Concept of Immunity

Concept of Immunity

• Immunity is the capability to ward off disease, whereas susceptibility is the lack of resistance.
• Pathogens like viruses, bacteria, and fungi, must be combatted for a place to live within the human body.

Lines of Defense

• First-line defenses include skin, mucous membranes, and antimicrobial substances to keep pathogens out or neutralize them before infection.
• Second-line defenses slow or contain infections if first-line defenses fail.
• Proteins that produce inflammation, fever to enhance cytokine activity, phagocytes, and natural killer (NK) cells are second-line defenses.
• Third-line defenses include lymphocytes that target specific pathogens that second-line defenses did not contain.

Innate vs. Adaptive Immunity

• Innate immunity is a defense against any pathogen, is rapid, and present at birth.
• Adaptive immunity is immunity or resistance to a specific pathogen, slower to respond, and has a memory component.

Toll-Like Receptors (TLRs) & Pathogen-Associated Molecular Patterns (PAMPs)

• A link exists between innate and adaptive immunity.
• Toll-like receptors (TLRs) on host defensive cells attach to pathogen-associated molecular patterns (PAMPs).
• PAMPs are molecular structures common to pathogens.
• LPS outer membrane of Gram-negative bacteria, peptidoglycan cell wall in Gram-positive bacteria, flagellin (protein) in flagella, and DNA and RNA of viruses are all molecular structures common to pathogens.

Cytokines

• TLRs bound to PAMPs induce the release of cytokines from the host defensive cells of the innate system.
• Cytokines are small cell signaling proteins that regulate the intensity and duration of immune responses.
• In the innate immune system, cytokines recruit defensive cells to isolate and destroy microbes as part of an inflammatory response.
• In the adaptive immune system, cytokines activate cells involved in adaptive immunity.

Skin - First Line of Defense

• The skin and mucous membranes are physical factors that act as the first line of defense.
• The epidermis is the outer portion of the skin, made of tightly packed epithelial cells containing keratin, a protective protein.
• Dermis is the inner portion made of connective tissue.
• Shedding and dryness of the skin inhibits microbial growth.

Mucous Membranes - First Line of Defense

• Mucous membranes are an epithelial layer that lines the gastrointestinal, respiratory, and genitourinary tracts.
• Mucus is viscous glycoproteins that trap microbes and prevent tracts from drying out.
• The ciliary escalator transports microbes trapped in mucus away from the lungs and propels them upwards towards the throat.

Physical Factors - First Line of Defense

• The lacrimal apparatus drains tears and washes the eye.
• Saliva dilutes and washes microbes from teeth and mouth.
• Peristalsis (food moving along GI tract), defecation, vomiting, and diarrhea expel microbes from the body.
• Earwax prevents microbes from entering the ear.
• Urine cleans the urethra via flow.
• Vaginal secretions move microorganisms out of the vaginal tract.

Chemical Factors - First Line of Defense

• Sebum forms a protective film and lowers the pH (3-5) of the skin.
• A low pH environment inhibits or destroys microbes.
• Saliva has a pH of 6.55-6.85.
• Urine has a pH of 6.
• Vaginal secretions and earwax each have a pH of 3-5.
• Gastric juice has a pH of 1.2-3.0.
• Lysozyme, found in perspiration, tears, saliva, and urine, destroys bacterial cell walls.

Normal Microbiota - First Line of Defense

• Normal microbiota compete with pathogens via microbial antagonism.
• Competitive advantage for space and nutrients, produce substances harmful to pathogens, and also alter conditions that affect pathogen survival.
• Probiotics are live microbial cultures administered to exert a beneficial effect.
• Probiotics produce lactic acid and bacteriocins (toxic peptides) that inhibit pathogen growth.

Formed Elements in Blood - Second Line of Defense

• Blood plasma is the fluid portion.
• Erythrocytes (red blood cells), leukocytes (white blood cells), and platelets are all formed elements.
• They are created in red bone marrow stem cells by hematopoiesis.
• Hematopoiesis is the creation of cellular components of blood.
• All blood cells arise from stem cells.

Leukocytes (White Blood Cells)

• Leukocytes are divided by appearance under a light microscope.
• Granulocytes have visible granules in the cytoplasm.
• Agranulocytes do not have granules that are visible via light microscopy.

Granulocytes

• Neutrophils are phagocytic and work in early stages of infection.
• Neutrophils are able to leave the blood and enter infected tissue.
• Basophils release histamine to mediate inflammation and allergic responses.
• Eosinophils are phagocytic, toxic against parasites and helminths, and can leave the blood.

Agranulocytes

• Monocytes leave the blood, enter body tissues, and mature into macrophages (which become phagocytic).
• Dendritic cells are found in the skin, mucous membranes, and thymus and are phagocytic to initiate an adaptive response.
• Lymphocytes include T cells, B cells, and NK cells and play a role in adaptive immunity.

