Foundations 2, Week 1

• Tunica Intima: contains the endothelium (a single layer of squamous epithelial cells), the basal lamina of the endothelium, and loose connective tissue called the subendothelial layer.  Capillaries and postcapillary venules consist entirely of tunica intima.
• Tunica Media: a layer of circumferentially layered muscle cells sandwiched between an internal and external elastic membrane. This layer is thick in arteries.
• Tunica Adventitia: Layer of longitudinally arranged connective tissue (mostly collagenous with some elastic fibers).  This layer is thick in veins.  In thick veins and arteries, this layer also contains a network of vessels called the vas vasorum that supplies blood to the vascular walls and autonomic nerves called the nervi vascularis that contracts smooth muscles in the vessels.

The diameter decreases from > 10 mm to as low as 4 micrometers. The tunica adventitia is consistently thinner than the tunica media.

The diameter increases from 10 micrometers to as large as 10 mm. Some of the tunica adventitia is consistently thicker than the tunica media.

• Small arteries: Up to 8 layers of smooth muscle. The tunica intima has an internal elastic membrane.
• Arterioles: have only 1 or 2 layers of smooth muscle. May not have a tunica intima.

A precapillary sphincter is a slight thickening of the smooth muscle at the origin of a capillary bed from an arteriole, that adjusts the blood flow into each capillary.

A single layer of epithelial cells and their basal lamina.

• Continuous capillaries: muscle and CNS
• Fenestrated capillaries: endocrine glands and sites of fluid absorption
• Discontinuous capillaries: liver, spleen, bone marrow - these are larger capillaries

• Endothelins (ET-1, ET-2, ET-3)
• angiotensin-converting enzyme (ACE)
• prostaglandin H2
• thromboxane A2

• Nitrous oxide (NO)
• prostacyclin (PGI₂ or prostaglandin I2)
• PAF
• Bradykinin (Platelet-activating factor)

When present, pericytes (AKA Rouget cells) surround the capillary with branching cytoplasmic processes to provide vascular support. They are sometimes involved in pathogenesis (tumor angiogenesis and diabetic retinopathy).

Proteins released to affect the behavior of other cells by inducing transcription (including influencing differentiation) in an autocrine or paracrine manner. Also called Interleukins (IL-#) and Lymphokines.

• MHC class I molecules present fragments of proteins from the cell’s cytosol onto the cell’s surface, allowing other cells to recognize them as healthy or unhealthy.
• Known as the cytosolic or endogenous pathway.

• MHC class II molecules present fragments of extracellular proteins, allowing for antigen presentation by APCs.
• Known as the endocytic or exogenous pathway.

CD## = Cell Differentiation, a system for naming and characterizing cell surface molecules.

Any molecule that enhances phagocytosis by marking an antigen for an immune response (ie, for phagocytosis or the complement system).

• Neutrophils: 40%-70%
• Lymphocyte (B and T cells): 20%-50%
• Monocytes (become dendritic cells and macrophages): 2%-10%
• Eosinophils: 1%-6%
• Basophils: <1%
• Remember! Never Let Monkeys Eat Bananas!

• Neutrophils
• Eosinophils
• Basophils
• Never Eat Bananas (they are too grainy)

• Neutrophils bind bacteria and cancer cells, engulf them, and then destroy them with the toxic contents of their granules.
• OR they can release granules to destroy pathogens without phagocytizing them.  
• After phagocytosis, the pH of the lysosome is increased using HClO.
• Neutrophils are attracted by cytokines released by endothelium, mast cells, and macrophages. They secrete additional cytokines as well.

• NK cells are innate immunity lymphocyte that act about 3 days after an infection.
• They respond to tumors and virus-infected cells.  
• They are very similar to NK T cells, but lack the T-cell antigen receptors.  
• NK cells have NKG2D receptors that bind to MIC ligands (expressed by unhealthy cells) and inhibitory receptors that bind to MHC class 1 ligands (expressed by healthy cells).

Monocytes are stored in the spleen, but then move quickly to infection sites where they differentiate into macrophages and dendritic cells.

