Immune System Test 3

Pyrogens

Chemicals, released by neutrophils, monocytes, and other cells. Stimulate fever production

Adenovirus Vaccines- COVID-19

-Adenovirus is really good at getting into cells. Scientists have disabled the genes in the Adenovirus cell that causes illness, while keeping the ability to enter the cell to treat/prevent disease. -Is a CARRIER that delivers a gene (SPIKE-Encoding DNA) that contain instructions to make the proteins that will bind to Lymphocytes --HE Emphasizes MHC Class-1 in PowerPoint: -Everything is the same as for how it is delivered. -All nucleated cells (Red blood cells and platelets do not, don't have a nucleus). -Present the viral protein to CD8 T-Cell (Cytotoxic Killer Cell)

T-Cell Clonal Selection (Active Immunity)

-An Antigen-Presenting Cell uses its MHC class 2 to present antigen to T cell receptors -Only a T cell with a MATCHING RECEPTOR will divide into many clones and begin circulation -NO ANTIBODIES IN CELL SURFACE (Only B-Cells have these) -Can protect person from getting the disease upon subsequent exposures

Autoimmunity

-Produced by failure of immune cells to recognize and tolerate "self"-antigens -Autoreactive T-Cells and Autoantibodies are produced by B-Cells--> Causes inflammation and organ damage.

B-Cell Clonal Selection (Active Immunity)

-When an immunocompetent B cell encounters an antigen for the first time, B cells with specific antibody receptors are stimulated to differentiate and proliferate into Plasma Cells (Produce antibodies fo Primary Response) and Memory Cells (Stimulated to secrete antibodies during the Secondary Response) -A differentiated B cell becomes a plasma cell and memory cell -PLASMA CELLS produce antibodies--> Primary Response -MEMORY CELLS--> Secondary Response (Secrete antibodies)--> Live longer than naive lymphocytes, are activated more easily, and are more effective once they are activated. -Subsequent (Secondary) exposure of B-Cell clones to specific antigens results in greater and more rapid production of specific antibodies! - The more rapid production of antibodies in secondary response is due to the development of B-cell (lymphocyte) clones produced during the PRIMARY RESPONSE -Can protect person from getting the disease upon subsequent exposures (SECONDARY RESPONSE) -Secondary Response--> Maximum amount of antibodies are achieved in blood in LESS THAN 2 HOURS vs. Primary Response TAKES 5-10 DAYS

mRNA Vaccines - COVID-19

-mRNA is a genetic material that instructs cells to produce proteins -mRNA (SPIKE-mRNA) in vaccine is wrapped in a LIPID SHELL(Fat particles) that protect and help it get taken up by Antigen-Presenting Cells (Dendritic Cells, B-Cells, and Macrophages) -Once inside cell, the mRNA dissociates from the lipid shell and is processed by the Antigen-Presenting Cell. -Once processed, pieces of the viral (COVID) cell released from ribosomes within the cell are displayed on the Antigen-Presenting Cells. -The Antigen-Presenting Cell then travels to the lymph node and presents (binds) to Helper T-Cells of the immune system -The Helper T Cells then promote the B-Cell response and they ultimately start producing antibodies that combat the spread of COVID!!! -HE Emphasizes MHC Class-1 in PowerPoint: -Everything is the same as for how it is delivered. -All nucleated cells (Red blood cells and platelets do not, don't have a nucleus). -Present the viral protein to CD8 T-Cell (Cytotoxic Killer Cell)

Comparison of Active and Passive Immunity

1. Active Immunity A) Inject person with ANTIGENS (Vaccine) B) Antibodies produced by individual's own cells (inoculated) C) Method: Injection with 1. Killed, 2. Attenuated Pathogens, or 3. Their toxins D) 5-14 Days to Develop E) Duration of Resistance: LONG (Perhaps YEARS) F) Used BEFORE exposure to pathogen 2. Passive Immunity A) Inject person with ANTIBODIES B) Source of Antibodies: 1. Natural (Mother's Milk) 2. Artificial (Injection with antibodies) C) 1. Natural (Transfer of antibodies across the placenta) 2. Artificial (Injection of antibodies) D) IMMEDIATELY AFTER Injection Develops E) Duration of Resistance: SHORT (days-weeks) F) Before or After Exposure to Pathogen

Ways to Acquire Adaptive Immunity

1. Active Immunity Immunity is provided by the individual's OWN Immune System. Produced by Secondary Response to a specific antigens. Requires prior exposure (Primary Response) to the specific antigen--> Due to slowness of Primary Response (5-10 days), person might develop the disease. 1. Natural Way- Antigens are introduced through Natural Exposure 2. Artificial Way- Antigens are introduced in a Vaccine 2. Passive Immunity Immunity is TRANSFERRED from anther person or an animal 1. Natural Way- Antibodies from the Mother are transferred to her Child across the Placenta (IgG antibody) or in the Milk (IgA antibody) 2. Artificial Antibodies are produced by ANOTHER PERSON or ANIMAL are injected into another individual. Used with very dangerous, viral infections such as Tetanus, Hepatitis, Rabies, and Snake Venom. --> Person is injected with "Antiserum/Antitoxin" (serum containing antibodies). --> Must be injected with Multiple doses, because person DOES NOT develop ACTIVE IMMUNITY (B-Cells do not produce antibodies against it)

Major Histocompatibility Complex (MHC)

1. All cells EXCEPT Mature Red Blood Cells (Erythrocytes) are genetically marked with Histocompatibility Antigens on the membrane surface. 2. Another name for MHC molecules is Human Leukocyte Antigens (HLAs) 3. MHC Genes produce 2 classes of MHC Molecules: Class-1 and Class-2 4. All MHCs (either 1 or 2) are THE SAME IN ALL CELLS within in an individual 5. Red Blood Cells DO NOT present MHC 6. TISSUE TYPING for organ transplants is based on MHC (expressed proteins). --> Greater the variance in MHC (antigens), the greater is the chance of transplant rejection. --> Closer 2 people are related, closer the match of MHC!

