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THREE LAYERS OF VASCULATURE:

• TUNICA INTIMA: Endothelium + Subendothelial loose connective tissue.
• TUNICA MEDIA: Smooth Muscle primarily
• Also connective tissue with Collagen III (Reticular Collagen), and some elastic fibers.
• Smooth muscle can also synthesize ECM components such as fibronectin, elastin, collagen.
• TUNICA ADVENTITIA: Outer connective tissue layer.
• CT contains Collagen I
• Vasa Vasorum: The tissue that supplies blood to the vasculature itself.

PERICYTES: Covers the outer surface of the capillary.

• Pericytes can contract. They aid in the blood flow of the capillary system.
• Help in INJURY -- the pericyte is pluripotential and can replace damaged tissue.

THREE TYPES OF CAPILLARIES:

• CONTINUOUS: Tight Junctions; lowest permeability.
• DISTRIBUTION:
• All tissues with blood-tissue barriers = brain, thymus, eye, gonads
• Muscle
• Lung
• Bone
• FENESTRATED: Capillary wall has little openings (fenestrations) that are covered by little diaphragms.
• There is usually a complete basement membrane.
• DISTRIBUTION: GI-Tract, Ciliary Body, Choroid Plexus, Endocrine glands
• Diaphragm Permeability: The diaphragms are rich in heparin sulfate which is anionic. Hence the diaphragm is impermeable to anionic plasma proteins (which most plasma proteins are).
• The diaphragm is permeable to water and small solutes.
• Anionic Proteins can get through by transcytosis through endothelial cells.
• DISCONTINUOUS: Basement membrane may be discontinuous or sporadic. There are large gaps between endothelial cells.
• DISTRIBUTION: Sinusoids of the liver, spleen, and bone marrow.

ENDOCYTOSIS:

• Pinocytosis
• Non-Specific Endocytosis: Heme, Decapeptides
• Receptor-Mediated Endocytosis: Insulin, Transferrin, LDL.

TRANSCYTOSIS: Endothelial cell transports some plasma constituents out of the blood. There are different methods (pathways) by which this can be done:

• Cell-Membrane Pathway: Transport permeable stuff through the cell, as in water and lipophilic substances.
• Vesicular Pathway: Transcytosis of vesicles through the cell.
• Intercellular Junctions for transport of water and permeating solutes.\
• The Channel Pathway: Fusion of Vesicles.
• Open Fenestra (Glomerular Capillaries)
• Closed Fenestra: (Visceral Capillaries)

METABOLIC FUNCTIONS OF ENDOTHELIAL CELLS: Endothelial cells make lots of different things.

• Production of basal lamina and other ECM components.
• Production of oligosaccharide moieties, which may function as recognition sites for some molecules in the blood.
• Monoamine Oxidase (MaO) is made in endothelial mitochondria, to inactivate catecholamines.
• Angiotensin Converting Enzyme is made in endothelial cells, (presumably in the lungs).
• It has specific anionic sites on exoplasmic surface, to prevent platelets from sticking to endothelial wall.
• Produces Prostacyclin, a potent antagonist of TXA₂. It is an anti-coagulant.
• Endothelial cells also produce some coagulant factors: Antihemophilic Factor, von Willebrand Factor, Plasminogen Activator
• Production of Nitric Oxide.
• Production of Endothelin.

ATHEROSCLEROSIS: Deposition of fatty tissue, usually on a muscular artery, to form a lesion called an atheroma. Progression of damage is as follows:

• Endothelium gets injured ------> endothelium somehow gets detached (via inflammatory mediators, mechanical damage, etc.), and underlying tissue gets exposed.
• Exposed subendothelial tissues attract blood cells and platelets.
• Smooth muscle cells accumulate lipid.
• Platelets can stimulate smooth muscle proliferation.
• Repeated injuries result in formation of an intimal plaque.

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THE EYELID:

• Conjunctiva:
• Inner (palpebral) epithelium is stratified columnar.
• Outer epithelium is stratified squamous keratinized (i.e. skin).
• Eyelashes:
• Has Meibomian (sebaceous) and Sweat Glands (of Moll) associated with it.

THE SCLERA: Dense collagenous tissue. Like the cornea, but it is moe opaque.

THE CORNEA: Collagenous tissue but it is more translucent.

• The Cornea has five layers:
• Corneal Epithelium: Outermost epithelium, stratified squamous.
• BOWMAN'S MEMBRANE: Basement membrane of the corneal epithelium.
• CORNEAL STROMA: This is continuous with the sclera.
• All the collagen fibers in the stroma are parallel to each other.
• Proteoglycans in the cornea take up a lot of water, aiding the translucence of the stroma.
• Descemet's Membrane: Basement membrane of the endothelial layer.
• Corneal Endothelium: Innermost epithelium, cuboidal.
• FNXN: It pumps excess water out of the corneal stroma. It is critically important in keeping the cornea transparent.
• LIMBUS: The very edge of the cornea, where the cornea meets the sclera.
• FUNCTION: The cornea is responsible for stationery refraction of light. It refracts about 70% of light, and the lens the other 30%.

