11. Basics of Immunity: Specific vs. Non-Specific

Basics of Immunity

• Immunity defends the organism against infection or unwanted biological invasions.
• The outer environment, like bacteria, viruses, fungi, protozoa, and cells of another organism, is protected by the immune system.
• The inner environment such as old, damaged, or even cancer cells, is protected by immunity.

Specific vs Non-Specific Immunity

• Non-specific immunity is innate
• Non-specific immunity does not need previous exposure to the foreign substance to work
• Specific immunity is acquired or adaptive
• Specific immunity depends on previous exposure to a foreign substance or antigen

General Features of Immunity

• The immune system can distinguish its own structure from foreign ones.
• Non-specific immunity uses phagocytic cells and NK, or natural killer, cells
• Non-specific immunity uses complement interferons and lysozymes for humoral response.
• Specific immunity uses T-lymphocytes for cell-mediated response.
• Specific immunity uses antibodies for a humoral response

Cells of the Immune System

• Immune system cells include phagocytes, lymphocytes, and helpers.
• Neutrophils, eosinophils, monocytes-macrophages perform phagocytosis functions.
• Natural killers, T cells, and B cells perform lymphocyte functions
• Basophils, mast cells, and dendritic cells perform helper functions
• These cells produce interferons, complement, cytokines, antibodies, and inflammatory mediators

Lines of Defence

• The first line of defense is the non-specific immunity.
• The second line of defense is non-specific immunity.
• The third line of defense is specific immunity.

Non-Specific Immunity

• Exists in all multicellular organisms.
• Response is quick and stereotyped.
• Response has no ability of immunological memory.
• Effective against molecular structures of microorganisms.
• Unique to pathogens like teichoic acids in Gram+ bacteria.
• Includes numerous barriers.
• Protects the body against many types of pathogens without recognition

First Line of Defence

• Mechanical mechanisms of protection include skin, which must be intact, and desquamation.
• Desquamation is a mechanical barrier that includes acidic protective film from sweat and sebum.
• Mucous membranes protect the surface of the GIT, respiratory, and urogenital tracts.
• Tight junctions rapidly exchange cells.
• The mechanical cleaning include cilia and mucus.
• There is also a release of antimicrobial substances such as cytokines and chemokines.

Physical Mechanisms of Defence

• Physical mechanisms help expel pathogens passing the initial barriers.
• Expelling pathogens can include longitudinal flow of air in the airways and fluid in the urinary tracts.
• Expelling pathogens also includes coughing, sneezing, vomiting and diarrhea

Mechanisms of Protection

• Chemical mechanisms include bacteriostatic substances.
• Chemical mechanisms include hydrochloric acid, lysozyme, and mucus.
• Chemical defense produced includes tears, saliva, sweat, and stomach juice.
• Biological barriers are normal flora within the body.
• Biological barriers compete with pathogens for attachment sites and sources.
• Biological barriers include the skin, mouth, throat, nasopharynx, GI tract, and vagina.

Second Line of Defence

• Protective proteins like complement and interferons.
• Cells like phagocytes and helper cells.
• Defensive processes like phagocytosis
• Defensive processes also include inflammation and fever.

Protective Proteins: Complement System

• A major part of the innate immunity.
• The complement system plays a central role in the inflammatory process.
• It includes more than 50 proteins.
• It includes a cascade of soluble proteins and membrane expressed receptors and regulators.
• Operates in plasma, tissues, on a cell surface, even within the cell.
• Exists as inactive forms that are activated in the presence of bacteria.
• Participates in pathogen opsonization, tagging it for engulfment by antigen presenting cells (APCs).
• Modulates the activity of T and B-cells.
• This induces Opsonisation and phagocytosis.
• Induces Cytolysis of pathogens and activation of mast cells and basophils.
• It also does Neutralization of viruses and Chemotaxis.
• Induces Inflammation.
• The cascade takes part in nearly every step of the immune reaction.

Protective Proteins: Interferons

• Belongs to cytokines
• The proteins have antiviral, antiproliferative, and immunomodulating effects.
• Produced by cells as a defensive response to viruses.
• Induce an antiviral state in cells that prevents virus replication.
• Plays a role in antitumor and immunomodulatory responses.
• Therapeutically used for viral infections, cancers, and autoimmune diseases.

Cells of the Non-Specific Immunity

• These Include phagocytes such are neutrophils, eosinophils, monocytes-macrophages.
• Natural killer cells also defend the body.
• The released products also defend the body such as interferons, complements, cytokines, antibodies and inflammatory mediators.