A powerful anticoagulant with the highest known negative charge density of any molecule.

• Mast cells release histamines and heparin when triggered by IgE receptors on their surface.
• They are similar in appearance and function to basophils despite having different progenitor cells.

• An anti-inflammatory drug released by basophils and mast cells.
• It increases vasodilation and recruits additional WBCs.

• Basophils release heparin and histamine when their receptors bind IgE.
• They are often found near parasites.
• When antigens or antibodies are detected, they release cytokines (including IL-4) to increase the production of effector T cells.
• They play a role in allergens as well.

Eosinophils attack helminths, worms, and other multicellular parasites (detected through the IgE antibody) by releasing cationic granule proteins, reactive oxygen species (superoxide, peroxide, etc), and enzymes.

• Neutrophils (the most potent)
• Dendritic cells
• Macrophages

• Dendritic cells
• Macrophages
• B cells.

• Macrophages engulf and then digest cellular debris, pathogens, and cancer cells.
• They also stimulate lymphocytes and other immune cells to respond to pathogens.
• They are produced from monocytes.

Interleukin 4 is a cytokine that induces differentiation of naive helper T cells (Th0 cells) to Th2 cells.

Erythropoietin (EPO).

Thrombopoietin (TPO).

• A respiratory burst (aka oxidative burst) is the rapid release of reactive oxygen species (superoxide radical (O₂^-) and hydrogen peroxide H₂O₂) and a metabolic change accompanied by an increase in oxygen consumption.
• Occurs in neutrophils and macrophages when they phagocytose pathogens.

• B cells make antibodies against antigens and act as antigen-presenting cells (APCs)
• B cells can develop into plasma cells and memory B cells after activation by antigen interaction.

In response to an antigen interaction, B cells can become plasma cells to release large volumes of antibodies.

Memory B cells last for an average of 10 years, retaining immunity and aiding in secondary responses should a pathogen reoccur.

• T cells are any lymphocytes containing a T-cell receptor, including:
• T helper cells (TH or CD4+ T cells): express the CD4 protein on their surface. They secrete cytokines when activated by MHC class II molecules.
• Cytotoxic T cells: T cells expressing CD8 glycoprotein (CD8+ T cells), bind to cells with antigen-bound MHC class I molecules to destroy virally infected cells and tumor cells.
• Memory T cells: persisting T cells that may express either CD4 or CD8 glycoproteins.
• Regulatory T cells: (aka suppressor T cells) shut down T cells after an immune reaction, and shutdown auto-reactive T cells that escape negative selection in the thymus.
• Natural Killer T cells: T cells that express NK properties as well.

• 1) By releasing exotoxins (like Vibrio Cholerae). Exotoxins can interact with membrane receptors, destroy cell membranes, or enter cells.
• 2) By releasing endotoxins (like Yersinia pestis, which causes plague)
• 3) By entering the cell and causing cell death (direct cytopathic effect, demonstrated by the influenza virus).

• Thrombocytes cause wounds to coagulate and release thrombocidens to kill pathogens in the region!
• These platelets also release cytokines and chemokines to prepare other defenses and activate neutrophils.

• Host defense peptides that are active against bacteria, fungi, and many viruses (especially phagocytosed pathogens).
• They work by attaching to the pathogen membrane to create a pore that allows ions and nutrients to escape and enter.
• α-defensins are mainly produced by neutrophils.  ß-defensins are primarily produced by epithelial cells.

Epithelial cells of the small intestine that secret defensins, lysozymes, and TNF-α.

Enzymes that damage bacterial cell walls.

Toxic lipopolysaccharides released by gram-negative bacteria when they are destroyed.

Powerful toxins secreted by bacteria, or released upon their destruction. Exotoxins can interact with membrane receptors, destroy cell membranes, or enter cells.

• A pyrogen that is able to induce fever, apoptotic cell death, and inflammation.
• It is able to inhibit tumorigenesis and viral replication.

When a T cell has seen an antigen, it downregulates a surface receptor.  If a T cell is missing the surface receptor, lymph nodes will reject them, allowing only naive T cells to enter.