CILIARY EPITHELIUM: The epithelial bilayer lining of the ciliary body.

• The epithelia are arranged apex to apex. Each respective basement membrane points outside.
• Non-Pigmented Layer faces the vitreous.
• It is continuous with the Neural Retina.
• Pigmented Layer faces the sclera.
• It is continuous with the Retinal Pigmented Epithelium.
• ORA SERRATA: The junction of the ciliary epithelium with the retina, where the two epithelial layers become respective retinal layers.
• FUNCTION: Production of aqueous humor, to fill the anterior and posterior chambers of the eye.
• Evidence says that the non-pigmented layer is the primary layer to secrete the aqueous humor.
• BLOOD SUPPLY: The stromal layer has fenestrated capillaries that supply the ciliary epithelia.
• AQUEOUS HUMOR:
• Trabecular Meshwork is around the iris angle.
• Canal of Schlemm drains the aqueous humor.
• GLAUCOMA: High intraocular pressure, usually from blockage of the drainage pathway of the aqueous humor.
• SYMPTOM: This results in cupping of the optic disc.
• TREATMENT is very difficult, because its hard to get a drug into the ciliary epithelium because of the blood-retina barrier.
• RESEARCH is currently being done on the connective-tissue properties of the trabecular meshwork and Canal of Schlemm, to see if their resistance to excessive aqueous humor can somehow be reduced.

RETINAL PIGMENTED EPITHELIUM (RPE): The underlying epithelia of the neural retina.

• Choroid: The name of the underlying layer, consisting of the RPE plus the capillaries that supply the RPE.
• STRUCTURE: Cuboidal or columnar epithelia, with tight junctions.
• Villi: The RPE tightly interdigitates with the outer segment of the rods and cones, so there is lots of surface area contact between the two layers.
• FUNCTION: There are four functions of the RPE.
• To supply the overlying photoreceptor cells and transport nutrients. The photoreceptor cells are completely avascular.
• Phagocytosis of materials shed from the rods and cones, on a daily basis. This is very important function -- the RPE disposes of and reprocesses the shed disk-membranes of the photoreceptor cells.
• Storage of Vitamin-A
• Pigment (melanin) absorbs any stray light that is not absorbed by the photoreceptors.
• BRUCH'S MEMBRANE: A double-layer membrane, consisting of the basement membrane of the RPE, + the basal lamina of the underlying choroidal capillaries.
• Things leaving the retina are transported through this membrane system.
• MACULAR DEGENERATION can occur when waste accumulates and Bruch's Membrane and diffusion through the membrane fails to occur.
• MULTIPLE LAYERS: From capillary to retina, we have:
• Basal Lamina of the Capillary
• A layer of collagen
• A layer of elastic fibers
• Basal Lamina of the RPE
• Blood Retinal Barrier: It is a multi-layer system
• The choroidal capillaries that serve the outer retina are fenestrated. For these guys, the RPE serves as the barrier.
• The capillaries that serve the inner layer of the retina are continuous. This is the blood-retinal barrier for the inner retina.

THE IRIS:

• Epithelia: The anterior surface has no epithelium! POSTERIOR SURFACE has two layers of epithelium.
• The posterior surface epithelium
• The anterior layer of myoepithelial cells: This forms the dilator muscle of the pupil, which is innervated by sympathetics.

THE LENS: It's pretty translucent.

• FNXN: Primary function is accommodation. It also does some refraction, but so does the cornea.
• Lens changes shape to accommodate for near-vision by contraction of the ciliary muscle ------> zonular ligaments let go lens ------> it restores its natural curvature.
• Relax ciliary muscle ------> zonular ligaments grab onto the lens ------> flatten it out for far vision.
• EQUATOR: New cells differentiate from the edges and proliferate inward.
• Lens cells never and are never replaced. This has implications for aging. See below.
• CRYSTALLIN: Protein that gives the lens its translucent quality. There are three isoforms
• alpha-Crystallin: This seems to be the primary form that is responsible for translucence.
• alpha-proteins decrease a lot with age. This helps to explain the occurrence of cataracts in old people.
• beta-Crystallin: These don't decrease with age so much as alpha-proteins do.
• gamma-Crystallin: Neither do these decrease with age.

THE RETINA: From the back of the eye (outer limit of eye) to the inner most layer...