Measuring Leukocytes in the Blood

• Differential white blood cell (WBC) counts measure leukocytes.
• Results are given as a percentage per 100 counted cells.
• High WBC counts (leukocytosis) may indicate bacterial infections, autoimmune diseases, or side effects of medications.
• Low WBC counts (leukopenia) may indicate viral infections, pneumonia, autoimmune diseases, or cancers.

Defenses in the Blood

• Basophils release histamines.
• Eosinophils kill parasites with oxidative burst.
• Mast cells are antigen-presenting cells and produce antibacterial peptides.
• Neutrophils phagocytize bacteria and fungi.
• Monocytes are the precursor to macrophages, some are fixed in place, other move through the tissues, causing inflammation.
• Dendritic cells phagocytize bacteria in the skin, respiratory, and intestinal mucosa and present antigens to T cells.
• Natural killer (NK) cells kill cancer cells and virus-infected cells.
• Plasma cells (B cells) recognize antigens and produce antibodies.
• T cells secrete cytokines; there are T helper (TH) cells, cytotoxic T lymphocytes (CTL), and T regulatory (Treg) cells.

Lymphatic System

• Lymph is the fluid in the lymphatic system.
• Lymphatic vessels are vessels that are similar to the circulatory system.
• Lymphoid tissues are the structures and organs such as the thymus and lymph nodes.
• Red bone marrow is material used in hematopoiesis.

Lymphatic System Overview

• Interstitial fluid flows into lymphatic capillaries.
• Fluid (now called lymph) flows in one direction and enters larger lymphatic vessels.
• Lymph flows through lymph nodes at intervals along the system.
• Nodes contain fibers to trap microbes, and defense cells kill them by phagocytosis.
• Lymph eventually passes through lymphatic ducts and enters the bloodstream, at which point it is now blood plasma.
• Blood plasma moves through the cardiovascular system and eventually becomes interstitial fluid again.
• This cycle repeats continuously.

Lymphatic Tissues

• Lymphatic tissues are scattered throughout mucous membranes that line GI, respiratory, urinary, and reproductive tracts.
• Specific organs and aggregations of lymphoid tissues include the spleen, thymus, tonsils, and Peyer's patches (in small intestine).

Phagocytes - Second Line of Defense

• Phagocytosis is the ingestion of microbes or other substances by a cell.
• Phagocytosis is performed by phagocytes.
• The process begins when granulocytes (mostly neutrophils) and monocytes move to the infected area.
• Neutrophils dominate the initial response.
• Monocytes mature into macrophages.
• Fixed macrophages are residents in tissues and organs.
• Free (wandering) macrophages roam tissues and gather at sites of infection.
• As infection progresses, macrophages become the predominant cell type.

Mechanism of Phagocytosis

• Chemotaxis: chemical signals attract phagocytes to microorganisms.
• Adherence: attachment of phagocyte to microbe surface (TLRs and PAMPs).
• Opsonization:enhanced by opsonization in which microbial antigens are marked with serum proteins (i.e. antibodies).
• Ingestion: pseudopods (plasma membrane extensions) engulf the microbe.
• Pseudopods fuse and form a phagosome.
• Phagosome pinches off the membrane and enters the cytoplasm.
• Digestion: phagosome fuses with a lysosome (contains digestive enzymes and bactericidal substances), forming a phagolysosome.
• A phagolysosome then digests the microorganism.
• Phagolysosome releases indigestible material outside the cell.

Inflammation

• Inflammation is a local defensive response triggered by injury to body tissue.
• Signs and symptoms of inflammation are pain, redness, immobility, swelling, and heat.
• Inflammation functions to destroy the injurious agent, limit side-effects or repair tissue damage.

Types Of Inflammation.

• Acute inflammation involves rapid development of signs and symptoms that last days to weeks.
• May be linked to Mild and self-limiting response, primarily involving neutrophils.
• Examples of acute inflammation are appendicitis, cold, flu, sore throat, minor cuts/scratches.
• Chronic inflammation causes more severe symptoms that develop more gradually months or even years.
• More severe and progressive, primarily involving monocytes and macrophages, and may be linked to peptic ulcers, tuberculosis, rheumatoid arthritis,

General Features Of Inflammation

• Acute inflammation begins when TLRs on phagocytes (neutrophils and macrophages) recognize PAMPs and release cytokines.
• The liver responds to cytokines in blood and activates acute-phase proteins.

Stages In The Inflammatory Process

• Vasodilation, in which there is vasodilation and increased permeability of blood vessels.
• Phagocyte migration and phagocytosis.
• Tissue repair.

