronchomediastinal trunk
    • deep parasternal nodes
    • where most lymph enters blood
  6. Axillary nodes
    • afferent from superficial arm lymph
    • deep arm lymph
    • breast and superficial trunk above navel
  7. Deep inguinal node
    • afferent from deep leg lymph
    • superficial inguinal nodes
    • which are afferent from superficial trunk below naval and superficial leg lymph except that which goes from lateral foot, ankle, posterior calf through lesser saphenous lymph
  8. Deep parasternal nodes
    • afferent from anterior intercostal lymph
    • also sort of breast and abdominal organs
  9. Histology of WBCs
    • Granulocytes are bigger than RBCs
    • polymorphal nucelar leukocyte aka neutorphil (antimicrobial)
    • eosinophil is darker (parasitic infections)
    • basophil is darkest (similar to mast)
    • Agranulocytes distinguish by size
    • lymphocytes are similar in size to RBCs (B and T)
    • monocytes are bigger (differentiates into macrophage)
    • B cells become plasma cells with clear staining golgi
  10. Clusters of differentiation markers
    • CD markers
    • distinguish B and T cells and their maturation point
    • some present only for certain disease
  11. Lymphatic supporting cells
    • parenchyma is cells that secrete
    • stroma is connective framework
    • reticular cells strongly associate with reticular fibers, protecting them from lymphocytes
    • langerhans cell, macrophage-like (dendritic) buried in stratified squamous epithelium
    • M cells antigen involved in the gut
  12. Lymphatic nodules
    • aka follicles
    • nodules have no capsule, are aggregations of B lymphocytes
    • light staining germinal center is where lots of division happens
    • nodules (peyer’s patches) define ileum
    • smaller lymphocytes at periphery
  13. Lymph node
    • afferent lymphatic vessels, sub-capsular, trabecular (cortex), medullary sinuses (medulla), efferent lymphatics at hilum with blood vessels
    • blood vessels are not capillaries, rather high endothelial venules in the trabecular
  14. Spleen
    • filters blood
    • red pulp is non lymphatic function like RBC and iron filtration
    • white pulp stains dark and contains nodules and periarterial lymphatic sheaths (PALS) branched off of tribecular artery and made of T cells
    • open circulation to splenic sinus where venous return begins
    • contains smooth muscle for pushing blood back into circulation
  15. Thymus
    • lobules folded and interconnected, separated by trabeculae
    • lobule contains cortex (darker staining) and medulla
    • incapsulated organ
    • stromal reticulum formed by epithelial cells (epitherlioreticular cells) (no collagen or reticular)
    • epithelioreticularcells coil up and keratinize called Hassall’s corpuscles
    • T cell maturation to CD4 (helper) or CD8 (killer) as they travel
  16. Signs of inflammation
    • rubor, calor, dolor, tumor
    • rubor, calor, tumor caused by vasodilation and permeability
    • dolor caused by inflammatory cells getting through endothelium releasing
    • inflammatory mediators
    • recruits all T and B cells via permeability changes equally regardless of ability, thus innate
  17. Antiinflammatory and proinflammatory
    • M1 are proinflammatory like TNF and IL 12 that do tissue destruction
    • can be detrimental
    • induce inflammation by chemokines IL 1, IL 12, IL 23
    • does phagocytosis and killing of microbes
    • activated by immune response or tissue injury
    • M2 are antiinflammatory
    • second wave
    • fibroblast growth factor, angiogenesis, metaloproteinases, IL-10, TGF beta
    • both from binding receptors on phagocytes
    • activates fibroblasts to produce collagen
  18. Acute inflammation
    • blood vessel response to injury
    • neutrophilic inflammation develops in minutes to hours, lasts days
    • can lead to chronic
    • also infiltration of eosinophils and mast cells (indicated by elevated levels of mast cell tryptase in tears)
  19. Vasodilation
    • one of the first steps of acute inflammation
    • arteriole and venule dilation and capillary bed expansion
    • no action of smooth muscle
    • response to histamine action on blood vessels
  20. Histamine
    • early effector in acute inflammation
    • stored already formed and ready in platelets and mast cells in vasculature
    • rapid response
    • binds H1 H2 H3 H4, which are tropic to different parts
    • H1 is tropic to endothelial and is an acute allergic response
    • antihsitamines are thus also tropic
    • H1 antihsitamines are diphenhydramine, loratadine, cetirizine
    • H1 is 7Tm GPCR cascade via NO results in phosphorylation of junctions to release them and open the space between the cells
  21. Steroids
    • all the -ones like prednisone
    • inhibit phospholipases so that cell membrane phospholipids cannot convert to arachidonic acid
    • arachidonic acid has 2 pathways, 5-lipoxygenase and cyclooxygenase
  22. Arachidonic acid pathways
    • 5-lipoxygenase does chemotaxis, vasoconstriction, bronchospasm and increased permeability by one pathway (5-HPETE)
    • 5-lipoxygenase by 12-lipoxygenase it does vasodilation, monocyte adhesion, and inhibits neutrophil chemotaxis (probably most important)
    • cyclooxygenase can be inhibited by COX-1 and COX-2
    • cyclooxygenase via prostacyclin does vasodilation and inhibits platelet aggregation by thromboxane A2 does vasoconstriction and promotes platelet aggregation
    • cyclooxygenase by prostaglandins (PGD2, PGE2, PGF2) does vasodilation and potentiates edema (this is probably most important for us)
  23. Prostaglandins (PG family)
    • PGD2, PGE2, PGF2
