Immunity: Specific and Nonspecific

• Immunity defends organisms against infection or unwanted biological invasions.
• It counters threats from both the outer e.g., bacteria, viruses, fungi, protozoa, and other organisms' cells and inner environment e.g., old, damaged, or cancerous cells.

Nonspecific Immunity

• Also known as innate immunity.
• It does not depend on prior exposure to a foreign substance.

Specific Immunity

• Also referred to as acquired or adaptive immunity.
• It relies on previous exposure to a foreign substance called an antigen.

Immune System Functions

• The immune system identifies its own structures from foreign ones.
• It is also cell-mediated and humoral.
• Cell-mediated nonspecific immunity includes phagocytic cells and NK cells.
• Humoral nonspecific immunity consists of complement, interferons, and lysozymes.
• Specific immunity cell-mediated consists of T-lymphocytes.
• Specific immunity humoral consists of antibodies.

Cells of the immune system

• This includes phagocytes (neutrophils, eosinophils, monocytes-macrophages), lymphocytes (natural killers, T lymphocytes, B lymphocytes), and helpers (basophils, mast cells, and dendritic cells).

Immune System Lines of Defense

• The first line of defense is nonspecific immunity, featuring physical, mechanical, and chemical barriers.
• The second line of defense is also nonspecific immunity, which uses NK cells and phagocytosis.
• The third line of defense is specific immunity, using cell-mediated and humoral responses, all leading to homeostasis.

Nonspecific Immunity Details

• It exists in all multicellular organisms.
• Response features include being quick and stereotyped without immunological memory.
• It is directed against the molecular structures found in many microorganisms, essential for microbial survival, or unique to pathogens like teichoic acids in Gram+ bacteria.
• Includes different barriers protecting the body from many pathogens without needing to recognize them.
• The first line of defense is the outermost layer, and the second line of defense activates if pathogens pass the first line.

First Line of Defense: Mechanical Protection

• The skin provides a mechanical barrier and desquamation and an acidic protective film (sweat, sebum).
• Mucous membranes cover the GIT, respiratory, and urogenital tracts, featuring cells connected by tight junctions, mechanical cleaning via cilia and mucus, and antimicrobial substances like cytokines and chemokines.

First Line of Defense: Physical Protection

• Expels pathogens passing initial barriers such as longitudinal airflow in airways, fluid in urinary tracts, coughing, sneezing, vomiting, and diarrhea.

First Line of Defense: Mechanisms of Protection

• Chemical protection involves bacteriostatic substances e.g., HCl, lysozyme, and mucus.
• Biological barriers are normal within the body, competing with pathogens for attachment sites and sources.
• Example areas with biological barriers occur on the skin, mouth, throat, nasopharynx, GI tract, and vagina.

Second Line of Defense

• Protective proteins include complement and interferons.
• Cells include phagocytes and helper cells.
• Defensive processes include phagocytosis, inflammation, and fever, increasing phagocyte action and decreasing certain pathogens' viability.

Protective Proteins: Complement System

• A major part of the innate immunity that plays a important role in inflammation.
• Is composed of over 50 soluble proteins and membrane-expressed receptors and regulators that all operate in plasma, tissues, on cell surfaces, and within cells.
• Inactive forms activate in blood circulation when bacteria are present.
• It participates in pathogen opsonization, tagging pathogens for engulfment by antigen-presenting cells (APCs), and modulates T- and B-cell activity.
• An activated complement cascade induces opsonization, phagocytosis, cytolysis, mast cell and basophil activation, neutralization of viruses, chemotaxis, and inflammation.

Protective Proteins: Interferons

• These belong to the cytokines family.
• They cause antiviral, antiproliferative, and immunomodulating effects.
• Produced by the body as a defensive response to viruses.
• Induce the antiviral state in cells by preventing virus replication.
• They provide a role in antitumor and immunomodulatory responses.
• It is used therapeutically for treating viral infections, cancers, and autoimmune diseases e.g., multiple sclerosis.

