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Division of Lymphatic system
- diffuse lymphatic tissue
- lymphatic nodules
- lymph nodes
- bone marrow
where are lymphocytes educated? what are they called once educated?
thymus, bone marrow, gut-associated lymphatic tissue (GALT)
what are examples of antigens and what is an antigen?
- antigen - anything that triggers an immune response
- could be a piece of a protein, polysaccharide,
- could be a toxin
what has to happen to antigen before immune system kicks in?
has to be processed by immune system cell first
what are the ALTs?
what is common about them?
- - they are the entering sites into the body, lymphocytes reside and mature here...
- (gut associated lymphatic tissue) – in nodules
- (bhroncial associated lymphatic tissue) – in nodules
- MALT (mucosal associated lymphatic tissue) – more diffuse in your mucosa, CT membranes, mucous membranes
Difference between Primary (central) and secondary (peripheral) lymphoid organs?
primary - bone marrow, thymus, GALT (become immunocompetent), soldier equipped to go to war but not in field yet, antigen independent differentiation... then they enter the blood or the lymph and hang out in CT where if they get triggered by antigen then they migrate to 2ndary organ....
secondary - spleen, lymph nodes and nodules, tonsils, appendix, and peyer's patches.... DEPENDENT ACTIVATION occurs
Nonspecific (innate) vs. Specific (Acquired) immunity?
cells that participate in each?
innate - first line of defense against microbial aggression (neutrophil, eaosionphil, monocyte, macrophage, NK lymphocyte) fastest, more general, can fight while you are building up army! (skin barriers, mucous membranes, chemical defenses, phagocytic cells, NK cells, chew things up that look abnormal...)
acquired - (t and b cell) refinement of more primitive innate reaction, more efficient, highly specific, and has memory
what are 2 types of specific defense?
humoral - production of proteins called antibodies that mark invaders for destruction by other immune cells
cellular immune response targets transformed and virus infected cells for destruction by specific "killer cells"
big pic of humoral?
microorganism will be attached to an antigen - that antigen will trigger a specific immunocompetent B cell (covered in antibodies) to make a clone army - it undergoes a lot of mitosis and differentiates into a plasma cell (antibody producing factory)... some of the b cells will stay in circulation as memory cells...
the plasma cell will - inactivate the substance, trigger destruction of the substance, coat the microorganism so it cant work, or trigger Fc receptors on neutrophils
big pic of cellular specific immunity?
T cells! ... kill and attack microorganisms, foreign cells (transplants and tumors)
t cell receptor will bind to the antibodies and activate cytotoxic t cells that will divide making more memory cells or differentiate into activated cytotoxic t cell that will release certain chemical
what chemical is secreted by active cytotoxic t cell ?
lymphocyte cells of the lymphatic system?
- b cells
- t cells
- natural killer cells (NK)
supporting cells of the lymphatic system?
- reticular cells - secrete reticular fibers that make meshworks
- macrophages - chew up cells and present food
- follicular dendritic cells - chew up cells and present food
- langerhans' cells - middle layer of epidermis, surveillance and defense
- epithelioreticular cells - in thymus, secrete meshwork
- about 70%
- go from the blood to the lymphatic tissue - immunologic surveillance of surrounding tissues - then go back into circulation
- these are mainly mature, t cells, and long lived
- short lived, immature or activated for specific destination of particular tissue (usually CT of respiratory, GI and urogenital tracts)
T cells - originate where? where do they go? what is subdivision?
- originate in bone marrow (independent of antigen) and then migrate to the thymus
- go through blood to other lymph tissues
- 1) helper t cells - CD4+, stimulate differentiation of b cells - viruses, microorganisms, pathogens
- 2) cytotoxic t cells - CD8+, kill virus infected cells, cancer transformed cells, cells infected with microorganisms, parasites, and transplanted cells - use perforins or induce apoptosis
- 3) memory T cells - react rapidly and stimulate production of cytotoxic t cells
- 4) gamma/delta t cells - migrate to epithelial tissues; first line of defense
B cells - orignate where? go where? what do they do?
- originate in bone marrow (independent of antigen)
- go through the blood to secondary lymphoid structures where they MATURE nest and profilerate and differentiate into plasma cells or memory b cells
- they express: MHC II, produce antibodies, express BCR (b cell receptors) that are antigen specific binding sites
what changes about the BCR when b cell matures?
- immature - expresses IgM
- mature - IgD
Natural Killer Cells: originate? mechanism of killing? what do they kill? what percent of circulating?
- develop in bone marrow (same precursor as b and t cells) but they are GENETICALLY programmed to kill cells, they do not need to mature in the thymus like cytotoxic t cells...