6 reasons why self-tolerance may fail:

1. An antigen that does not normally circulate in the blood may become exposed to the immune system. Hashimoto's Disease (Thyroglobulin exposed) 2. A self-antigen that is otherwise tolerated may be altered by combining with a foreign hapten Thrombocytopenia (Low platelet count) 3. Antibodies may be produced that are directed against other antibodies Rheumatoid Arthritis (IgG) 4. Antibodies produced against foreign antigens may cross-react with self-antigens Rheumatic Fever and Glomerulonephritis (Streptococcus bacterial infection cross-reacts with heart and kidneys, causing damage) 5. Self-antigens, such as receptor proteins may be presented to the Helper T-Cells together with Class-2 MHC Molecules Graves' Disease (Immune System produces antibodies against TSH receptor proteins in the thyroid cells, causes overproduction of thyroid hormone) Type-1 diabetes (Beta-cells of pancreatic islets abnormally produce class-2 MHC molecules, leads to destruction of the insulin-producing cells.) 6. Autoimmune disease may result when there is inadequate activity of regulatory (suppressor) T-Cells (Treg)

B-Cell Activation

1. Antibodies on B-Cell surface that function as receptors bind to a specific antigen 2. PROLIFERATION--> MITOSIS causes formation of a clone B-Cell in order to produce more plasma and memory cells. Cell division and the maturation of the B-cell progeny (descendents) into 1. Memory Cells and 2. Plasma cells occurs as a result of antigen binding to antibodies on cell surface 3. Plasma cells (Short-lived, Primary response) produce and secrete large amounts (2,000/second) of the ANTIBODY released to bind to antigens 4. Memory Cells are longer-lived (Secondary Response) and provide a pool of cells that can respond quickly and effectively upon a subsequent exposure to the SAME antigen!

Summary of Events in a Local Inflammation (Adaptive)

1. B cells are stimulated to produce specific antibodies 2. Phagocytosis is enhanced by antibodies attached to the bacterial surface Antigens (opsonization) 3. Specific activation of complement proteins occurs, which stimulates phagocytosis, Chemotaxis of new phagocytes to the infected area, and secretion of histamine from tissue mast cells 4. Extravasation (diapedesis) allows jew phagocytic leukocytes (neutrophils and monocytes) to invade the infected area. 5. Vasodilation and increased capillary permeability (As a result of histamine secretion) produce redness and edema (swelling)

Summary of Events in a Local Inflammation (Innate)

1. Bacteria enter a break in the skin 2. Resident phagocytic cells (Neutrophils and macrophages) engulf the bacteria 3. Nonspecific activation of complement proteins occurs

Helper T Lymphocytes (Cells)

1. CD4 surface molecules 2. Enhance immune response (As name implies) A) Activate B-Cells Improve the ability of B-Cells to differentiate into plasma cells and secrete plasma antibodies B) Activate other T-Cells and Macrophages Increase the ability of Cytotoxic T-Cells to mount a cell-mediated immune response. NOTE: Helper T-Cells secrete chemical regulators called LYMPHOKINES (More specific name for cytokine of a lymphocyte)--> Activates B-Cells, other T-Cells, and Macrophages 3. NOTE: Subtypes perform DIFFERENT TASKS and respond differently (DON'T WORRY ABOUT THIS)

Killer/Cytotoxic T Cells

1. CD8 Surface Molecules Designated as "CD8+ Cytotoxic T Lymphocytes" 2. Cell-Mediated Destruction Kill their victim cells by coming into physical contact with the victim cells. 3. Secrete killing molecules When T-Cell comes into physical contact with victim cell, secrete: A) Perforins (Molecule) --> MAKE PORES (Similar to Complement Protein pore formed) B) Granzymes (Enzyme) --> ENTER PORES, TRIGGER APOPTOSIS by OSMOTIC DESTRUCTION (Same method of death as with Complement Proteins) 4. Defend against viral and fungal infections 5. Kill Infected Cells--> SELF 6. Kill Cancer Cells--> SELF 7. Produce Delayed Hypersensitivity Reactions Injections of some bacteria are pursued by T-Cells. (Target of Cell-Mediated Attack) Inflammation of the skin 48-72 hours after exposure (WHY IT IS CALLED DELAYED HYPERSENSITIVITY)

Types of Tolerance (Immunological Tolerance)

1. Central Tolerance Occur in the Thymus (T-Cells) and Bone Marrow (B-Cells) "Negative Selection" against self-antigens (Removal of Autoreactive T-Cells by apoptosis) -->CLONAL DELETION 2. Peripheral Tolerance Anywhere OUTSIDE the Thymus or Bone Marrow Regulator T-Cells (Tregs) produce CLONAL ANERGY

Complement Fragment Functions (From powerpoint)

1. Chemotaxis C3a,C4a, and C5a act as a CYTOKINE (Chemokine in particular) to attract neutrophils and monocytes/macrophages to the site 2. Opsonization Phagocytes have receptors for C3b--> Forms bridges between phagocyte and victim cell. 3. C3a and C5a stimulate mast cells to secrete histamine This increases blood flow and capillary permeability, which brings in MORE phagocytes as a result. Edema can also occur from release of histamine

Two Pathways of Complement Activation

1. Classical Pathway 1. Initiated by the binding of antibodies of the IgG and IgM antibodies to antigens on the invading cell's plasma membrane. 2. Complement Protein C1 is activated--> Catalyzes the hydrolysis of C4 into 2 fragments, C4a and C4b. 3. C4b fragment binds to plasma membrane (is "fixed") and becomes an active enzyme. 4. Through intermediate step, C2 and C3 proteins are SPLIT and is cleaved into C3a and C3b. (THE TWO PATHWAYS CONVERGE AT THIS POINT WHERE C3a AND C3b ARE CLEAVED) 5. C3b converts C5 into C5a and C5b. 6. C3a and C5a stimulate MAST CELLS to release HISTAMINE. They also serve as powerful CHEMOKINES to attract macrophages, neutrophils, monocytes, and eosinophils to the site of infection. 7. Meanwhile, C5b and C6-C9 are inserted into the bacterial cell membrane to form a MEMBRANE ATTACK COMPLEX (MAC)--> Is a large pore that can kill the bacterial cell through OSMOTIC REFLUX OF WATER. (Complement proteins DIRECTLY KILL the cell, NOT the Antibodies) More rapid and efficient than the Alternative Pathway! 2. Alternative Pathway (HE told us not to worry about studying this one as much) Initiated by the unique polysaccharides that COAT BACTERIAL CELLS

Mechanisms that stop Lymphocytes attacked Self-Antigens

1. Clonal Deletion Lymphocytes that recognize the self-antigens are DESTROYED (apoptosis) 2. Clonal Anergy Lymphocytes that recognize the self-antigens are PREVENTED from becoming ACTIVATED ^^Regulatory T-Lymphocytes (Treg) performs Clonal Anergy

Direct and Indirect Functions of Antibodies

1. Direct Antibodies directly take virus off of surface of cells, making it impossible for virus to enter cells. (Can do this with bacteria and viruses) 2. Indirect A) Complement-Mediated Killing: Activates Complement Protein, which attracts phagocytic cells to infection site to kill cell. Complement proteins can also kill cells by assembling to form a hole in the cell causing it to die. B) Phagocytosis Attract phagocytic cells by coating foreign particles.