• Retinal Epithelium: Not officially part of the retina.
• Choroid -- Not officially part of the retina. It is the blood supply to the retina.
• Retinal Pigmented Epithelium -- Not officially part of the retina.
• Neural Retina: Photoreceptor Layers
• OUTER SEGMENT: Photoreceptor Cells.
• It contains the disk membranes of the rod-cells, which contains rhodopsin.
• These disk membranes contain 1:1 phosphatidylcholine to phosphatidylethanolamine, giving them unusual amount of fluidity.
• Experiments show that these disk membranes are continually synthesized at the inner limit of the segment, and they are continually turned over via phagocytosis in the RPE.
• This is also the demarcation point between Bruch's Membrane and the beginning of the Neural Retina.
• EXTERNAL LIMITING MEMBRANE really isn't a membrane, but consists of tight junctions between the cytoplasmic extensions of Muller Cells.
• RODS -vs- CONES
• Rod-Cells harvest low-intensity, monochromatic light. Dark-adapted eyes are using primarily rod-cells.
• Cone-Cells harvest high-intensity, colored light.
• INNER SEGMENT LAYER: Continuation of the Photoreceptor Cell layer.
• It contains the mitochondria and other support organelles for Photoreceptor cells.
• OUTER NUCLEAR LAYER: Contains the cell-bodies of the photoreceptors.
• Neural Retina: Second-Order Neurons
• OUTER PLEXIFORM LAYER: Contains synaptic connections between the photoreceptor-cells and the integrating neurons (amacrine and horizontal cells).
• INNER NUCLEAR LAYER: Contains the cell-bodies of the integrating cells. There are three integrating cell types:
• Amacrine Cells
• Horizontal Cells: Process lateral information.
• Bipolar Cells: This is the basic second-order neuron. The "Standard Synapse" is photoreceptor cell ------> bipolar cell ------> ganglion cell.
• Muller Cells: This cell extends almost the entire length of the retina.
• Their tight junctions form the external limiting membrane on the outer surface of retina.
• They extend all the way through retina, and parts actually lie on the internal limiting membrane.
• INNER PLEXIFORM LAYER: Contains synaptic connections between the integrating cells and the Ganglion Cells.
• Neural Retina: Ganglion Layers
• GANGLION CELL LAYER: Contains the cell-bodies of the Ganglion Cells. They're afferent fibers make up the optic tract.
• INTERNAL LIMITING MEMBRANE: Separates the neural retina from the Vitreous Body.

FUNDUS OF THE EYE:

• Optic Disk: An indentation right in the middle of the optic nerve. This is the blind spot of the eye.
• Glaucoma patients, again, have cupping of the optic disk due to high intraocular pressure.
• Vascular Supply to the inner retina enters and exits through the optic disk, along with ganglion cells.
• These vessels supply the secondary neurons of the inner retina -- they don't supply the photoreceptors. Those are supplied by the RPE!
• Macula Lutea: Area on retina, lateral to optic nerve, where the retina is at its thinnest point.
• Fovea: In the Macula, the region of highest visual acuity, as it contains the greatest concentration of rods and cones, without overlying neural structures.

CLINICAL STUFF FROM DR. WARREN:

• Anatomical Considerations: Attachment of the Retina: the Retina is only attached to the eye-socket at two places: the ora-serrata and the optic nerve -- nowhere else.
• Those are the only mechanical attachments. Beyond that, the retina is held in place by its interdigitations with the RPE.
• CLINICAL THINGS:
• Retinitis Pigmentosa: Good central vision because the cones are fine, but peripheral vision is bad.
• Macular Degeneration
• Diabetic Retinopathy: Scar tissue on the retina from poor blood supply or blood clots in the microvasculature. The scars can be surgically removed for better vision.

PHOTOTRANSDUCTION:

• THE ROD CELL:
• The INNER SEGMENT is like a neuron, with synaptic vesicles that will synapse with secondary neurons at the inner plexiform layer.
• Synthesis of Rhodopsin occurs in the inner segment.
• The OUTER SEGMENT contains lots of mitochondria (this is an energy-intensive cell) and the disk-membranes which contain studs of rhodopsin on them.
• The cell operates a Na⁺-K⁺-ATPase pump at full speed, hence it needs lots of E.
• RHODOPSIN:
• STRUCTURE: It is a seven-alpha-helix transmembrane receptor that sits on the disk-membranes in the inner segment of the rod-cells.
• RETINAL (Vit-A derivative) sits in the "pocket" of the receptor, inside the membrane, covalently attached to the Rhodopsin via the Lys-296 residue.
• ACTIVATION of Rhodopsin occurs when a Photo of Light strikes. It is a multi step reaction, but the reaction that is important in biological time is Rhodopsin ------> ------> Meta-Rhodopsin-II.
• Once Activates, the Retinal, in all-trans-form, detaches from the rhodopsin, at which point we have fully active rhodopsin.
• RETINAL: It is sits in the "pocket" of the Rhodopsin receptor.
• Photon of Light CHANGES THE CONFIGURATION of RETINAL from 11-cis-Retinal ------> all-trans-Retinal. This is the chemical basis for phototransduction.
• TRANSDUCTION PROCESS: Light causes the Rod-Cell to hyperpolarize, via a cGMP-mediated signal transduction pathway.
• TRANSDUCIN: The G-Protein on the disc-membrane. It is activated by a photon of light ------> conversion of Rhodopsin to Meta-Rhodopsin (R*)
• When activated, its alpha-subunit-GTP-Complex aids phosphodiesterase (the target enzyme) in converting 3',5'-cGMP ------> 5'-GMP.
• This is the opposite of what normally happens!
• The loss of the cGMP then causes cGMP-activated Na⁺-Channels on the plasma membrane of the rod-cell to close ------> hyperpolarization of the rod-neuron.
• The GTP is auto-hydrolyzed, in time, from the alpha-subunit, thus deactivating it. So activation is temporary, just like other transduction pathways.
• MODULATING RHODOPSIN: In intense light, we don't Rhodopsin to be continually activated.
• Rhodopsin Kinase can phosphorylate Rhodopsin, decreasing its activity.
• ARRESTIN: It also inhibits Rhodopsin, to accommodate the eyes to intense light. This makes it so Rhodopsin is not being continually activated in light.
• IN THE DARK: The rod-cell is depolarized.
• High levels of cGMP are in the rod-cells.
• Na⁺-Ca⁺²-Channels are open. The channel accommodates both Na⁺ and Ca⁺², although Na⁺ is the major ion to come in.
• The cell is depolarized as Na⁺ continually comes in, and is pumped back out via Na⁺/K⁺-ATPase located in the inner segment.
• The cell is releasing excitatory neurotransmitter (glutamate, aspartate) onto the secondary neurons.
• IN THE LIGHT: The rod-cell becomes hyperpolarized.
• cGMP gets cleaved to GMP by phosphodiesterase.
• The Na⁺-Channels close.
• Na/K-ATPase quickly restores the cell to what we normally think of as resting potential -- cell is hyperpolarized.
• The cell stops releasing neurotransmitter.
• RETINITIS PIGMENTOSA: It is multifactorial. Some of its genetic forms appear to be mutations in the Rhodopsin molecule itself.
• CONE CELLS: There are at least four different Opsin Molecules involved in color vision.
• Each opsin molecule has a different lambda_max and thus responds to different colors.
• COLOR BLINDNESS occurs from a mutation in one of the opsin molecules.
• BLUE OPSIN resides on Chromosome #7
• RED OPSIN and GREEN OPSIN reside on the X-Chromosome (hence X-Linked RG-Color Blindness)

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HEMATOPOIESES: Development of erythrocytes and leucocytes

• HEMATOPOIESES DURING DEVELOPMENT:
• LOCATIONS:
• First it occurs in the Yolk Sac.
• Then it occurs in the Liver and Spleen.
• Then it occurs in the Bone Marrow
• Red Marrow (hematopoietic) is replaced by Yellow Marrow in the adult, in the peripheral bones. Hematopoieses continues to occur in the axial skeleton.
• Yellow Marrow may convert back to red marrow in disease or severe blood loss.
• Extramedullary Hematopoieses: Spleen and liver can revert back to being hematopoietic in some pathological conditions.
• STEM CELL DIFFERENTIATION:
• STEM CELL: It is pluripotential and divides by asymmetrical division (i.e. division results in one differentiated daughter cell and one undifferentiated stem cell.)
• PROGENITOR CELL: Multipotential cell that also divides by asymmetrical division.
• LYMPHOID will form B-Cells and T-Cells
• MYELOID will form erythrocytes, megakaryocytes, monocytes, and granulocytes.
• PRECURSOR CELL: The blast cell. It is monopotential.
• MATURE BLOOD CELL: Only the mature blood cell will exit the sinusoids and enter the blood stream.

Microenvironmental Factors that Regulate Cell Differentiation:

• Colony Stimulating Factors (CSF):They stimulate the formation of specific cell colonies from multipotential stem cells.
• Granulocytes CSF's: Stimulates Neutrophils (G-CSF), or Neutrophils, Eosinophils and Monocytes (GM-CSF)
• Monocyte/Macrophage CSF (m-CSF): Stimulates differentiation of monocytes and macrophages.
• Erythropoietin (EPO): Produced in kidneys, it induces globin synthesis and promotes differentiation of rubriblasts into erythrocytes.
• Interleukins (IL):
• IL-1: Stimulate granulocytic cells.
• IL-3: Stimulates growth in all phagocytes.
• IL-6: Stimulates multiple cell-types to differentiate.
• Stem Cell Factor (SCF):
• Stimulates early stem cells to differentiate.
• Stimulates the proliferation of mast cells.
• Transforming Growth Factor (TGF-beta): Inhibits hematopoieses.
• Directly inhibits proliferation of progenitor cells.
• Inhibits expression of GM-CSF, G-CSF, and IL-3 receptors.
• Interrupts the function of other local factors.
• Extracellular Matrix (ECM): Fibronectin, collagen, laminins. These ECM proteins are essentially for the proper binding of other local factors.