- they have similar mech of killing to cytotoxic t cell though - secrete perforins and granzymes (fragmentins - induce apoptosis
- cells they kill: tumor cells and virus infected cells
check out slide 9 of powerpoint
structure of antibody:
- 2 heavy chains and 2 light chains held together by disulfide bonds
- c terminus = constant
- n terminus = variable due to different scrambled genes, this is the part that binds to the antigen!
- isotopes (which of the 5 types of immunoglobulins) are deteremined by the type of heavy chain
what are antibodies?
immunoglobulins - circulating glycoproteins
-80-85% of antibodies in serum
-Blood, lymph, intestinal lumen
- -Activates phagocytosis, neutralizes antigens,
- protects newborn (cross placental barrier)
-B cell surface as monomer (also IgD) and circulating
-First abs produced in initial immune response
-Bound activates B cells
-Free activates complement system
-Dimer; 10 - 15%
- -Produced in plasma cells of lining mucous membranes and
- presents as dimers in secretion (saliva, milk, tears, bronchial and intestinal
- vaginal secretions, etc.)
Monomer; 0.2% in serum
-Not completely understood
-Presents only on surface of B cells
-Receptor to antigens triggering B cell activation
-Produced by plasma cell
-Bound to surface of mast cells and basophils
-When bound to epitope, triggers histamine, heparin, eosinophil-chemotactic factor, etc.
Participates in allergic reaction and lyses parasitic worms
Types of Immune Responses
- first response - inflammation (nonspecific) digest, neutralize, phagocytose the antigen, present to immunocompetent cells
- --> triggers specific immune response (primary - first encounter, mainly b cells.... or secondary - second = more rapid and intense)
what type of immunoglobulin is involved in primary immune response? secondary response
IgM = primary
IgG = secondary
normally which type of specific response happens?
cell mediated AND humoral happen, one kinda predominates though
big pic of helper and cytotoxic t cells:
when does each recognize an antigen?
both have t cell receptors. t cell receptors recognize and bind to MHC molecules
helper t cells - can only recognize antigen when it is PRESENTED to them (on silver platter) by antigen presenting cells
cytotoxic t cells - recognize antigen on other body cells such as those transformed by cancer or infected with a virus
most lymphocytes are t or b cells?
- target cytotoxic t cells (CD8)
- all nucleated cells and platelets present these
- these molecules present self peptides (endogenous) on their surface (this means all peptides that the cell is producing)
- will be abnormal if it is infected by a virus or cancer
- all antigen presenting cells present this type
- display chewed up FOREIGN proteins to helper CD4 cells
what happens when a helper/cytotoxic t cell bins to a mhc-antigen complex?
CD3 will transmit signal to the interior of the cell and stimulate release of cytokines (specifically interleukins) which stimulate differentiation and proliferation of other T, B and NK cells
processing of antigens from microorganisms:
general: proteosomes in cytosol chew up proteins into little pieces that become antigens - shipped to rough ER - bind to MHC1 in lumen - go through endomembrane system - shipped to cell surface
what 2 things do you need to stimulate a T cell?
1) first signal - TCR binds to antigen. CD8 binds to antigen.
2) costimulatory response signal - interaction between membrane molecules of antigen presenting cell and t cell
how do b cells get stimulated to differentiate into plasma cells?
- 1) BCR recognizes specific antigen, b cell endocytoses the antigen and with help of MHC II it presents it on surface
- 2) helper t cells with complementary TCRs bind the b cells and provide second costimulatory signal. t cell secretes specific interleukins that caus b cell to differentiate into plasma cells and also some memory B cells
when b cell is activated how to the immunoglobulins change?
go from IgM to IgG
does b cell need helper T cell?
it cannot do it very well on its own, with help it gives ROBUST response!
how do antibodies bind to antigens to protect the organism?
- agglutination - clump the antigen, localize them so they cant diffuse away, kills toxic fx
- opsonization - makes it more likely to be phagocytosed
- neutralization - neutralizes receptors so toxin cant function
- cytotoxicity- induce mast cells or eosinophils, stimulate other immune system cells to release granules
- complement activation - cascade of enzymatic reactions lead to cell lysis
what mechanism is used to activate NK cells to kill target?