• 1: Histamine is stored in the granules of platelets, basophils, and mast cells.  
• 2: Histamine and serotonin granules are released from platelets during aggregation.
• 3: Granule release from mast cells and basophils is stimulated by trauma, IgE-antigen interaction, or by the binding of C3a and C5a, substance P, IL-1 and IL-8 to their respective receptors on mast cells.
• 4: Histamine induces increased vascular permeability by binding to H1 receptors on endothelial cells (causing contraction of myosin resulting in endothelial gaps).

• C3 is converted to C3a and C3B through one of three pathways.  C3B then covalently bind to the surface of pathogens, labeling them for destruction by phagocytes.  Hence, defects in C3B are the most severe.  
• Additionally, the pathogen can be destroyed directly by continuing the complement cascade on the pathogen surface.  C3B causes C3b2Bbto form, causing C5 to attach, which cleaves C5 to C5a and C5b. C5b binds to C6 and then to C7. This complex attaches to the lipid bilayer where C8 attaches, followed by a number of C9 molecules, which form a pore. (aka C3b-C5b-C6-C7-C8-C9{n} pore)
• C3a and C5a are also active as anaphylatoxins, causing inflammation, chemotaxis, increased receptors, and increased wall adherence for WBCs. C5a is more stable and potent.  These anaphylatoxins can cause anaphylactic shock.

C3 convertase iC3bBb is the converting enzyme.  The C3B molecule causes more C3B to attach through a positive feedback mechanism, making the cell very easy to identify.

Mannose-associated serine proteases (2 MASP 1 and 2 MASP 2 - a total of 4) bind Mannose-binding lectin. This cleaves C4 to C4a + C4b, and C2 to C3b and C3a. C4b and C32a form C2aC4b classical C3 convertase, which cleaves C3.

C1 binds to a C-reactive protein on the pathogen surface. This creates the same C2aC4b classical C3 convertase, which cleaves C3.

Macrophages and other phages have CR1 (Complement receptors) that bind C3b coated pathogens, allowing for phagocytosis.

• Naive T cells express low affinity IL-2 receptors (having ß and gamma chains). Active T cells express high affinity IL-2 receptors (α, ß, and gamma chains) and secrete IL-2.
• Antigen binding causes activation of the high affinity IL-2 receptor and secretion of IL-2.
• IL-2 causes T cells to proliferate.  IL-2 is an interesting cytokine because it can also act in an autocrine fashion, activating its own receptors.

The JAK/STAT pathway consists of 2 Jak (a tyrosine kinase receptor) strands that bind a cytokine to dimerize, causing the JAK proteins to phosphorylate their strands and attract STAT proteins. 2 STAT proteins dimerize and then travel to the nucleus to induce transcription.

G-coupled receptors.

• Interleukin 8 is a chemokine that interacts with CXCR8 G-coupled receptors to attract neutrophils.
• Think, "Interleukin 8! Don't be late!" -it's a chemokine that makes neutrophils hurry to their destination.

Hageman factor (aka, clotting factor XII) is activated by exposure to negatively charged surfaces such as basement membranes, proteolytic enzymes, bacterial liposaccharides, and foreign materials.

• Conversion of plasminogen to plasmin, which degrades fibrin clots.
• Conversion of prekallikrein to kallikrein, which cleaves kininogen to kinins, which induce vasodilation. (ie, inflammation)
• Activates the alternative complement pathway.
• Activates the coagulation system.
• Ie, degrades fibrin clots, causes inflammation, coagulation, and activates the alternative complement pathway.

• red=Karyolysis
• yellow=karyorrhexis
• black=pyknosis
• blue=protein coagulation
• green=acute inflammation

• Bradykinin causes inflammation through the release of prostacyclin, nitric oxide, and Endothelium-Derived Hyperpolarizing Factor.
• Bradykinin is degraded by ACE, so ACE inhibitors increase the amount of bradykinin and promote vasodilation.

• Histamine
• Bradykinin
• PAF
• C3a
• C5a
• Leukotrienes

• IL-1b
• TNFa