HOMING: In bone-marrow transplants, the process of stem-cells finding their way to the bone-marrow.

• Sinus Endothelial Cells express specific glycoproteins that the stem cells recognize.
• Stem Cell transport into the bone marrow occurs by transcytosis through the sinus endothelial cells. That is, the stem cell travels through an endothelial cell -- not between them.
• Once inside, the stem cell interacts with stromal cells in the bone marrow, also by ligand-ligand interactions of glycoproteins on each respective cell membrane.

BONE MARROW:

• B0NE MARROW SINUSES contain hematopoietic cords of mitotically identical blood cells.
• Adventitial Cells are the structural components of the sinuses. They form the barrier between the bone-marrow sinuses and the blood stream.
• Mature blood cells displace the adventitial cells to enter the blood stream; at the same time the basement membrane depolymerizes.

ERYTHROCYTES:

• STRUCTURE: Biconcave disk, of size 7.0 - 7.2 micron.
• Poikilocytosis: A general term meaning anemia from abnormal RBC size, such as spherocytosis, etc.
• Hypochromic Anemia: Reduction in cell size or hemoglobin resulting in anemia, as in microcytic anemia.
• Hyperchromic Anemia: Anemia from cells that are too large, such that there are too few cells, as in pernicious anemia.
• The Red Blood Cell Hematopoietic Series:
• RUBRIBLAST: Most immature cell has a nucleus, nucleolus, and blueish cytoplasm.
• PRORUBRICYTE: Nucleus compacts a little. It appears smaller.
• RUBRICYTE: Becomes more red (as basophilia is changed to hemoglobin). Nucleus continues to get compacted.
• METARUBRICYTE: Full complement of hemoglobin, compacted nucleus, eosinophilic pigmented cytoplasm.
• Mature ERYTHROCYTE: The nucleus is lost, and the cell is, by definition, in the blood stream.

BONE-MARROW TRANSPLANTATION:

• Types of Transplantation:
• Syngeneic Transplantation: Transplant stem cells from an identical twin.
• Allogenic Transplantation: Transplant stem cells from someone other than identical twin.
• Autologous Transplantation: Transplant stem cells from one's self.
• Aplastic Anemia is an auto-immune disease against stem-cells.
• Chronic Myeloid Leukemia: Disorder of the stem cell, from characteristic chromosomal abnormality, the Philadelphia Chromosome.
• SYMPTOMS patient will have enlarged spleen, and one will find immature myeloid cells in the bloodstream where they shouldn't be.

LEUCOCYTES: White blood cells, composed of Granulocytes and Mononuclear Leucocytes.

• GRANULOCYTES: Granules in these cells means lysosomes and lysosomal activity.
• NEUTROPHILS: Most prominent of the granulocytes. Constitutes about 70% of the WBC-count.
• FNXN: Inflammatory response to tissue injury. Particularly digestion of bacteria.
• MORPHOLOGY: Multilobed nucleus, granular, somewhat neutral (yeah, right) color.
• You can see a BARR BODY as a "drumstick chromosome" in the nucleus, in female cells. It is the extra X-chromosome which is quiescent and condensed.
• EOSINOPHILS:
• MORPHOLOGY: Sometimes the nucleus is obscured by the same-color cytoplasm.
• It is a bilobed nucleus, when you can see it.
• It is bright red, i.e. eosinophilic.
• FNXN: They function in the allergic response. They are thought to attack some parasites.
• They also counteract the histamine granules released by basophils and mast cells. Thus they serve to balance the effect of the basophils.
• BASOPHILS: They resemble mast cells. There are very few of them in circulation.
• MORPHOLOGY: It is basophilic and it again has a bilobed nucleus which may be difficult to see.
• FNXN: Again, immunological responses to parasites.
• Basophils and Mast Cells release histamine granules to cause vasodilation and inflammatory response.
• MONONUCLEAR LEUCOCYTES:
• LYMPHOCYTES: They are agranular.
• MORPHOLOGY: Lymphocytes are divided into small, medium, and large, according to size.
• MONOCYTES: They are precursors of Macrophages.
• MORPHOLOGY: It looks agranular, but it actually does have granules.
• Key to identification is a HORSESHOE-SHAPED NUCLEUS, or Nuclear Indentation.
• The cell is largest of the leucocytes, and the nucleus is relatively large and eccentrically placed.