- Antibody-dependent cell -mediated cytotoxicity (ADCC)IFN y activates the IFN y receptor on NK cells - this causes the Fc receptor on the NK cell to bind to the IgG antibody that is coating the antigen, then the NK cell secretes 1) perforins - to increase permeability to 2) the granzymes (serine protease activates caspases - inducing apoptosis)
compare limitations of NK cells to B and T cells:
- b and t cells are more robust
- but NK cells are not limited to needing SPECIFIC antigen to kill
happens to bacteria
20 proteins in the liver triggered by 2 mechanisms (adaptive or innate, adaptive is the classic and more efficient one) and has 2 effects: 1) produce a complex that causes damage to bacterial membrane and 2) prepares the bacteria to attach more easily to macrophages (opsonization)
- ultimate effect:
- modulates inflammation, promotes degranulation of mast cells, decreases histamine release, chemotaxis, increases rate of opsonization, aid in bacterial lysis
mechanism of cytotoxic t cells?
their TCR recognizes a bad MHC1, they bind to it, they undergo CLONAL EXPANSION, so a large number of perforins and granzymes are made that kill the cell
most cytotoxic t cells die, but some are left as memory cells
what lymphocytes is used as an indicator of progress of infection of HIV?
CD4+ helper t cells, dendritic cells, and macrophages because all those express CD4 (MHCII)
how do antibodies bind to antigen? what kind of bond?
reversible noncovalent, complement system makes it a covalent bond to make it stronger
how does HIV virus work?
it has a protein GP 120 that is bound to GP41 - GP120 binds to the CD4 on the helper t cell allowing it to also bind to the chemokine receptor on the t cell, once bound to both of these the membranes can get close enough so taht the virus' reverse transcriptase (can make DNA from RNA) so the helper t cell starts producing foregin endogenous proteins (Expresses it on MHC1 so the cytotoxic t cells end up coming in and killing the helper t cells!)
what does AIDS stand for?
acquired immune deficiency - most people wil die of cancer, pneumonia bc they cant launch immune system
3 diff types of diseases of the immune system:
- 1) allergic reactions - abnormal and intense reaction in an attempt to neutralize the effects of some antigens.
- 2) immunodeficiency -Depression of the reaction against antigens; caused by defiency in components of the complement system, defects in the phagocytic activity of macrophages and neutrophils, or by abnormalities in B and T cells
- 3) autoimmune diseases- t cells that attack self antigens
what are the antigen presenting cells?
MPS (mononuclear phagocytotic system) system: macrophages, kupffer cells, langerhans' cells, reticular dendritic cells of spleen and lymph nodes
- b lymphocytes
- epithelioreticular cells of the thymus
how do antigen presenting cells present antigen?
they endocytosis it, chew it up into 10 amino acid bits, those bits bind with MHC II molecules, the MHC II-antigen complex is then shipped to the membrane and presented
what are immunologic functions of macrophages?
- endocytose and degrade antigens, present on MHC 2 to helper cd4 cells
- they digest pathogenic microorganisms though lysosomal action in combo with the helper t cells
- secrete cytokines and interleukis
how do helper t cells activate macrophages?
they recognize the mhc2 that is presented, they secrete interleukins to start cloning more t cells, these t cells release interferon y (cytokine) that stimulates macrophage to destroy bacteria inside its phagosomes
how do lymphatic vessels begin?
as networks of blind capillaries in LCT, pick up crap from ECF
whats diff about the walls of lymphatic capillaries vs. blood caps?
lymph cap walls are thinner and more permeable, can pick up bigger molecules (such as antigens)
compare starts of blood caps to lymp caps
- blood caps = continous loop
- lymph caps = have an exact start
where are the lymph caps most commonly found?
beneath epithelia and mucous membranes
what are lymph nodes?
- "in line" filters, have a bunch of antigen presenting cells, lymphocytes, macrophages
- all tissue derived lymph HAS TO filter through at least one lymphnode before returning to circulation
- distributed through out whole body, but concentrated in certain regions (axilla, groin, mesenteries)
what are the 2 routes that lymphocytes can enter lymph node?
- 1) afferent lymphatic vessels (from lymph)
- 2) post capillary venule/high endothelial venules (from blood)
efferent vs. afferent lymphatic vessels:
- efferent - goes away from the node (through the hilium)
- afferent - goes towards the lymph node, from ECM
what are high endothelial venules?
- tall cuboidal cells
- present in tonsils, appendix, peyer's patches
- most common site of recirculation
- possess receptors for antigen -primed lymphocytes
what is the hilium?
part of the lymph node that contains the efferent vessel, also serves as the entrance and exit for blood vessels and nerves
3 elements of lymph nodes?