Functions of Antibodies

1. Enhance phagocytosis by coating foreign particles (Opsonization) 2. Inactivate toxins (bacteria and viruses) 3. Activates Complement Protein Attracts neutrophils, monocytes, macrophages, and eosinophils to infection site 4. Enhance lymphocyte cytotoxic structure 5. Initiate inflammatory response in Mast Cells and Basophils

Structures and Defense Mechanisms of Innate Immunity

1. External Skin (Physical barrier to penetration by pathogens, secretions contain lysozyme (enzyme that destroys bacteria)) Digestive Tract (High acidity of stomach; kills a lot of Bacteria entering body) Respiratory Tract (Secretion of mucus; movement of mucus by cilia; alveolar macrophages) Genitourinary Tract (Acidity of urine; vaginal lactic acid) 2. Internal Phagocytic Cells (Ingest and Destroy Bacteria, cellular debris, denatured proteins, and toxins) Interferons (Inhibit replication of viruses) Complement Proteins (Promote destruction of bacteria; enhance inflammatory response) Endogenous Pyrogen (Secreted by leukocytes and other cells; produces fever) Natural Killer (NK) Cells (Destroy cells infected with viruses, tumor cells, and mismatched transplanted tissue cells) Mast Cells (Release histamine and other mediators of inflammation, and cytokines that promote adaptive immunity)

Human Antibody Classes (Immunoglobulin/Antibody Sizes)

1. IgG (Can cross PLACENTA because of small size, can be protective/harmful) Small 2. IgA (Dimer) Medium 3. IgE Small 4. IgM (Pentamer) Large 5. IgD Small

Immunological Tolerance

1. Immunological Competence (Ability to produce antibodies against non-self antigens, while tolerating self-antigens) 2. Immunological Tolerance- Continued recognition and tolerance of SELF-CELLS Requires continuous of the immune system to these self-antigens. 3. In some instances, Self-Cells are attacked by Antibodies and Autoreactive T-Cells (Cytotoxic T-Cells that attack self-antigens)

Regulatory T Lymphocytes (Treg)

1. Inhibit the activity of Cytotoxic (Killer) T-Cells and B-Cells Provide a "brake" on the Specific (Adaptive) Immune Response 2. DO NOT have a Defined Cell Marker (surface molecule) Most often seen: CD4+ and CD25 3. Help prevent Autoimmune Diseases (when antibodies attack self) and Immune Tolerance to Self-Antigens Do this by suppressing inappropriate Adaptive Immune System responses. 4. DOWNSIDE (Can enhance diseases): Too many Treg cells present can be recruited by Cancer Cells to PROTECT themselves from IMMUNOLOGICAL ATTACK

Monoclonal Antibodies Process

1. Inject antigen into mouse and then extract spleen cells (Because full of blood and EASY to extract from) 2. Fuse in Polyethylene Glycol and mix Spleen Cells with Myeloma Cells to make hybrid cells (Hybridoma) 3. Once hybrid cells have been grown, select the cells making the antibody of desired specificity. 4. Inject the antibodies into the mice with the induced tumors from the antigen injected to see if it works to remove the tumor 5. Then grow the hybrid cells in mass culture that are producing desired antibodies and then HUMANIZE them.

2 Categories of the Immune System

1. Innate (Nonspecific) Immunity 2. Adaptive (Specific) Immunity

Innate vs Adaptive Immunity

1. Innate immunity: An individual's genetically predetermined resistance to certain diseases. Resistance does not improve with repeated exposure. In all normal people. 2. Adaptive immunity: Ability of the body to react to specific microbial infection. ANTIGEN SPECIFIC. Resistance gets betters with repeated exposure.

Two ways to Categorize the Immune System

1. Innate vs. Adaptive Innate: Complement System, Phagocytosis, Degranulation Adaptive: Antibodies and lymphocytes 2. Cellular vs. Humoral (He doesn't like this one) Cellular: T Cells Humoral: Complement System, Antibodies

Adaptive Immunity (Specific)

1. Involves the ability to recognize, response to, and remember a PARTICULAR substance 2. Stimulants: A) Antigens (Two types) Large molecules that STIMULATE the immune system B) Haptens Small molecules, COMBINE with large proteins and then produce an adaptive immune response (basically turn into an antigen)

Movement of leukocytes (Ex: Neutrophils and Monocytes) from the blood to site of infection —-> Term for this= Diapedesis (Extravasation)

1. Leukocytes roll along the endothelial wall ^^Attracted by bacteria that are secreting certain chemicals, which attract and activate the white blood cells by binding to their toll-like receptors 2. Are tethered 3. Are captured and activated ^^For this to happen, require binding of particular molecules on the WHITEBLOOD CELL SURFACE to receptor molecule on SURFACE OF ENDOTHELIAL CELLS. 4. DIAPEDESIS: Then crawl to exit sites at the junctions between endothelial cells —> (Signals between the leukocytes and endothelial cells cause these sites to temporarily open, allowing Neutrophils and Monocytes to exit the vessel wall and enter into the surrounding connective tissues) Leukocytes leave through the walls of postcapillary Venules (consist only of endothelial cells and surrounding supporting cells) —-> Leukocytes can cross endothelial within several minutes, but may be held up by basement membrane (up to a half hour)

Types of Inflammation

1. Local Confined to specific area of the body. Symptoms: Redness, heat, swelling, pain, loss of function 2. Systemic Occurs in many parts of the body Same symptoms as local BUT ALSO HAS: A) Increase in neutrophils (released by bone marrow) B) Fever due to production of Pyrogens by various kinds of cells.—> Improves performance of the immune system C) Widespread increased vascular permeability due to histamines (from mast cells). Large volume of plasma enters interstitial spaces—> Leads to SHOCK

Phagocytic Cells and Their Locations

1. Neutrophils (Blood and all tissues) 2. Monocytes (Blood) 3. Tissue Macrophages (all tissues, including: spleen, lymph nodes, bone marrow) 4. Kupffer Cells (Liver) 5. Alveolar Macrophages (Lungs) 6. Microglia (Central Nervous System)

ACRONYM to Remember Complement Functions

1. Opsonization Involved: C3b, Clqrs (Antibody) 2. Inflammation A) Chemotaxis: C3a, C4a, C5a B) Anaphylatoxin: C3a, C4a, C5a 3. Lysis A) Membrane Attack Complex (MAC): C5b and C6-C9

Innate (Nonspecific) Immunity

1. Physical Barriers: Prevent entry or remove microbes. Epithelial membranes including: epidermis of the skin, and mucous membranes of gastrointestinal, reproductive, respiratory, and genitourinary tracts, cover ALL body surfaces. 2. Chemical Mediators: Promotes phagocytosis and inflammation 3. Cells: Ones involved in phagocytosis (1. Neutrophils, 2. Mononuclear Phagocyte System (Macrophages, Monocytes, and Dendritic Cells), 3. Organ-specific phagocytes in the liver, spleen, lymph nodes, lungs, and brain) and production of chemicals