Neutrophils

• The most numerous of the white blood cells, at 60-70%.
• Has a multilobed nucleus and a rapid turnover rate.
• There are granules with microbicidal peptide, lysozymes, and proteolytic enzymes.
• Migration to infected area is done by chemotaxis.
• Chemotaxins include protein fragments released after complement activation.
• Also includes products of other leucocytes and platelets and some products of certain bacteria.

Neutrophil Recruitment

• First, signs of inflammation are recognized via chemotaxis.
• Second, migration to the areas of inflammation.
• Next, capture by stimulated endothelial cells by exposing selectins.
• After, selectin-mediated rolling along chemoattractant gradients.
• This is followed by integrin-mediated firm adhesion.
• Finish by traversing through the endothelium

Neutrophils Functions

• Neutrophils perform phagocytosis.
• Neutrophils degranulation by use of chemotaxins to communicate with other immune cells.
• Degranulation also works by granular antimicrobial molecules
• Degranulation uses vasodilators and ROS.
• Formation of neutrophil extracellular traps (NETs) is used.

Phagocytosis

• The ability of cells to absorb, kill, and decompose a foreign particle or damaged or dead cell.
• Professional phagocytes include neutrophils, monocytes aka macrophages, and dendritic cells
• A phagocyte recognizes PAMP, a pathogen-associated molecular pattern, through its surface receptors.

Neutrophils Phagocytosis

• Attachment- PRRs recognize and bind to PAMPs.
• PRRs are receptors on the surface of Neu.
• PAMPs are pathogen-associated molecular patterns on the surface of the pathogen
• Internalization of the microbe into a phagosome.
• Fusion of the phagosome with a lysosome to produce a phagolysosome.
• Pathogen killing occurs by ROS or lysosomal enzymes.
• At the end of inflammation, apoptosis comes to activated neutrophils.

Neutrophils - NETs Formation

• Extrusion of a meshwork of chromatin fibers associated with granule-derived antimicrobial peptides and enzymes is performed.
• The enzymes include neutrophil elastase, cathepsin G, and myeloperoxidase.
• This will immobilize and kill invading microorganisms.

Inflammation

• The process is aimed at increasing the number of immune cells at the site of infection.
• Include increased blood supply to the infected area.
• Includes increased capillary permeability (immune cells and substances with large molecules can pass).
• Also includes coagulation of interstitial fluid proteins in the tissue spaces.
• Immune cells migrate to the site of infection.
• Alerts the immune system and promotes neutrophil recruitment.
• Microbes trigger the production of proinflammatory lipid mediators like leukotrienes and prostaglandins by resident macrophages.
• The signs of inflammation are heat, swelling, redness, and pain.

Inflammation Progression

• Production of anti-inflammatory lipid mediators.
• Block neutrophil and promote monocyte recruitment.
• Monocytes differentiate into macrophages to ingest apoptotic neutrophils.
• Production of the anti-inflammatory cytokines returns to homeostasis.
• Reduction of neutrophil infiltration.

Neutrophil Communication

• Interacts with a variety of cell types.
• Aids the Recruitment of monocytes and dendritic cells (DCs) to infected tissues.
• Enhances macrophage and DC activity.
• Secretes IL-12, that activates T cells.
• Acts as antigen-presenting cells by presenting antigen to cytotoxic T cells.

Mast Cells

• Multifunctional immune cells.
• Originate in hematopoietic bone marrow progenitor cells.
• They are at places where pathogens may enter, like the skin, lungs, stomach, and intestines.
• They recognize pathogens and release mediators such as histamine, heparin, serotonin, and prostaglandins.
• Involved in immune reactions against parasites.
• Involved in all steps of tissue repair and continuous growth and remodeling.
• Involved in allergic reactions.

Natural Killers (NK)

• A subpopulation of lymphocytes making up 15%.
• A component of the innate immune system.
• Recognizes cells that have an abnormally small amount of MHC on their surface, commonly cancerous cells.
• Analagous to cytotoxic T cells, this causes apoptosis of infected cells.
• They have no antigen-specific receptors.
• Kills cells that have been infected by certain viruses and cancer cells.
• Acting at around 3 days after infection.

Other Physiological Factors

• Affecting non-specific immunity.
• Body temperature of 37°C is unsuitable for the growth of many pathogens
• Oxygen in tissues creates an unsuitable environment for anaerobes.
• Age affects changes in the number and function of immune cells.
• Hormonal changes during various times of life can affect the immune system.
• Short-term stress stimulates immune processes and vice versa.