- capsule - DCT around the node
- trabeculae - DCT form a gross framework
- reticular tissue - supporting meshwork
structure of a lymph node:
- cortex - aggregates of lymphocytes called lymphatic nodules, which may contain a lighter center called a germinal center
- deep cortex - between the cortex and medulla, has t cells, high endothelial venules, nodule free portion
- medulla - innermost region, lymphatic tissue that has irregular cords separated by medullary sinuses
- capsule - DCT that surrounds lymphnode, trabeculae extend into the center
- trabeculae are surrounded by subcapsillary sinuses and trabecular sinuses
afferent vessels enter into which sinus?
high endothelial venules are where?
in deep cortex
what happens at the hilium?
- the medulla extends all the way to it
- blood vessels enter and leave
- efferent lymphatic vessels leave here
where does the immunoservalience occurr in the lymph node?
in the cortex
circulation of antigens?
percolate through the sinuses and penetrate the nodules
explain how the sinuses work? and how macrophages interact?
- lymph gets drained into them...
- discontinous, not open spaces, macrophages will extend pseudopods into discontinuous parts (mechanical and cellular filter)
which one has b cells?
-irregular spaces containing lymph-reticular cells and fibers often bridge the spaces (converge near the hilium)
-branched extensions of inner cortex that contain b lymphocytes and some plasma cells
cells of the reticular meshwork in a lymph node?
- reticular cells - synthesize and secrete type 3 collagen (reticular fibers)
- dendritic cells - APCs, very efficient, express both MHC 1 and 2
- macrophages - phagocytic and APC, less efficient, both MHC1 and 2
- follicular dendritic cells - multiple thin hairlike processes that interdigate between b cells in germinal center, not APCs bc lack mhc 2 molecules, but presents antibody/antigen complex via Fc receptors on cell surface (can last a while bc such a strong noncovalent bond)
what do proliferating b cells look like?
large basophilic cells with prominent nucleoli - in the lymphoid nodule
what does a presence of a germinal center mean?
there has been a hit! a lymphocyte has found an antigen and is proliferating! the light color suggests immature lymphocytes
which sinus has cells in it?
what happens to 99% of the antigens/debris in lymph?
phagocytosed by macrophages
why do lymph nodes enlarge?
germinal center cells have bigger cytoplasms
digestive, respirator, and genitourinary tracts - protected by non encapsulate lymphatictissue (has diffuse lymph tissue and lymph nodules)
- found in lamina propria (subepithelial tissue) of these tracts
what happens in the MALT?
- contact to antigen, travel to regional lymphnode, proliferate and differentiate, return as effector T or B cell
germinal center - often located in center If lymphocytes recognize an antigen Light staining due to large lymphocytes; Cell division, formation of plasma cells, antibody production, macrophage activation
lymphatic nodule: where are they found?
- randomly dispersed but also found aggregated
different parts of tonsils:
Palatine (tonsils) – lateral walls of oral part of pharynx
- Pharyngeal (adenoids) – single tonsil; roof of pharynx (no
Lingual – base of tongue (single crypt)
collection of nodules in distal portion of intenstine (ileum)
what antibody secreted when you have a hit in an ALT?
Structure of the Thymus:
capsule and trabeculae - contain blood vessels, efferent lymphatic vessels, and nerves
cortex- extensive population of T cells, dispersed epithelioreticular cells, and a few macrophages, Richer in small lymphocytes (basophilic
Medulla - Contains Hassall’s corpuscles, Same cell population as cortex; larger number of epithelioreticular cells, More mature T cells
how the thymus changes with age?
- peak development from birth to puberty
- at puberty developent starts to reduce, most tissue replaced with adipose tissue, can be restimulated if needed
- at 30 yrs- degeneration is completed
what are epithelioreticular cells?
- not classic epithelia but not classic connective
- cell junctions
- it is reticular like because it provides framework for cells to be embedded in
what are thymocytes?
immature t cells
epithelioreticular cells in cortex:
- Type I – Boundary of cortex and capsule/trabeculae (also surround adventitia of cortical
- blood vessels), Lots of occluding junctions, Serve as barrier (isolates developing T cells from connective
- Type II – In cortex, lots of desmosomes that join adjacent cells, Compartmentalize cortex into isolated areas, Contain MHCI and MHCII complexes involved in thymic education
- Type III – Boundary of cortex and medulla, Occluding junctions, Possess MHCI and MHCII
epithelioreticular cells in medulla:
- Type IV - Boundary of cortex and medulla (considered part of medulla), Occluding junctions, Type V- Located throughout medulla, Desmosomes; provide framework and compartmentalize lymphocytes
- Type VI - Form Hassall’s (or thymic) corpuscles (found only in medulla), Function unknown (produce interleukins)
hassall's corpuscle ?
concentrically arragned, flattened type VI cells often filled with keratin, sometimes calcified, only find in the medulla, unknown function
blood thymus barrier structure?