Examples of Innate Immune Mechanisms

1. Physical/Mechanical Barriers A) Skin B) Respiratory Tract (Cilia, coughing and sneezing) C) GI Tract (Cilia motility and smooth muscle and vomiting) D) Urine Flow E) Tears (Contain lysozymes) 2. Chemical A) Gastric Acid (low pH kills bacteria) B) Histamine, Prostaglandins, Leukotrienes C) "Acid Mantle"- Sebum + Sweat (coating of skin) D) Mucous 3. General A) High body Temperature (Fever) B) High oxygen tension in blood C) Normal bacterial flora D) Low available iron in blood 4. Cells A) Granulocytes (inflammation) B) Monocytes/Macrophages (technically same) C) Natural Killer (NK) Cells D) NORMAL FLORA 5. Peptides/Proteins A) Complement (Inflammation) and Kinins B) Cathelicidins and Defensins (Epithelial) C) Lactoferrins D) Collectins (Lung) E) Interferons F) Lysozyme G) Cytokines/Chemokines (IL's)

Cytokines

1. Polypeptides secreted by T-Cells and other cells (Macrophages) that serve as regulators (autocrine) 2. General term is Cytokine, a more specific term is Lymphokine (when working with Lymphocytes) 3. DON'T WORRY ABOUT SPECIFIC CYTOKINES (There are a shit ton) 4. The name "Interleukin" followed by a number (IL-n) indicates a cytokine. (ex: Interleukin-1) 5. >30 Interleukins 6. Different cytokines do different things to different cells!! (very diverse)

MHC Class 1 Proteins

1. Produced by ALL Nucleated cells of the body EXCEPT Red blood cells and Platelets 2. Picks up cytoplasmic peptides (from inside of the cell) and TRANSPORTS to the cell membrane. Normally present "self" antigens, but can present foreign antigens that have entered the cell (ex: virus) --> Leads to apoptosis of the cell (if presents foreign molecule) 3. Cytotoxic (Killer) T-Cells interact with antigens Coreceptor CD8 (Located on Cytotoxic T-Cells) interacts ONLY Class-1 MHC molecules. 4. Source of antigen--> Endogenous (comes from cytoplasm of cell to the cell membrane)! 5. Once Cytotoxic (Killer) Cell is activated, and it senses that there is a foreign antigen in the cell--> It releases Perforins (Proteins that form holes in cell) and Granzymes (Enter pores and trigger Apoptosis by Osmotic Destruction)

MHC Class 2 Proteins

1. Produced only by "Professional" ANTIGEN-PRESENTING CELLS (APCs) --> 1. Dendritic Cells, 2. Macrophages, 3. B-Cells These cells take in the foreign proteins through ENDOCYTOSIS, process them, and move the foreign antigens to the surface.--> At the surface, present the antigens together with their class-2 MHC molecules to HELPER T-CELLS! 2. Activates Helper T-Cells (Promote B-Cell response) 3. Class-2 MHC appears only on cell membrane when cell is PROCESSING ANTIGENS 4. Co-receptor CD4 (On surface of Helper T Cell) interacts ONLY with the class-2 MHC molecules 5. Source of antigen: OUTSIDE CELL (Exogenous) 6. Once Antigen-Presenting Cell process the Foreign Antigen and activates the Helper-T Cell, the Helper Cells stimulate B-Cells to form Memory cells and antibody-producing Plasma Cells and also aid in the proliferation of Cytotoxic T-Cells! --> Required for Optimal Adaptive immune response!!!!

Immunoglobulins (Antibodies) (More info from powerpoint)

1. Proteins composed of amino acids and carbohydrates 2. 2 polypeptide chains A) Heavy Chain determines the class (IgA, IgB, etc..) B) Light Chain 3. Secreted by activated B-Lymphocytes (Plasma Cells--> Primary Response) 4. Bind to Antigens 5. Make up the gamma globuin component of plasma 5 Plasma Proteins: 1. Albumin 2. Alpha-1 globulin 3. Alpha-2 globulin 4. Beta globulin 5. Gamma Globulin) 6. Immunoglobulin of the G type= IgG 7. Classes (Types) of human immunoglobulins: 1. IgG 2. IgM 3. IgA 4. IgD 5. IgE

Steps in Phagocytosis

1. Recognition and adherence (binding) 2. Engulfment (ingestion) 3. Phagosome (Vacuole containing particle in cell) 4. Fusion with lysosome 5. Destruction

Characteristics of a Local Inflammation

1. Redness and Warmth Due to histamine stimulated vasodilation from mast cells 2. Swelling (Edema) Created by mast cell molecules cause endothelial cells to contract away from each other, creating gaps and allowing escape of more fluid and plasma protein (increases permeability) 3. Pus Dead neutrophils. Viscous protein rich fluid. 4. Pain Prostaglandin E2 (PGE2) released as cytokine during inflammation, lowers pain threshold. 5. Thrombosis (Clots) —> (Didn't see in book, but is on his slide, keep in mind)

Adaptive Immunity pt 2

1. Soluble Factors: Antibodies 2. Cells: Lymphocytes 3. Memory?: Yes 4. Antigen Specificity?: Yes

Innate Immunity pt 2

1. Soluble factors: Gastric acid, Lysozyme, Complement, Interferon 2. Cells: Phagocytes 3. Memory?: No 4. Antigen Specificity?: No

General Characteristics of the Immune System

1. Specificity 2. Memory 3. Mobility (Amoeboid motion of leukocytes) 4. Replicability 5. Cooperativity

Adaptive (Specific) Immunity

1. Specificity: Ability to recognize a particular substance 2. Memory: Ability to remember previous encounters with a particular substance and respond rapidly (because of antibodies)

Effects of Interferons

1. Stimulates Macrophage phagocytosis (Gamma Interferons) and inhibits cell division (viruses can't replicate) —-> Main one you need to know 2. Stimulates activity of cytotoxic (Killer) T Cells and inhibits tumor growth 3. Stimulates activity of Natural Killer Cells and inhibits maturation of adipose cells 4. Stimulates production of antibodies (Adaptive Immune System) and inhibits maturation of erythrocytes (red blood cells). Note: Upregulation of MHC (Major Histocompatibility Complex Type 1, is a diverse set of cell receptors on all cells with a nucleus, helps the body recognize its own self (autorecognition) specifically T-Cells) —> Viruses try to turn this off.