    • G protein coupled receptors
    • regulate gene transcription and mediate cell cell contact
    • cause vasodilation and increased permeability
    • inhibited by COX-1 COX-2
  24. Leukocyte capture surface receptors
    • L-selectin binds GlyCAM
    • beta1 and beta2 integrins (CD11/18) bind VCAM-1 and ICAM-1
    • mucin like PSGL-1 and ESL-1 bind P-selectin and E-selectin (sugar binding lectins associate with mucin like glycoproteins)
    • constituitive expression
  25. Leukocyte migration
    • chemotaxis by chemokines and leukotrienes
    • capture by selectins (PSGL1)
    • rolling, arrest, adhesion, transmigration
    • rolling and slowing by E and P selectins
    • chemokines change integrin conformation to be more sticky
    • integrins arrest the cell
    • chemokine receptors on leading edge bind chemokines to cause shape change via actin and myosin
    • paracellular squeeze through by PECAM
    • transcellular less understood
    • protease through basement membrane
  26. CNS and eye leukocyte migration
    • immunoprivileged
    • not much leukocyte migration by changing VLA-4 (beta integrin)
    • VLA on T cell lymphocytes
    • VLA avidity regulated by chemokines
    • VLA binds to VCAM on endothelium
  27. Microbial killing agents in inflammation
    • ROIs are in neutrophils and for extracellular bacteria
    • RNIs are in macrophages and for intracellular bacteria
    • Lysosomal acid proteases degrade dead bacteria and particles like necrotic tissue, pigments and minerals
  28. Leukocyte phagocytosis and killing
    • recognition, attachment, engulfment, fusion
    • respiratory burst on engulfment
    • Chediak Higashi syndrome cannot fuse
    • oxygen makes ROI and then spontaneously converts to H2O2 which is also bactericidal
    • some bacteria neutralize superoxide anion and/or hydrogen peroxide
    • myeloperoxidase converts H2O2 to HOCL
    • can have mutation in MPO
    • fenton reaction uses Fe2+ to convert H2O2 to OH radical
    • uses Fe3+ from engulfed bacteria converted to Fe2+ by superoxide radical
  29. Chemotaxis
    cell movement to a certain area based on chemical signaling
  30. Chronic inflammation
    • mononuclear inflammation (macrophages/lymphocytes)
    • develops in weeks to months and lasts years
  31. Granuloma
    • focus of chronic inflammation
    • aggregation of macrophages that transform into multinucleating epithelial cells
    • Langerhans giant cell is an example (not langerhans)
    • necrotizing lacks tissue organization and cell nuclei in the center
    • non necrotizing, non-necrotizing is usually non-infectious, cellular to the center
    • involves elevated TNF
  32. Tumor necrosis factor (TNF)
    • increases CCL2
    • CCR2 expressed by macrophages binds CCL2 chemokines causing chemotaxis to region
    • this is an NFkappaB gene activation pathway
    • TNF also regulates CAMs on endothelium so that leukocytes bind
  33. Leukocyte adhesion deficiency
    • genetic deficiency
    • leukocytes cannot bind and roll
  34. Chronic granulomatous disease
    • genetic autosomal recessive or x linked
    • cannot produce oxygen radicals because no membrane oxidase pathway
    • alternative pathways not as good
  35. Steps of inflammation resolution
    • return to normal vasculature
    • drainage of edema to lymphatics
    • macrophages pinocytose or phagocytose debris, phagocytose apoptotic neutrophils, and release growth factors
    • macrophages are disposed
    • angiogenesis, new tissue growth or tissue replacement
  36. Stem cell generation
    • stem cells differentiate into the tissue of interest
    • some evidence of this
    • stem cells have antiinflammatory effect (not well understood but important)
  37. TGF beta
    • Transforming growth factor beta
    • two chain protein with 3 isoforms
    • produced by platelets, endothelial cells, lymphocytes, macrophages
    • stimulates fibroblast growth, collagen production
    • inhibits endothelial and lymphocyte growth
    • TGF beta receptors bind TGF beta and aggregate
    • this phosphorylates RSMAD which dimerizes with SMAD4
    • this is a transctiption factor for miRNA
  38. Collagen
    • doesn’t have normal function, so keloid causes loss of some funciton
    • SMAD 4 genes cause collagen signal chains
    • enough energy to wind 3 together then secreted
    • enough energy extracellulary to associate into fibrils
    • transverse covalent bonding with stagger rather than end to end bonding
  39. Angiogenesis
    • Statins block HMG which increases VEGF
    • VEGF is vascular endothelial growth factor produced by mesenchymal cells and mitogenic cells for endothelial cells
    • this is in endothelial tip cell
    • VEGF receptor causes gene transcription to upregulate delta like ligand 4 Dll4 which is transmembrane extracellular and can bind to notch on an adjacent cell (stalk cell)
    • causes internal cleavage of notch to activate genes involved in angiogenesis
    • Dll4 downregulates VEGFR to cause a cycle
    • this cycling results in a tube
  40. Macrophages in repair (post inflammation)
    • remove exciting stimulus
    • release TGF beta to cause angiogenesis and collagen
    • remodel by destroying out of place collagen and secreting TGF beta to make more
    • chemotaxis
    • debridement and removal of injured tissue
    • antimicrobial
  41. Sepsis and cytokines
    • robust, high concentrations of cytokines
    • causes leukocyte mobilization from bone marrow, lots of damage,
    • results in acute phase protein production by liver
    • progressing low cardiac output and blood vessel injury
Card Set
lymph system inflammation
the lymph, the lymph, the lymph is on fire