- only in the cortex
- connective tissue capsule penetrates into cortex
- Endothelium (occluding junctions) Particularly impermeable to macromolecules, May also include pericytes and extra thick basal lamina
- - Perivascular connective tissue Contains macrophages (capture “escaping” antigens)
- - Type I epithelioreticular cells, With occluding junctions and its own basal lamina
blood thymus barrier function?
prevents circulating antigens from reaching thymus cortex where T cells are forming
big pic of thymus?
multipotent stem cells migrate to the cortex of thymus, go through education, winners migrate to medulla, enter bloodstream through walls of venules and migrate to nonthymic lymphic structures and accumulate in specific sites as T cells
start out at double negative stage (lack cd4 and cd8) then they express both (double positive) then epithelioreticular cells type II and III present MHC molecules to them POSITIVE SELECTION (death by neglect - loose binding), then they enter medulla whre they undergo NEGATIVE SELECTION (death if they bind too hard) then they lose either cd8 or cd4 and enter single positive stage
how are all t cells different?
scrambling of the TCR gene occurs!
what does the spleen do?
- pretty much what lymphnodes do for the lymph, spleen does for the blood
- defense against microorganisms that invade bloodstream
- productions site for activated lymphocytes
- site of destruction of aged erythroblasts
- storage of blood
structure of spleen:
- capsule and trabeculae (DCT - contains myofibroblasts) white pulp, red pulp,
- hilium - site of passage for the splenic artery and vein, nerbes, and lymphatic vessels
- splenic artery divides as it penetrates into the spleen, it gos along the capsule, down the trabeculae and enters the white pulp where it is called the CENTRAL ARTERY
- lymphatic tissue
- appears basophilic
- lymp gathers around the central artery (called PALS - periarterial lymphatic sheath)
what does the cross section of PALS look like?
a lymphatic nodule, but it is distinguised by the presence of the central artery
what types of cells are in the PALS?'
what is the structure of the PALS + nodule called?
- t cells - thymic dependent- like the deep cortex of a lymph node
- b cells are in the nodules
- filters and degrades large numbers of red blood cells
- consists of splenic sinuses and splenic cords
loose meshwork of reticular cells and fibers, contains large numbers of RBC, macrophages, lymphocytes, plasma cells, and granulocytes
- very elongated endothelial cells, very leaky endothelial cells bc of fenestrations, few contact points so prominent intracellular spaces, incomplete basal lamina
- processes of macrophages extend into the lumen of the sinuses so they can pick up antigens and present them to the other side
what is role of splenic macrophages?
phagocytose damaged red blood cells
what is big pic of open v closed circulation?
how does blood from the central artery enter into the red pulp?
blood from sheathed caps goes directly to the splenic sinuses of the red pulp
who does it?
- exposes blood more efficiently to the macrophages of the red pulp
- blood from the pencillar arteries goes to the capillaries (sheathed) and percolate through the splenic cords where they are exposed to macrophages and THEN they return to the circulation by squeezing through the walls of the splenic sinuses
- what humans do
what is in the sheath of the sheathed capillaries?
reticular cells, macrophages, and lymphoid cells
how does blood leave the spleen?
blood collected in sinuses drains to trabecular veins that convere into larger veins and leave the spleen by the splenic vein
pencillar arterioles: where and what are they? what do they continue into?
- the central artery extends through the white pulp, emerges out of it and enters the red pulp, and then it branches off into straight arterioles called penicillar arterioles
- they continue on into arterial capillaries
what are sheathed capillaries?
what do they do?
when penicillar arterioles turn into capillaries, some of the caps are surrounded by aggregations of macrophages called sheath capillaries
sheathed capillaries enter directly into reticular meshwork of the splenic cords rather than connecting to the endothelium-lined splenic sinuses
what is the purpose of margnial zone sinuses?
they are sinuses at the periphery of the white pulp, at the end of the central artery, increase chances of blood being exposed to white pulp
which type of circulation do humans do?
immune system functions of the spleen:
- Antigen presentation of APCs and initiation of immune response
- Activation and proliferation of B and T cells
- Production of antibodies against antigen present in blood
- Removal of macromolecular antigens from blood
hemopoietic functions of the spleen:
- Removal and destruction of senscent, damaged, and abnormal RBCs and platelets (macrophages)
- Retrieval of iron from erthrocyte hemoglobin
- Formation of erythrocytes during early fetal life
- Storage of blood, especially RBCs (in some species)