Innate Immune Mediators

1. Surface Chemicals 2. Histamine 3. Kinins 4. Interferons 5. Complement 6. Prostaglandins 7. Leukotrienes 8. Pyrogens

Effects of Aging and Stress on the Immune System

1. Susceptibility to Cancer varies greatly a) Strong Genetic Component b) Environmental Components (Increase likelihood of getting it. Ex: Coal Mines) 2. Cancer Risk INCREASES with Age a) 10,000 MUTATIONS occur PER CELL PER DAY that are fixed (thankfully) Immune System is Actively Killing Cancer Cells!! (Natural Killer Cells and Cytotoxic T-Cells (nearly identical) kill Cancer kills) b) May be due to AGING MUTATED LYMPHOCYTES 3. Thymus Functions are REDUCED in the ELDERLY Causes a decrease in CELL-MEDIATED Immune Competence 4. TUMORS grow faster in lab animals under STRESS Stress induces the release of cortisone (from adrenal cortex), which is known to SUPPRESS the Immune System.

T-Cell Recombination

1. T-Cell Receptor genes undergo the SAME KIND of GENETIC RECOMBINATION as B-Cell antibody genes Same RAG1 and RAG2 (Recombination-Activating Genes) used for both NO HYPERMUTATION, NO CLASS-SWITCHING (fixed) 2. Made up of 2 heavy chains (but 2 different genes) --> No light chains present (However are present in B-Cells)

Innate Inflammatory Response (Momany Slide)

1. Tissue injury, regardless of type, can cause inflammation 2. Response initiated by chemical mediators that produce heat, vasodilation, chemotactic attraction, increases vascular permeability (edema). Fibrinogen converted to fibrin—> Walls off infected area

Hypersensitivity Reactions (Not in book)

1. Type-1 IgE-based "allergies" immediate 2. Type-2 IgG or IgM (may involve complement) A) Autoimmune Hemolytic Anemia B) Graves' Disease C) Rheumatic Heart Disease (Rheumatic Fever caused by strep throat) D) Hashimoto's Disease 3. Type-3 Immune Complex Disease (IgG and Neutrophils) A) Systemic Lupus Erythematosus ("Lupus") B) Rheumatoid Arthritis 4. Type-4 Delayed-type T-Cell A) Multiple Sclerosis B) Coeliac Disease C) Transplant Disease

Schematic Immunoglobulin Description

1. Variable Region at the top of the Y Antigen binding region 2. Compliment Binding Region located in the middle of the Y 3. Cell-Binding Region located at the bottom of the Y Note: Fab region makes up forks of Y and the Fc region makes up the base.

Immunoglobulins (Ig) --> AKA Antibody Proteins!

Def: A collection of antibodies that bind to many different (or unspecified) antigens. Five Ig Subclasses: 1. IgG MAIN FORM of antibodies in circulation (blood and lymph) Production increased after immunization Secreted during Secondary Response 2. IgA Main antibody type in the body (grams made per day) in the Digestive Tract and Tears 3. IgM ANTIGEN RECEPTORS ON LYMPHOCYTE SURFACE prior to Immunization Secreted during Primary Response 4. IgD ANTIGEN RECEPTORS ON LYMPHOCYTE SURFACE prior to immunization 5. IgE Responsible for allergic symptoms in immediate hypersensitivity reactions

Antibody

Def: refers to a specific immunoglobulin that binds to a specific antigen. Released by B-Lymphocytes (B-Cells) Structure: 2 antigen-binding sites per antibody molecule (Y) ! Consist of 4 interconnected polypeptide chains. 1. 2 long, heavy chains (H-Chains) 2. 2 shorter, lighter chains (L-Chains) Arranged in the form of a Y (Heavy chains make up the base, light chains are bonded at each fork of the Y) ! Bottom of antibody is called the "Crystallizable Fragment" (Fc) Top of antibody is called the "Antigen-binding Fragment" (Fab) Constant amino acid sequences abbreviated "C" Variable amino acid sequences abbreviated "V" --> Antigens bind to the V region!!!

Histamine

Amine released from mast cells, basophils, and platelets; Causes: 1. Vasodilation 2. Increases vascular permeability 3. Stimulates gland secretions (mucous and tears) 4. Smooth muscles contraction or airway passages (bronchioles in lungs) 5. Attracts eosinophils

Isotope Response varies Over Time and With Repetition

Analyzing the Graph (X-Axis: # of Antibodies made, Y-Axis: # of Days passed) 1. First Exposure occurs at day 0 2. After a week, some IgM antibodies have been produced (Secreted during Primary Response) Creation of Memory and Some Plasma B-Cells (Release antibodies) 3. Second Exposure occurs at day 28 4. Memory B-Cells proliferate into Plasma B-Cells (which release a large amount of antibodies) (SECONDARY RESPONSE) --> IgG antibodies are better able to provide a response, shoot up in less time because of Memory Cells --> (Long-Lived, so they are able to produce a response upon Second Exposure)

Noncytotoxic Innate Helper Lymphoid Cells

Equivalent to Helper-T Cells of the Adaptive Immune System!! Lack the T-Cell Receptors for antigens characteristic of T-Cells, but produce lymphokines such as IL-5, IL-6, and others that contribute to to immunity and allergy. Prominent in the intestine and other mucosal barriers.

Fc and Fab regions of Antibody

Fc regions are constant (the same in all people) Fab regions are variable, because they are the binding site where antigens bind to to the antibody receptor on the B-Cell. They are specific to that antigen.

T-Cell Receptor

Antigen receptors on a T cell. Unlike antibodies, T cell receptors are never produced in a secreted form. Structure: Note: Think of this as an antibody (Fab) that is tethered to the T-Cell and consists of 2 heavy chains instead of a light and heavy chain in B-Cells!! (NO light chains) From top to bottom: (Cell Exterior) 1. Antigen-Binding Site 2. Variable 3. Constant Region

Common Autoimmune Diseases

Antigens are attacked and damaged by the immune system (antibodies produced by B-Cells and T-Cells) 1. Rheumatoid Arthritis Antigen: IgG (Antibody is made to antibody, really bad) 2. Type-1 Diabetes Antigen: Beta-Cells in Pancreatic Islets (produce insulin) 3. Multiple Sclerosis Antigen: Components of Myelin Sheaths (Cells attack myelin sheath) 4. Graves' Disease Antigen: Receptor proteins for TSH (Thyroid-Stimulating Hormone) (Thyroid overproduces hormone) 5. Pernicious Anemia 6. Hashimoto's Disease Antigen: Thyroglobulin (Thyroid LOSES function) 7. Psoriasis 8. Lupus Antigen: DNA, Nucleoprotein, RNA, etc. (Anti-nuclear antibodies made) 9. Postvaccinal and Postinfectious Encephalomyelitis Antigen: Myelin, cross-reactive 10. Aspermatogenesis Antigen: Sperm 11. Sympathetic Ophthalmia Antigen: Uvea 12. Autoimmune Hemolytic Disease Antigen: I, RH, and others on surface of Red Blood Cells 13. Thrombocytopenic Purpura: Antigen: Hapten-platelet or hapten-absorbed antigen complex 14. Myasthenia Gravis: Antigen: Acetycholine Receptors (Can't work muscles) 15. Rheumatic Fever: Antigen: Streptococcal, cross-reactive with heart valves (Caused by Strep throat, can cause heart damage) 16. Glomerulonephritis Antigen: Streptococcal, cross-reactive with Kidney (Caused by strep throat, can cause kidney damage)