MEGAKARYOCYTES: They shed fragments of their cell bodies to form Platelets.

• MEGAKARYOCYTES Morphology: They're huge. Ya can't miss 'em.
• PLATELETS
• MORPHOLOGY: Cytoplasm is purple and agranular. They are small and non-nucleated.

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Natural Immunity:

• Skin and Mucous Membranes = First line of defense
• Enzymes and pH effects are second-line defense.
• COMPLEMENT SYSTEM: Soluble, circulating proteins that interact in a sequential manner, to help cell-mediated immunity. At the end of the cascade, the effects are as follows:
• Vasodilation
• Cell Lysis
• Opsonization: Coating cells with protein that makes them easier targets for phagocytosis.
• Leucocyte Attraction (Chemotaxis)
• Monocytes / Macrophages: Natural, non-specific, phagocytic immunity that is always in effect, to attack critters once they penetrate the skin.
• Granulocytes: Non-specific immunity that kicks in when you get an acute infection.

CELL-MEDIATED IMMUNITY: T-LYMPHOCYTES

• DEVELOPMENT: They migrate from the bone-marrow to the thymus where they mature.
• In the Thymus, the majority of T-Cells are destroyed or suppressed, resulting in self-tolerance.
• Macrophages dispose of the dead T-Cells.
• T-Cells acquire T-Cell-specific markers (CD2+CD3, and CD4 or CD8)
• Naive T-Lymphocytes are T-Cells in the thymus that have not yet come into contact with antigen.
• PRE-PROGRAMMING: Humans are genetically pre-programmed for every possible antigen you could be presented with.
• SUBGROUPS of T-CELLS: All T-Cells have the Pan-T-Cell-Markers of CD2, CD3, and T-Cell-Receptor (TcR) markers.
• HELPER (T_H) T-CELLS:
• FNXN: They help other T-Cells perform their function by secreting interleukins
• They activate B-Cells to produce antibody.
• T_H1-CELL: Preferentially activates Cytotoxic T-Cells.
• T_H2-CELL: Preferentially activates B-Cells.
• MARKER: CD4⁺ is the distinguishing marker for a T-Helper Cell.
• CYTOTOXIC (T_C) T-CELLS:
• FNXN: They kill host-cells infected by viruses or bacteria.
• MARKER: CD8⁺ is the distinguishing marker for T_C Cells.
• They require help from T-Helper Cells in order to become activated.
• SUPPRESSOR (T_S) T-CELLS:
• MARKER: Also CD8⁺
• FNXN: Thought to be responsible for switching off the immune response.

HUMORAL IMMUNITY: B-LYMPHOCYTES

• DEVELOPMENT: B-Cells undergo differentiation in the bone-marrow.
• Stem-Cells mature into Pre-B-Cells which contain IgM in cytoplasm
• Pre-B-Cells ------> Immature B-Cells which contain IgM on cell surface.
• Immature B-Cells ------> Mature B-Cells which may express any antibody. Antigen specificity is determined by gene rearrangement.
• Maturation process is facilitated by bone-marrow stromal cells and the growth factors they secrete.
• ANTIGEN-EXPOSURE: When B-Cells are exposed to antigen, they differentiate into two cell-types:
• PLASMA CELLS: Antibody-secreting cells that circulate the blood.
• B-MEMORY CELLS: They mediate secondary immunity.
• FNXN: They make antibodies or immunoglobulins. Once made, the antibodies can do one of two things:
• They can be secreted into the general circulation where they travel as free proteins.
• They can stay bound to the plasma membrane of the B-Cell, where they become antigen-receptors.
• With the help of T_H-Cells, the antigen-receptor will activate the B-Cell when the appropriate antigen is bound.
• B-CELL ACTIVATION: B-Cells are activated in the Primary Immune Response, the first time an antigen is encountered.
• Once activated, B-Cells will clone themselves, creating multiple cells of the same antigen specificity.
• At this point the B-Cell has two fates:
• Many of these B-Cells will become Plasma Cells and secrete that specific antibody.
• A few of them will become B-Memory Cells and will remain dormant, and keep the antigen-specificity, until the same antigen comes along in the future to reactivate the B-Cells.
• This reactivation of B-Cells is the secondary immune response.

ANTIGEN-PRESENTING CELL (APC): They control the activation of T-Cells.

• They are usually monocytes or macrophages. They can also be B-Cells.
• FNXN: They ingest foreign material, reprocess it, and put it on their plasma membrane in a form that is recognizable by the T-Cell Receptors on T-Cells.
• REPROCESSING involves combining the antigen with HLA markers.
• HLA Class II markers are combined with the antigen to present to T-Helper Cells.

LYMPHOCYTE SURFACE ANTIGENS: These are really just surface markers on T and/or B Cells. There are four general types of surface antigens.

