lecture 4b Flashcards
shock organ for dogs & rodents
liver
overwhelming release of cytokines from macrophages which causes inflammation
clinical signs: vomiting and diarrhea
treatment options for endotoxemia: polymyxin B
polymyxin B
antibiotic that binds LPS of gram - bacteria used for treatement of endotoxemia (liver shock organ to toxic shock syndrome)
shock organ of cats, ruminants, pigs and horses
lungs (pulmonary intravascular macrophages)
clincial signs: primarily dyspnea
gut is also shock organ in horses
persistent inflammatory responses
recruit more monocytes become activated macrophages (IFNg) -eventually can lead to forming a wall around stubborn organisms (granuloma) neutrophils usually present may recruit T lymphocytes
chronic infections/chemical insults/parasites pathway
prolonged tissue irritation (macrophage destruction) -> M2 macrophages accumulate (1. phagocytosis of irritant 2. removal of damaged tissue) -> IL1, TGFbeta, FBF, angiogenic factiors (fibroblasts) -> fibrosis + other macophages + granulocytes + lymphocytes -> granuloma
lymphocyte subsets
B cells
T cells
Natural Killer Cells
lymphocytes key points
- b and t cells: major effector cells of adaptive immune sys
- recognize and respond to foreign antigens (or self if want to cause problems)
- all look the same but can be differentiated by their cell surface molecules
- surface molecules are classified by the CD (cluster of differentiation system)
- have antigen receptors plus the signal transducing molecules required to activate the cell
- have receptors for cytokines, immunoglobulins, and complements
- in domestic animal species some cell surface molecules are unique to each species and classified by WC (workshop cluster)
- collection of cell surface molecules on lymphocyte is called immunophenotype
lymphocyte development
bone marrow -> multipotent stem cell -> lymphoid stem cell -> A. pre B cell B. pre T cell
A. bursa -> B cell -> memory or plasma
B. thymus or NK cell -> T cell committed -> TH1, 2, 7 or Treg
B cells develop in
Bone marrow/bursa
peyers patches
primary lymphoid organs
bone marrow/bursa
thymus
peyers patch
secondary lymphoid organs
lymph nodes & spleen
B cell major surface receptors
BCR - recognize antigens MHC class 1 & 2 immunoglobulin antigen complement cytokine
make antibodies
make cytokines and respond to cytokines
T cell major surface receptors
TCR (complex molecule) - cannot directly recognize antigen and needs MHC molecule to work MHC class 1 regulatory receptors antigen receptor complex transport receptor
major B cell function
block infections and eliminate extracellular microbes (OUTSIDE INVADERS)
secrete antibodies against antigens: proteins, complex carbohydrates, sugars, lipids, phospholipids, nucleic acids
APC! antigen presenting cell
secrete cytokines
major T cell function
killing of infected cells (INSIDE INVADERS)
key points
- B cells express multiple identical antigen binding receptors on their surface (BCR)
- BCRs shed into body fluids: immunoglobulins (antibodies)
- BCRs: two heavy and two light chains bound together by disulfide bonds
- B cells recognize most antigens without prior processing: optimal B cell response usually requires stimulation by helper T cells
- Helper T cells stimulate B cells through costimulatory molecules and interactive receptors: B cells require costimulation by cytokines
- responding B cells may become: memory cells or antibody secreting plasma cells: plasma cells are progeny B cells that have differentiated to secrete large antibody amounts
- differentiation of B cells take places in germinal centers of lymph nodes and other secondary lymphoid organs (spleen/peyers patches)
- cancerous plasma cells: myeloma cells produce large quantities of pure immunoglobulin: if fuses with normal plasma cell the resulting hybridomas produce large quantities of pure monoclonal antibodies
BCR
igM all recognize specific/same antigen
shedding of antibodies (soluble igm in blood)
antigen binding site + light chain + hinge + heavy chain + signal transducing component
fab region: variable region - arms (fragment antigen binding - light chain end)
fc region: constant region - legs (bind WBC and start response - heavy chain end)
have CDR’s (complementary determining regions (1 at N terminus and 3 closer to center - 3 most diverse)
VDJ recombination
generation of diversity
heavy chain has VDJ
light chain has V J
mechanisms:
- combinatorial diversity
- juncitonal diversity
VDJ function
rearrangement of BCR genes drives generation of BCR diversity
- each b cell (or t cell) produces an antigen receptor with a unique antigen binding structure
- functional antigen receptor genes are produced in immature B cells in the bone marrow and in immature T cells in the thymus
- gene rearrangment: site specific double strand breaks and repair of these breaks by nonhomologous end joinging (RAG 1 &2 recombination activating genes) VDJ
- BCR (and TCR) gene rearrangement also involves random addition & removal of nucleotides bw gene segments being joined in order to maximize diversity
combinational diversity
- antigen recepotrs are encoded by several gene segments that are separate from one another in the germline and recombine during lymphocyte maturation
- combinatorial diversity is limited by the number of available VDJ gene segments
junctional diversity
- terminal deoxyribonucleotidyl transferase (TdT) catalyzes the random addition of nucleotides that are not part of germline genes to the sites of VDJ recombination - forming N regions
- during intermediate stage in process of VDJ recombination before breaks in DNA are repaired, overhaging DNA sequences may be generated that are then filled in by P nucleotieds
- junctional diversity is nearly unlimited
artemis
cut hairpin loops
N nucleotides
rebinds the two newly made gene segments of RAG
TdT catalyzes the random action of addition of nucleotides
containing old sequence + p nucleotide (nontemplated)
P nucleotides
fill in overhang of artemis (cut in hairpin loops)