DAMPs (danger-associated molecular patterns)

Apart of the Innate immune system Include a variety of molecules (nucleic acids and certain proteins included) Occurs when tissue damage causes necrosis in the ABSENCE OF INFECTION—> In this case the immune system is exposed to DAMPs! —> Stimulates the innate immune system and local inflammation. Note: When cells die via apoptosis (good cell death), they do not express DAMPs, so no inflammation occurs. NECROSIS= Bad cell death

Instances when Self-Cells are attacked

Attacked by Antibodies and Auto-Reactive T-Cells Occurs when: 1. If Mutations occur in Lymphocytes (Usually good and adds to what the body can defend against) 2. If cells in particular organs are never exposed to the immune system (Ex(s): Lens protein in the eye and Thryoglobulin in the thyroid gland) Lymphocytes that attack self-antigens are called AUTO-REACTIVE

Stem Cells

unspecialized cells (hematapoietic cells) in bone marrow that retain the ability to become a wide variety of specialized cells Lymphocytes produced through these are located in: 1. Thymus 2. Spleen 3. Lymph Nodes Self-replacing lymphocyte colonies are in these organs!

Prostaglandins

Group of lipids (PGEs—> Prostaglandin E, PGFs—> Prostaglandin F, Thromboxanes, and Prostacyclins) Cause: 1. Smooth muscle relaxation and vasodilation 2. Increase vascular permeability 3. Stimulate pain receptors

Leukotrienes

Group of lipids, produced primarily by mast cells and basophils Cause: 1. Prolonged smooth muscle contraction (especially in bronchioles of lungs) 2. Increase vascular permeability 3. Attract neutrophils and eosinophils

Complement

Group of plasma proteins that: become activated when antibodies bond to their molecular targets (antigens), a local inflammation also occurs!: 1. Increase vascular permeability 2. Stimulate release of histamine 3. Activate Kinins 4. Late cells 5. Promote phagocytosis 6. Attract neutrophils, monocytes, macrophages, and eosinophils (these are all white blood cells)

The Complement System

Immune destruction of bacteria is promoted by antibody-induced activation of a system of serum (liquid part of blood) proteins known as complement. ANTIBODIES serve to identify the targets for immunological attack (They don't kill, they just mark the pathogen) 1. NONSPECIFIC defense system that is activated by the bonding of antibodies to antigens 2. 9 Complement Proteins: (C1-C9). 3. Three Components of Function: 1. Recognition (C1) 2. Activation (C4,C2, and C3 IN THAT ORDER) 3. Attack (C5-C9) --> Complement proteins attach to the plasma membrane and destroy the victim cell (form a hole in the cell: COMPLEMENT FIXATION)

Function of Each Complement Protein in the Classical Pathway

In Order: 1. C1 Catalyzes the hydrolysis of C4 into 2 fragments (C4a and C4b) 2. C4b Binds to the plasma membrane (is "fixed") and becomes an active enzyme. 3. C3 Convertase C3--> C3b and C3a 4. C3a, C4a and C5a Stimulate mast cells (ONLY C3a and C5a) to release histamine and are also powerful chemokines, which attract macrophages, neutrophils, monocytes, and eosinophils to site of infection. --> (Chemotactic Factors and Anaphylatoxins (Complement Peptides))--> CHEMOKINES (C3a, C4a, and C5a) Note: As a result of histamine release, helps bring in more phagocytic cells to combat the infection, and also results in edema (swelling). 5. C3b FACILITATES OPSONIZATION. --> Phagocytic Cells have a receptor for C3b. (Opsonin)

Secondary Lymphoid Organs

Include: 1. Lymph Nodes (450) 2. Spleen 3. Tonsils 4. Peyer's Patches These organs are located across epithelial membranes in areas where antigens can enter the blood or the lymph into them. Capture and concentrate pathogens, present them to macrophages and other cells, and serve as sites where circulating lymphocytes can come into contact with the foreign antigens. (They will destroy them)

Vaccination

Injection of pathogens that have been "Deactivated" (the viral aspect doses not work) . Cause the development of lymphocyte clones that can combat the viral pathogens by producing secondary responses. (Are much faster than primary response, essentially make people immune to the pathogen) Multiple doses are given to gradually increase lymphocyte clones that will produce antibodies against the specific antigen. --> 2 doses is usually given (Ex: COVID shot is given as first shot and a booster, they are technically the same shot, they just increase the amount of lymphocytes that will produce antibodies against the COVID Antigen)

Antigens

Large molecules that stimulate the immune system (production of antibodies and T-Cells) Ability of body to recognize antigens depends on how large the molecule is AND how complex it is —> (Why plastics in artificial implants are not antigenic, they are simple) Contain antigenic determinant sites (EPITOPES). —> stimulate production of and combine with different antibodies Two Types: 1. Foreign Not produced by body, come from the outside Consist of: Bacteria, Viruses, and other microorganisms that cause disease Also: Pollen, animal dander, feces of mites, food, drugs, overreaction of immune system (allergic reaction) 2. Self Antigens Produced by the body Response to self antigens resulting in tissue destruction—-> AUTOIMMUNE DISEASES

Germinal Centers

Located in Secondary Lymphoid Organs (Spleen and lymph nodes etc..) --> Following exposure to antigens Develops from a B-Cell that has been stimulated by an antigen and activated by Helper T-Cells. Where B-Cells undergo very rapid cell division to become the founder of clone (Clonal Selection).

Memory T Cells

Long-Lived Most abundant lymphocytes in an adult. Upon re-exposure to specific antigens, memory cytotoxic t-cells (for example) quickly acquire the ability to kill infected cells (through perforins and granzymes) Located in the circulation and in various lymphoid organs, and their numbers increase through childhood to middleage. --> Decrease after age 70!!

Surface Chemicals

Lysozymes (in tears, saliva, nasal secretions, and sweat) lyse cells; acid secretions (sebum in the skin and hydrochloric acid in the stomach) prevent microbial growth or kill microorganisms; mucus on the mucous membranes traps microorganisms until they can be destroyed.