Specific Immunity

• The organism can quickly identify a pathogen.
• The organism can prepare a specific response to only that invader.
• It can remember it for most of life, thanks to immunologic memory.
• Response slower but better targeted and strong.
• Only in fish, amphibians, reptiles, birds and mammals
• Lymphocytes play a crucial role and include B-cells mature in the bone marrow or fetal liver for humoral-mediated response.
• T-cells mature in the thymus for cell-mediated response.

Specific Response to Antigen

• Antigen is a molecule or proteins/polysaccharides that induce a specific immune response by reacting with specific receptors on T and B cells.
• The molecule can be on the surface of a foreign cell, cancer or transplanted cell.
• Antigens can also be a toxins produced by a pathogen
• First, Phagocytosis of an antigen is performed by the antigen-presenting cell APC.
• Next, the APC processes the antigen and presents it on its cellular surface.
• Then, the presented antigen is recognized through binding a specific T-cell population.
• Then clonal expansion begins with antibody-mediated and cell-mediated responses.

Antigen Presenting Cells (APC)

• Macrophages (monocytes), B-lymphocytes, dendritic cells (DC).
• Detects foreign particles.
• Phagocytes the particle, then partially degrades it by proteolytic enzymes within phagolysosome.
• Presents the antigenic peptide is present on its surface bound to MHC molecule.
• Stimulates Th-lymphocytes.

Dendritic Cells

• Antigen-presenting cells.
• Originate in hematopoietic bone marrow progenitor cells.
• The immature forms are found in blood and the mature forms in the skin, lungs, stomach, and intestines.
• Messengers between the innate and the adaptive immune systems.
• They process antigen material and present it on the cell surface.
• Can activate a specific immune response or induce immunological tolerance.
• Responsible for activation of T-lymphocytes.

Macrophages

• Macrophages are transformed and developed Monocytes.
• They exist in all tissues and organs.
• Some subpopulations of macrophages are Kupffer's cells, histiocytes, alveolar macrophages, microglia and osteoclasts. Functions are phagocytosis
• Perform antigen presentation .
• Play a role in tissue repair by production of pro-inflammatory mediators.
• There is some production of the anti-inflammatory cytokine IL-10 in the population of macrophages.

Lymphocyte Activation

• Due to binding of antigen to receptor - antigen recognition.
• Through cell division occurs clonal expansion.
• Creates a Clone and progeny of one lymphocyte
• Cells produced include effector lymphocytes and memory cells.
• Autotolerance - ability to tolerate the organisms own tissue.

Effect of Activated Lymphocytes

• Activated effector lymphocytes are used to attack against all antigen of the kind that initiate stimulation.
• There is antibody production by B-lymphocytes.
• There is direct attack to cells bearing the antigen by cytotoxic T cells.
• Apoptosis of activated cells creates a homeostatic response.
• Memory cells persist.

Characteristics of Specific Immunity

• Specificity, which is the ability to recognize and eliminate particular microorganisms and foreign molecules with antigenic characteristic
• Diversity which is the ability to respond to millions of kinds of invaders, each recognized by its antigenic markers by a unique antibody producing lymphocyte.
• Selftolerance(self/non-self recognition ) - any lymphocytes with receptors for molecules present in the body (self) are destroyed.
• There are no antigen receptors for an organism's own molecules.
• Memory is the ability to remember antigens it has encountered and to react quickly and effectively against them a second time around.

Humoral Immunity

• Named because it involves substances found in the body fluids, aka humor
• Its an antibody-mediated system involving B-lymphocytes
• There are other macromolecules also found in extracellular fluids, such as complement proteins and certain antimicrobial peptides.

B-Lymphocytes

• Are produced and developed in bone marrow.
• Make up about 25% of circulated lymphocytes.
• Are Genetically programmed to encode a surface receptor specific for a particular antigen.
• When activated by contact with the antigen, they multiply and differentiate into plasma and memory cells.
• Plasma cells can produce large amounts of antibody specific against the antigen.
• Memory cells can preserve the immunological memory for a particular antigen for later restimulation and confer lasting immunity.

Antibody Production

• Primary response occurs with initial contact with an antigen.
• Antigen bids to a receptor on a specific B lymphocyte, activating it.
• B lymphocytes with non-complementary receptors remain inactive.
• Proliferation occurs to form a clone to activate plasma cells and memory cells.
• Secondary response occurs with repeated contact with the same antigen.
• Antigen binds to a receptor on a memory B cell.
• Clones of cells identical to ancestral cells are made.

Primary vs Secondary Immune Response

• Secondary exposure to antigen X, and first exposure to antigen Y causes the secondary immune response to antigen X.
• First exposure to antigen X causes the primary immune response to antigen X.