• IMMUNOGLOBULINS: "Antibodies" secreted by or found on B-Cells.
• Has a huge range of specificities achieved by DNA rearrangement.
• Five general types (see below): IgG, IgA, IgE, IgD, IgM
• MAJOR HISTOCOMPATIBILITY (HLA) ANTIGENS: These are the antigens that are integral to acceptance or rejection of transplanted organs.
• HLA Class I: Found on virtually all cells, except erythrocytes.
• FNXN: They activate Cytotoxic T-Cells. They combine with intracellular antigenic proteins, such as viral proteins and tumorigenic proteins, to present the antigen to T-Cells.
• STRUCTURE: One transmembrane heavy chain.
• APC: HLA Class-I APC's will secrete Interleukin-1 (IL-1) to initiate the immune response.
• HLA Class II: Present on B-Cells, Activated T-Cells, and Antigen-Presenting Cells.
• FNXN: They aid in activation of both Cytotoxic T-Cells and B-Cells. They combine with exogenous proteins from phagocytic and lysosomal degradation products.
• STRUCTURE: It has two transmembrane chains.
• FNXN: These molecules function in Antigen Presentation.
• They combine with the antigen, in APC-Cells, and then the HLA-Antigen Complex is presented to the T-Cells.
• VARIABILITY: Genetically it is expressed codominantly, giving it a huge variability in structure. That's what makes organ transplantation so tough.
• T-CELL (TcR) RECEPTORS: They bind to the Antigen-Presenting Cell.
• VARIABLE REGIONS are on the T-Cell Receptor. They allow us to develop variability and diversity in the immune response.
• They give us specificity.
• "CD" ANTIGENS: Systematic classification of surface-antigens with diverse functions. Cell-surface markers.

THYMUS: Site for maturation of T-Cells.

• STRUCTURE: Thymus has multiple lobules, each containing a cortex and medulla.
• THYMIC CORTEX: Primordial T-Cells are found at the outer edge of the cortex.
• Thymic Epithelial Cells help the T-Cells in the maturation and learning process.
• The cortex is highly basophilic.
• THYMIC MEDULLA: Has fewer lymphocytes and is less basophilic.
• THYMIC CAPSULE: Blood-Thymus Barrier. Blood vessels are enclosed within the extracapsular space. The only supply to the inside of the thymus is via the epithelia.
• HASSALL'S CORPUSCLES: Characteristic of the thymus, but their function is unknown.
• INVOLUTION: Thymus in adult is largely fatty. However the thymus continues to operate no matter how much fat has infiltrated.

LYMPH NODES: Filters both blood and lymph, trapping antigenic substances and lymphocytes.

• STRUCTURE:
• Afferent Lymph Vessels: They come in under the lymph capsule all over the place.
• They have valves to provide directional flow.
• Efferent Lymph Vessels: One or two efferent vessels exit at the hilus and enter venous blood.
• Lymph Capsule: Made of connective tissue. Vessels come in under the lymph capsule.
• Lymph Cortex: Contains Lymphoid Follicles, with germinal centers in the middle.
• The Follicles contain lots of B-Cells.
• The germinal centers are sites of B-Cell proliferation.
• Paracortical Zone: Rich in mature T-Cells.
• The T-Helper-Cells secretes lymphokines which the neighboring B-Cells (in the follicles) can detect. This is a part of B-Cell activation.
• HIGH ENDOTHELIAL POST-CAPILLARY VENULES can be seen in the paracortical zone, specialized for the entrance of T-Lymphocytes into the Lymph Node.
• This directed entrance of lymphocytes is mediated by adhesion molecules.
• WEAK ADHESION AND ROLLING: The early stage is mediated by selectins.
• STRONG ADHESION AND EMIGRATION: The later stage is mediated by integrins.
• Lymph Medulla: Contains primarily Plasma Cells
• Contains medullary sinuses that converge on the hilum.
• Also contains medullary cords consisting of Plasma Cells.
• PATHWAY OF LYMPH: Afferent vessels enter around cortex ------> travels from the cortex toward the medulla, where it is filtered through multiple layers ------> out the hilum.
• Lymphocytes tend to stick around the nodes for a while, because of selectins. Then they will exit again and continue circulating.
• LYMPH-NODE PATHOLOGIES:

• Thymic Hyperplasia: No T-Cell in the lymph nodes are present.
• The Paracortical Zone of lymph node is missing -- There is only the medulla and outer cortex.
• Agammaglobulinemia: Antibodies cannot be produced.
• The medulla of the lymph nodes is missing.
• Combined Immunodeficiency (SCID): Both T and B cells are missing.

SPLEEN: Filters only blood, not lymph.