Migration of Antigen-Presenting Cells (Dendritic, Macrophages, B-Cells) to Secondary Lymphoid Organs (Lymph Nodes, Spleen, Tonsils, Peyer's Patches) Activates T-Cells

Note: In order for T-Cells to respond to foreign antigens, the antigens MUST be presented to the T-Cells on the membrane of Antigen-Presenting Cells--> T-Cells CANNOT bind to FREE ANTIGENS Steps: 1. Antigen-Presenting Cell processes (attaches to antigen) 2. Antigen-Presenting Cell activates the T-Cell by allowing it to bind to the Antigen. 3. Activated T-Cell then produces a CLONE--> Some of these cells then migrate from the lymphoid organ into the blood. 4. Once in the blood, the activated T-Cells go to the site of infection because of CHEMOTAXIS (Chemokines produced during the inflammation)--> bind to endothelial cell and enter connective tissue via diapedesis (Extravasation)

Complement System

Part of Innate Immune System. Helps integrate innate and adaptive immune responses. Consists of proteins in plasma and other body fluids that becomes activated when antibodies (part of adaptive immune system) bond to their molecular targets (antigens).—> Complement proteins then promote phagocytosis, lysis (destruction) of the targeted cells, and other aspects of a local inflammation.

Kinins

Polypeptides derived from plasma proteins Cause: 1. Vasodilation 2. Increase vascular permeability 3. Stimulate pain receptors 4. Attract neutrophils

B Lymphocytes (B-Cells)

Produced in the Bone marrow Combat bacterial and viral infections by secreting antibodies into the blood and lymph. Body fluids (Blood and Lymph)= Humors Provide Humoral Immunity

Interferons

Proteins, produced my MOST CELLS Interfere with virus production and infection

Interferons (more detail)

Purpose: Produce nonspecific, short-acting resistance to viral infection When nucleic acids from bacteria and viruses enter the host cell cytoplasmic, a protein called STING (Stimulator of Interferon Genes) is produced. STING then stimulates production of interferons and proinflammatory cytokines required for innate immunity. 3 types: 1. Alpha and Beta Interferons Produced by almost all cells in body in response to microbial infections. Act as messengers that protect other cells in the vicinity from viral infection (prevents virus from spreading). Virus can still penetrate cells, but the ability of the viruses to replicate and assemble new virus particles is inhibited. 2. Gamma Interferon Stimulates genes involved in many functions of the immune cells. ^^These include phagocytosis and the production of Chemokines and anti microbial molecules that help combat infections and cancer. Secreted by innate lymphoid cells (Including Natural Killer Cells) in the early stages of infection and then in greater amounts by the Helper and Cytotoxic T Lymphocytes of the adaptive immune system.

Fevers

Regulated by preoptic area of hypothalamus. Prostaglandin PGE2 is paracrine regulator. Pyrogens are chemicals that provokes PGE2 to produce a fever. —> Include: 1. Exogenous —> Lipopolysaccharides from bacteria (ENDOTOXIN) and 2. Endogenous Pyrogens—> Interleukin-1 (IL-1), IL-6, and Tumor Necrosis Factor Produced by body's response to infection, NOT by bacteria Mild fever is beneficial, because it aids recovery from bacterial infections and BOOSTS immune response! (increased activity of neutrophils and increased production of interferons—>so virus doesn't spread)

Fixation of Complement Proteins

Steps according to picture in book: 1. Formation of an antibody-antigen complex on the bacterial membrane causes--> 2. Complement C4 to be spit (by C1) into --> 3. 2 subunits: C4a and C4b--> The C4b is fixed to the membrane of the cell to be destroyed (along with the bacterial cell)--> This event triggers the activation of other complement proteins, some of which attach to the C4b on the membrane surface.--> The C4a is involved in chemotaxis!! 4. C5b and C6-C9 are inserted into bacterial cell membrane--> Forms a Membrane Attack Complex (MAC)--> Creates a large pore in the cell membrane, which causes osmotic influx of H2O, killing the bacterial cell.

Monoclonal Antibodies

Steps: 1. Animals are injected with an antigen 2. Mix of B-Lymphocytes (Cells) that makes the desired antibodies are extracted from the animal 3. B-Lymphocytes (Cells) are fused with a cancerous myeloma cell in vitro (outside of the body) --> Myeloma Cell is IMMORTAL---> Makes a hybrid cell 4. The Hybridoma produces many clones that produce antibodies specific for the antigen 5. A SINGLE CLONE is identified by screening (dilution) that makes the desired antibodies NET RESULT: Immortal B-Cell that makes antibodies!!

Movement of Lymphocytes (Increase chance to come into contact with antigen)

Steps: 1. Lymphocytes move from the primary lymphoid organs (Bone marrow and Thymus) to the blood. 2. Exit the blood through specialized post-capillary venules in lymph nodes to travel in the lymph from lymphoid organ to lymphoid organ. 3. Antigen-Presenting Cells (Dendritic Cells) migrate from lymph node to lymph node, increasing the likelihood of an encounter with the lymphocyte specific for that antigen. Note: This ceaseless travel through the lymph from organ to organ increases the likelihood that a given lymphocyte for a particular antigen will be able to encounter that antigen!

Opsonin

Substance (ex: Antibody) that makes an antigen more susceptible to phagocytosis

Immunity

The ability of an organism to resist damage from foreign particles such as microorganisms and harmful chemicals

Innate Immunity: PAMPs and PRRs

The innate immune system distinguishes between the body's own tissue cells and invading pathogens by recognizing molecules termed as "Pathogen-Associated Molecular Patterns (PAMPs)" that are unique to invaders. —> Found on bacteria, fungi, Protozoa, virus-ish PAMPs= Located on bacteria (pattern) PRRs= Located on humans (receptor) Best known PAMP: 1. Lipopolysaccharide (LPS)—> Gram-Negative bacteria and 2. Peptidoglycan—> Gram-Positive bacteria. 3. dsRNA (double stranded RNA virus) and 4. DNA Some cells of the innate immune system have receptor proteins called "Pathogen Recognition Receptors (PRRs)" that recognize PAMPs—>Inherited through germ cells (sperm and egg) Important PRRs: 1. Toll-Like Receptors (10 different in body, specific for a different type of molecule that is characteristic of invading pathogens and not human cells) 2. NOD-Like Receptors (Located in cytoplasm, needed to recognize intracellular molecules derived from certain bacteria)

Chemotaxis (Phagocytosis)

Tissues have a population of resident macrophages that can replenish themselves and through activation of their Toll-Like Receptors, secrete pro-inflammatory cytokines—> some of these attract resident neutrophils and monocytes within connective tissues, which are recruited to site of infection by CHEMOTAXIS PROCESS (Movement toward chemical attractants called Chemokines) phagocytes (Ex: Neutrophils and Monocytes) recruited by chemical attractants (Chemokines—> subclass of cytokines) (products of microorganisms, phospholipids from injured host cells, chemokines, C5a)