Immunoglobulins

• Antibodies are immunoglobulins (Ig).
• Immunoglobulins are proteins - gamma globulins.
• Produced by plasma cells in response to stimulation by a specific antigen.
• Can bind to the antigen that stimulated their production.
• Have at least two identical antigen-binding sites.

Mechanisms of action of antibodies

• Direct attack on the invader by way of agglutination and precipitation.
• Agglutination involves multiple large particles with antigen on their surface are bound together.
• Precipitation means the molecular complex of soluble antigen and antibody becomes so large it becomes insoluble.
• Neutralization which means antibodies cover the toxic sites of the antigenic agent.
• Then indirect lysis occurs, and the, Ig attacks membrane of cellular agents.
• The immunocomplex binds via Fc-receptor to phagocytes or NK bb to rupture the pathogen.
• Activation of the complement system forms MAC (membrane attack complex) to cause pathogen cell lysis.
• It also induces phagocytosis, inflammation and cell lysis

Antibody Classes

• IgG antibodies are a monomer and the most prevalent in the serum.
• IgG provides naturally acquired passive immunity and neutralizes bacterial toxins.
• IgG participates in complement fixation and enhances phagocytosis.
• IgG can cross the placental barrier.
• IgM is the first secreted antibody after B-cell activation and indicates a new infection.
• IgM is secreted as a pentamer and involved in agglutination and complement fixation.
• IgA antibodies can be serum IgA a monomer that is a secretory dimer.
• IgA protects mucosal surfaces.
• IgA a neutralizing antibody, does not activate the complement system.
• IgA is major antibody in milk
• IgD is a monomer involved in the maturation of B-cells to plasma cells that exists in serum in small amounts and unknown function.
• IgE is monomer that binds to mast cells and basophils and is involved in allergic reactions and reactions against parasites.

Humoral Immunity: Active

• Own antibodies are made via natural exposure to infectious agents.
• Own antibodies also made by artificial immunization.

Humoral Immunity: Passive

• Ready made antibodies occur via natural maternal antibodies.
• Ready made antibodies also occur via artificial transfer of antibodies from other sources.

Cell-Mediated Immunity

• Involves the activation of phagocytes and antigen-specific cytotoxic T-lymphocytes.
• It also involves the release of various cytokines in response to an antigen.

Mechanisms of Cellular Immunity

• T cells can be activated performing apoptosis on body cells that display epitopes of foreign antigen on their surface.
• Macrophages and natural killer cells are involved in the destruction of pathogens.
• There is secretion of a variety of cytokines influence the function of other cells involved in adaptive immune responses and innate immune responses.

T-Lymphocytes

• Found in the blood, lymph nodes and spleen.
• In the blood, T-lymphocytes make up about 70% of peripheral lymphocytes. -There are millions of different T cell populations, each expressing a TCR that differs in its variable domain.
• A single T cell will express thousands of identical copies of one specific TCR variant on its cell surface.
• TCR diversity is achieved by the mutation and recombination of genes that encode these receptors in stem cell precursors of T cells
• T-cells recognize/combines with the complex of a specific antigen bound to MHC T helper are cells is one form of T- Lymphocyte
• T cytotoxic cells is another form of T-Lymphocyte
• T regulatory cells is another form of T-Lymphocyte

T-Helper Cells

• Master regulators and the Most numerous mature T-cells at about 70%.
• Recognize peptides presented on MHC molecules, which are found on APCs
• B-cells and cytotoxic T-cells could not function adequately without stimulation by cytokines from T-helper cells

T-Cytotoxic Cells

• CTLs are called attack cells.
• They are 30% of T-cells.
• It must enter the blood and seek out the target.
• Directed against cancerous or cells infected by intracellular pathogen; virus, bacteria, parasite
• Bind to MHC molecules which are on all cells.

T-Regulatory Cells

• Tregs - formerly called suppressor T-cells.
• Regulates or suppress the functions of T-helpers and T-cytotoxic.
• Produce immunosuppressive cytokines
• Prevention of excessive immune reactions
• Plays a Role in limiting the ability of the immune system to attack a persons own tissues which ensures immune tolerance.

Immune Tolerance

• Self-tolerance or autotolerance prevents harmful reactivity against the organism's own tissue.
• The immune system generates a vast diversity of antigen specific receptors, some of which are self-reactive, that may be in need for elimination.
• T-cell deletion occurs mainly in the thymus and allows for deletion of all T-cells recognizing intrathymic self-antigens
• B-cell Deletion occurs in bone marrow.
• Also helps differentiate B-cells expressing immunoglobulin receptors with high binding affinity to self membrane bound antigens which are deleted.