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2 branches of immunity, and the two major branches of one of the original branches
- adaptive specific (humoral mediate[B-cells], cell-mediated [T-cells])
Two main branches of hematopoietic stem cells?
- Myeloid progenitor cells
- Lymphoid progenitor cells
What cells are derived from myeloid progenitor cells
- monocyte macrophage
What cells are derived from lymphoid progenitor cells?
Which cells are polymorphonuclear/granular? What do each of the cells chiefly do? How What percentage of total leukocytes are they?
- neeutrophils (50-60%)-phagocytose invading pathogens
- Eosinophils (1-4%)-destroy parasites, modulate allergic inflammatory rxns
- Basophils (0.5-2%)- release histamine, serotonin, bradykinin, heparin, cytokine; converts arichodonic acid to Prostaglandins+ leukotrienes
Which cells are mononuclear leukocytes? What does each cell do? Percentage of total leukocytes?
- Lymphocytes (T and B cells)- 20-40% mediate cytokine release, phagocytose and kill ingested microbes
- Monocytes + Kupffer cells (2-9%)- macrophages in extravascular tissue, kill virally infected cells+tumour cells, offer natural and adaptive immunity, move via amoeboid movement
- Megakaryocytes (platelets)- initiate blood clotting- release histamine and serotonin
What do neutrophils do? What percentage of total leukocytes are they?
- Phagocytose invading pathogens
What do eosinophils do? What percentage of total leukocytes are they?
- Destroy parasites, modulate allergic inflammatory reactions
What do basophils do? What percentage of total leukocytes are they?
- 0.5-2 percent
- release histamine, serotonin, bradykinin, heparin, cytokines
- convert arachidonic acid to prostaglandins and leukotrienes
What do lymphocytes do? What percentage of total leukocytes are they?
- Mediate cytokine release
- phagocytose and kill ingested microbes
What do monocytes and natural killer cells do? What percentage of total leukocytes are they?
- macrophages in extracascular tissue
- kill virally infected cells + tumour cells
- offer natural and adaptive immunity
describe the activation of leukocyte NADPH oxidase
- NOX is found on the vesicle.
- attached to the vesicle is cytochrome b558
- when the cytosolic subunits (3) bind the cytochrome b558, nox becomes active and releases superoxide radicals inside the vacuole
- the vacuole will then fuse with the phagosomal membrane, releasing superoxide anion into the phagosome
NADPH oxidase deficiency leads to what? Describe the disease
- Chronic granulomatous disease
- can't kil bacteria that have high catalaze activity or low H2O2 production,
- can kill bacteria with high H2O2 production and low catalaze activity.
leads to higher incidences of pneumonia and sepsis
How many nox enzymes? Describe them, which is most important?
- Nox-1= colon> prostate, uterus, breast, macrophage
- Nox-2= neutrophils>>hepatocyte, B lymphocye, cardiomyocytes, endothelium
- Nox 3= inner ear, fetus
- Nox 4= kidney, bloodvessels, cardiomyocytes, endothelium
- nox 5- lymphoid tissue, testes
What are some properties of protein isoforms?
- usually single nucleotide polymorphism
- varying levels of functionality
- resistance to mutation
- overlapping distributions
- good for drug therapy (selectively affect an isoform)
What is rheumatoid arthritis?
- Autoimmune inflammatory disease which principally attacks joints
- -proliferative synovitis progressing to catilage destruction/ joint akylosis
pathogenesis: genetic susceptibilty + joint damage mediated by leukocyte or exogenous arthritogen
treated with NSAIDs
- cox-1 inhibitor
- cox-2 inhibitor
Side-effects of NSAIDs
GI ulcer formation as a result of stomach cell mitochondrial uncoupling and acidosis
- Cox-1 inhibition causes: increased tisue unsaturated fatty acid (acidosis)
- decreased PGE2 levels-> decreased protection of stomach
- (unsat. fatty acids and prostaglandin synthase attacks protective mucous layer)
- Cox-2 inhibition cuases inhibition of thromboxane and platelt aggregation
How do eosinophils protect from infection
- Form hypobromite (as opposed to chlorite) to destroy worms, parasite, tumours, fungi
- Produc cytokines (Platelet activating factor, Leukotriene C4)
How do macrophages protect the body?
- 1) endocytosis/exocytosis via specific receptors for IgG and C3 coated on bacteria
- 2) H2O2 production by NOX to kill mycobacteria
- 3) arachidonate oxidation to prostaglandin
- 4) cytokine production- upon activation by:
- -lipopolysaccharide (endotoxin)
- -immune system activation
- -inflammation or interferon (IFN-y)
- 5) endocytosis and delivery to lysosomes (via scavenger receptor) of oxidized LDL can result in formation of foam cels (basis of atherosclerosis plaque)
What does TNFa do?
- Primary trigger for inflammatory response
- macrophages, lymphocytes, monocyte, kertinocyte
Is increased in chronic inflammation diseases (rheumatoid arthrirites, encephalitis, tumours)
Drug therapy: NSAIDS, GLUCORTICOIDS, DMARTDs (disease modifying anti-rheumatic drugs)
Immune mediated drug activated hepatocyte cytotoxicity
- 1) toxic doses of drugs injure jepatocytes-> releases Kupffer-cell attracting factor
- 2) additional mononuclear phagocytes also recruited from blood and bone marrow precursors
- 3) macrophages become activated
- 4) activated macrophages and endothelial cells release cytokines (ex. TNFa+ PAF-> activates Kupffer cells (which produce ROS and release more cytokines)
- 5) Attraction of neutrophils by cytokines