Antibody Diversity (Genetic Recombination in the absence of Antigens)

Two mechanisms explain antibody diversity: (Genetic Recombination occurs in both of them!) 1. Antigen-Independent Genetic Recombination Occurs in the bone marrow Has different combinations of heavy (H) and light (L) chains (make up antibodies), that produce different antibodies with different specificities. Few hundred genes code for different H-Chains and a few hundred for different L-Chains, different combinations of these could produce millions of different antibodies! VDJC RECOMBINATION: Different segments of DNA that code for the antigen-combining regions of the heavy and light chains. -->Can be combined in different ways to produce many different antibodies. (1. V-Variable, 2. D-Diversity, 3. J-Joining Antibody Regions). C-Stem Cell DNA 2. Antigen-Dependent Cell Division of Lymphocytes Occurs in Secondary Lymphoid Organs B-Cells proliferate (mitosis) in the germinal centers of secondary lymphoid organs (Ex: Spleen and Lymph Nodes) in response to antigens. SOMATIC HYPERMUTATION is a high rate of mutations of single-base pairs in DNA. It is literally a HIGH RATE OF MUTATIONS and results in lymphocytes (B-Cells) that produce antibodies with greater affinities for specific antigens. Gene Recombination referred to as CLASS SWITCH RECOMBINATION occurs within germinal centers. There is a switch in the constant regions (Fc) of the antibodies---> Results in original IgM antibodies (Antigen receptors on B-Cell surface) are converted into IgG, IgA, or IgE antibodies!

Natural Killer Cells

Type of Innate Lymphoid Cells (ILC) that does not have receptors for specific antigens on their surface and do not respond in a specific way to antigens. Part of Innate Immune response because they have NO ANTIGEN-SPECIFIC RECEPTORS!!--> The Cytotoxic T-Cells of the Innate immune system. Respond quickly to signals from infected or injured tissues as part of the INNATE Immune Response. Analogous to Cytotoxic T-Cells of the Adaptive Immune System, but lack the receptors . Instead, they INHERIT receptors that allow them to target CANCER CELLS and cells infected with intracellular pathogens (Ex: Viruses). Also have receptors that interact with Class-1 MHC Molecules on the person's own cells (all nucleated cells), giving them Immunological Tolerance to the person's self-antigens and preventing Autoimmune Attack!

VDJC Recombination

VDJC RECOMBINATION: Different segments of DNA that code for the antigen-combining regions of the heavy and light chains. -->Can be combined in different ways to produce many different antibodies. (1. V-Variable, 2. D-Diversity, 3. J-Joining Antibody Regions). C-Stem Cell DNA RANDOM PICK of (V,D,J,C) that makes an antibody that MIGHT WORK (Happens by chance). --> If it doesn't work, start over and try again! IF B-Cell makes antibody that is harmful to self, they are automatically KILLED by NEGATIVE CLONAL SELECTION---> Known as Central Tolerance (ability of cells in bone marrow to kill off cells that recognize self)

Haptens

antigens too small to provoke immune responses; attach to larger proteins, which allows them to become an antigen and provoke an immune response

Epitopes (Antigenic Determinant Sites)

certain regions of an antigen molecule that stimulate immune responses. The area (Receptor if you will) where antibodies bind onto the antigen Most antigens stimulate production of many different antibodies with specificities for these sites (Have multiple epitopes)

NOD-Like Receptors

cytoplasmic receptors for recognition of pathogens Once binded, the NOD-Like receptors then form inflammasomes (multimolecular protein complexes that activate the enzyme CASPASE and production of certain cytokines)—> Leads to cell death of infected cells in order to stop infection.

Toll-Like Receptors

each recognize a specific "danger" molecule (pathogen) AND are embedded in cellular membranes. Upon binding of toll-like receptor, cells (dendritic cells and macrophages) secrete 1. Chemokines (cell attractant molecules) which recruit other cells of the immune system, and 2. cytokines (Cell growth and regulatory molecules), which promote responses of both the innate system (phagocytosis and a fever) and the adaptive immune system ( B and T Lymphocytes)

Innate-Inflammatory Response

when the pathogen (microbial infection) break through the skin. Innate system becomes activated by its toll-like pathogen recognition receptors. Macrophages and Mast Cells (ones already there) which are resident in the tissue, are activated by binding of their Pathogen Recognition Receptors (PAMPs) of invading bacteria. They then release cytokines and Chemokines that attract phagocytic neutrophils and promote innate immune responses of phagocytosis and complement activation Activated complement further increases the innate (nonspecific) responses during an inflammation by attracting new phagocytes and mast cells to the area. Mast cells (Degranulate) —> release histamine, which causes vasodilation in blood vessels. Also release chemicals that cause endothelial cells to contract away from each other, creating gaps that allow the escape of more fluid and plasma proteins into Extracellular space (creates EDEMA). Also allows increased Diapedesis of leukocytes into the inflamed area. Mast cells also release tumor necrosis factor (acts as Chemokine) to recruit neutrophils to infected site. Leukocytes roll toward the particular chemicals (Chemokines) where infection is (Movement is called Chemotaxis). Neutrophils (First Responders) come first and take 2-5 minutes to cross endothelial and another 5-15 minutes to cross basement membrane. Then Monocytes (Change into macrophages) and T-Cells follow. Neutrophils kill pathogens via phagocytosis. They also release NETs (Neutrophil Extracellular Traps), which immobilize bacteria to help kill them. Pus is formed through action of proteases (protein digesting enzymes). It is made of dead neutrophils and is a viscous, protein-rich fluid. Can be beneficial because produces pressure that closes lymphatic and blood capillaries, blocking spread of bacteria away from battle site. Macrophages ingest pathogens and fragments of Extracellular matrix by phagocytosis. Also release NO (Nitric Oxide) which helps to kill bacteria. Also remove dead neutrophils via phagocytosis from infection site. They then release growth factors that help end inflammation and promote repair. After some time, B-Lymphocytes produce antibodies against specific antigens (Adaptive Immune System) that are part of invading bacteria. Binding of antibodies greatly increases the previously nonspecific response. This (along with complements) promotes phagocytic activity of neutrophils, macrophages, and monocytes. These effects produce characteristics of local inflammation—> 1. Redness, 2. Warmth (Histamine-Stimulated Vasodilation causes heat to leave), 3. Swelling (Edema caused by mast cells causing endothelial cells to pull apart, releasing fluid), 4. Pus (Dead Neutrophils) and 5. Pain (Prostaglandin E2 released as a cytokine during inflammation lowers pain threshold) Note: IF infection continues, release of endogenous pyrogen from leukocytes and macrophages may also produce a FEVER.