Vasodilation

• Vasodilation and increased permeability of blood vessels occurs immediately following tissue damage.
• Vasodilation is the dilation of blood vessels, causing redness (erythema) and heat.
• Permeability is the state in which defensive substances can leave blood vessels and enter an injured area, causing fluid accumulation (edema).
• Inflammation is caused by vasoactive mediators (chemicals that promote inflammation).
• Vasodilation and increased permeability is intensified through histamine.
• Kinins is done through chemotaxis, attracting neutrophils
• Prostaglandins help phagocytes move through c. walls
• Leukotrienes increases permeability of blood vessels and help attach phagocytes to pathogens.
• Complement stimulates the release of histamine, attracts phagocytes, and promotes phagocytosis.
• Interferons cause vasodilation and increased permeability of blood vessels.
• After chemical release, blood clots form, which prevents the spread of microbes or toxins.
• An abscess forms, creating a cavity caused by the breakdown of tissue, and contains pus, a mixture of dead cells and body fluids.

Phagocyte Migration/Phagocytosis

• Margination occurs as blood flow decreases, and phagocytes (neutrophils and monocytes) stick to the inner surface of the blood vessel.
• During diapedesis, phagocytes sqeeze between endothelial cells of the blood vessels
• Phagocytosis of microbes occurs.

Tissue Repair

• Tissue repair begins during active inflammation but cannot be completed until all harmful substances are removed or neutralized.
• Either stroma or parenchyma produce new cells.
• Parenchyma is the function part, while stroma is the supporting part.
• Repair involving only parenchymal cells = near perfect repair.
• Repair involving stromal cells = scar tissue.
• Chronic inflammation leads to cytokines released by macrophages which cause stromal cells to synthesize connective tissue.
• Fibrosis occurs as accumulation of connective tissue which gives rise to scar tissue.

Fever

• Fever is defined as an abnormally high body temperature.
• It is a systemic response to infection and triggered by bacterial or viral agents.
• Released cytokines cause the hypothalamus ( body's thermostat) to reset to a higher temperature.
• High temp is maintained until cytokines are eliminated.
• Its defensives is to a certain point, increasing the production and efficiency of antimicrobial molecules.
• Complications include dehydration, rapid heart rate, and electrolyte imbalances.
• Death occurs above 44-46oC (112-114oF)

Antimicrobial Substances - The Complement System

• A group of >30 proteins produced by the liver that circulate in blood serum and body tissues aiding/enhancing immune systems destroy microbes.
• Activated fragments are indicated with lowercase a and b (i.e. C3a).

Complement Activation

• Proteins act in a cascade, and reaction will trigger another.
• Three activation pathways result in activation of C3.
• Classical pathway, initiated when antibodies bind antigens.
• Alternative pathway, is activated by contact between complement proteins and microbes.
• Lectin pathway, is when lectin binds carbohydrates on microbe surface; Lectin is a protein that bind to carbohydrates

Complement Activation - Outcomes

• Cytolysis, opsonization, and inflammation.

Cytolysis

• Activated complement proteins create a membrane attack complex (MAC).
• MAC creates a hole in the plasma membrane, leading to fluid inflow that bursts the cell.
• Is more effective against Gram negative bacteria.

Opsonization

• Complement proteins bind microbes.
• Promotes attachment of phagocytes to microbes.

Inflammation

• Activated complement proteins bind to mast cells, releasing histamine.
• The presence of histamine makes blood vessels become more permeable.

Regulatory and evasive actions

• Regulatory proteins break down complement proteins, minimizing host cell destruction.
• Lack of complement proteins causes susceptibility to infections.
• Capsules prevent complement activation.

Antimicrobial Substances - Interferons (IFNs)

• A class of cytokines with antibacterial and antiviral activity, having great variation between types.
• There are three primary types of human IFNs.
  • IFN-α and IFN-β is and produced by cells in response to viral infections
• IFN-α and IFN-β cause neighboring cells to produce proteins that inhibit viral replication.
• IFN-γ causes neutrophils and macrophages to kill bacteria.

Antimicrobial Substances - Iron-Binding Proteins

• Iron is essential for survival of humans and pathogens.
• The concentration of free iron in body is low, which is due to competition between pathogens and human cells.

Antimicrobial Substances - Iron-Binding

• Human iron-binding proteins include:
• Transferrin: found in blood and tissue fluids.
• Lactoferrin: found in milk, saliva, and mucus
• Ferritin: found in the liver, spleen, and red bone marrow
• Hemoglobin: located in red blood cells
• Bacteria produce siderophores to compete with iron-binding proteins.

Antimicrobial Substances - Antimicrobial Peptides

• Short peptides produced in response to protein and sugar molecules on microbes.
• Possess a broad spectrum of activity.
• Works against bacteria, viruses, fungi, and eukaryotic parasites
• Inhibits cell wall synthesis.
• Forms pores in the plasma membrane.
• Destroys DNA and RNA.
• Other benefits include working alongside other antimicrobial agents to provide synergies