• FNXNS:
• Immunological responses against blood-born antigens.
• Collection and removal of particulate matter (old RBC's) from the blood.
• STRUCTURE
• Red Pulp: Contains dead and living erythrocytes.
• Old RBC's express a sugar-marker on surface, which macrophages recognize and bind to bring them out of circulation.
• White Pulp: T-Lymphocytes centered around a "central artery." The central arteries have been demonstrated well in animals but not humans.
• The White Pulp, then, is the site of immunological activity against blood-born antigens.
• RETICULAR FIBERS: They stain silver. They are prevalent in the spleen. The reticular fibers hold the lymphocytes in place in the spleen.
• SPLEEN CIRCULATION: Trabecular Artery ------> branches into Central Arteries ------> Smaller Branches ------> Sinusoids
• The smaller branches may have closed or open circulations.
• Either way, lymphocytes can exchange with each other in the white pulp of the spleen.

MUCOSA-ASSOCIATED LYMPHOID TISSUE (MALT): Lymphoid tissue found along the GI and Respiratory tracts, there to protect from outside antigens.

• PEYER'S PATCHES are streaks of lymphoid tissue found along the GI-Tract. They are like MALT, except they are not diffuse -- they are concentrated areas of lymphoid reactivity.
• LOCATION: They are directly under the epithelial cells of the GI lining.
• The Colon in particular has lots of Peyer's Patches (because it has lots of bacteria).
• HOMING to the region of the patches occurs. The patches don't just spring up from nowhere!
• These patches start as T-Cells that originated in Lymph-Nodes.
• Macrophages or other APC's travel to the lymph node from the site of infection and present the Antigen at the lymph node.
• The T-Cells then migrate back to the infection by the process of homing.

THE PRIMARY IMMUNE RESPONSE: This occurs in lymph nodes, at the interface between T and B-cells (paracortical area and follicles).

• Antigen Presenting Cell presents the antigen to T-Helper Cell.
• T_C ACTIVATION:
• HLA Class I and II are combined with antigen before presentation.
• T_H1 is the specific T-Helper cell for Cytotoxic T-Cell activation.
• TH1 also produces interferon-gamma (inflammatory mediator) and Tumor Necrosis Factor, both of which further aid the Cytotoxic T-Cell.
• B-CELL ACTIVATION:
• Only HLA II is combined.
• T_H2 is the specific T-Helper cell for B-Cell activation.
• APC binds with the T-Helper Cell: INITIATION OF IMMUNE RESPONSE. IL1 and IL2 are crucial to initiation.
• Interleukin-1 (IL-1): It is the cytokine that activates the T-Helper Cell. The APC makes IL-1 in response to the binding of the naive T-Helper Cell.
• Interleukin-2 (IL-2): An autocrine growth factor, made and recognized by the T-Helper Cell after activation.
• PROLIFERATIVE PHASE: T-Helper cells proliferate and lymph nodes swell.
• Each of the T_H cells is identical to the original activated one.
• CYTOTOXIC ACTIVATION: T-Helper cells activate Cytotoxic T-Cells via expression of interleukins.
• B-CELL ACTIVATION: T-Helper cells specifically activate B-Cells via expression of interleukins.
• This stimulates the B-Cells to turn into Plasma Cells and B-Memory Cells, and then to secrete antibodies.

IMMUNOGLOBULIN STRUCTURE AND FUNCTION:

• GENERAL STRUCTURE: Two identical heavy chains and two identical light chains, covalently linked to each other. The different classes have different numbers of these basic units, connected to each other in different ways.
• Antigen-Binding Regions are in both heavy and light chains. The genes coding for this region come from multiple places on the genome, with sophisticated RNA-Splicing going on to come up with the final product . IN the genome we have:
• Variable Region: One gene from this region is used.
• Diversity Region: One gene from this region is used.
• Joining Region: One gene from this region.
• Constant Region: This region determines the anti-body class.
• IgD: Made in tiny amounts and no one is certain what it does.
• IgM: It is the earliest antibody produced, and it is prevalent early in the primary immune response.
• STRUCTURE: Five monomers held together by the J-Chain.
• FNXN: It is a wonderful activator of the Complement System
• Immature B-Cells have IgM on their plasma membranes.
• IgM has a low affinity (hence it is early on) but it can sweep up a lot of antigen.
• IgG: Most common mature antibody. It is the main antibody found in secondary immune responses, in the blood.
• It has a very high affinity and hence high specificity.
• IgA: It is the main antibody found in secretions.
• SECRETION: First it forms a dimer and then combines with a secretory component from the secretory epithelial cell. This component aids in the transcytosis of the globulin to the lumen of the gland.
• IgE: It is the main antibody involved in allergic reactions.
• ALLERGY: IgE binds non-specifically to Mast Cells, causing degranulation. If the Mast-Cell has a particular antigen and there is enough IgE around, then an allergic reaction will ensue.

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