Cells of Nonspecific Immunity

• Phagocytes (neutrophils, eosinophils, monocytes-macrophages), natural killer cells, basophils, mast cells and dendritic cells.

Neutrophils

• Most numerous white blood cells, constituting 60-70% of WBCs.
• Have a multilobed nucleus with rapid turnover.
• Contain granules with microbicidal peptides, lysozymes, and proteolytic enzymes.
• Migrate to infected areas by chemotaxis.
• Chemotaxins include protein fragments that release after complement activation, products of other leucocytes and platelets, and products of certain bacteria.

Neutrophil Recruitment

• Neutrophils recognize inflammation signs (chemotaxins), migrate to affected areas, capture by stimulated endothelial cells exposing selectins, and roll along chemoattractant gradients.
• Process requires integrin-mediated firm adhesion to traverse through the endothelium.

Neutrophil Functions

• It includes phagocytosis in a professional manner, degranulation via chemotaxis releases antimicrobial molecules and vasodilators, and formation of neutrophil extracellular traps (NETs).

Phagocytosis

• Cells have the ability to absorb, kill, and decompose a foreign particle whether it be a pathogenic microorganism or own damaged or dead cell.
• Professional phagocytes include neutrophils, monocytes (macrophages), and dendritic cells.
• Phagocytes recognize PAMPs through surface receptors.

Neutrophil Phagocytosis Phases

• Attachment occurs when PRRs recognize and bind to PAMPs on receptors located on the surface of the cell.
• Next, the microbe internalizes into a phagosome, fuses with a lysosome to become a phagolysosome, and ultimately kills the pathogen by ROS or lysosomal enzymes.
• At the end of the inflammatory process, activated neutrophils undergo apoptosis.

Neutrophils: NETs Formation

• NET's extrude a meshwork of chromatin fibers combined with granule-derived antimicrobial peptides and enzymes.
• NET's help immobilize and kill invading microorganisms.

Inflammation

• A set of processes increase the number of immune cells at an infection site.
• Involves increased blood supply to the infected area, increased capillary permeability, coagulation of interstitial fluid proteins in the tissue spaces, and immune cells migration.
• Alerts the immune system, promoting neutrophil recruitment.
• In the early stages of inflammation, microbes trigger the production of proinflammatory lipid mediators like leukotrienes and prostaglandins via resident macrophages.
• Signs include heat, swelling, redness, and pain.
• During the progression of inflammation, the production of anti-inflammatory lipid mediators block neutrophil and promote monocyte recruitment.
• Monocytes become ingest apoptotic neutrophils, which drives the production of the anti-inflammatory cytokines.
• Ultimately leading to reduced neutrophil infiltration and return to tissue homeostasis.

Neutrophil Communication With Other Immune Cells

• Neutrophils interact with a variety of cell types and recruit monocytes and dendritic cells to infected tissues.
• It enhances macrophage and dendritic cell activity, secretes IL-12 to activate T cells, and acts as antigen-presenting cells by presenting antigen to cytotoxic T cells.

Mast Cells

• Mast cells are multifunctional immune cells originating from hematopoietic bone marrow progenitor cells.
• They localize in potential pathogen entry sites e.g., skin, lungs, stomach, intestines.
• They have various functions, they recognize pathogens, releasing mediators, involving immune reactions to parasites and tissue repair, and involving allergic reactions.

Natural Killers (NK)

• They represent a subpopulation of lymphocytes (15%) and are a component of the innate immune system.
• Recognize cells with abnormally small amounts of MHC on their surface, which is typical for cancer cells.
• Role is similar to that of cytotoxic T cells, which cause apoptosis of infected cells.
• They have no antigen-specific receptors and act at around 3 days after infection.
• Kill cells infected by viruses and cancer cells.

Other Physiological Factors Affecting Nonspecific Immunity

• Body temperature of 37°C unsuitable for the growth of many pathogens.
• Oxygen tensions unsuitable for anaerobes.
• Age changes the number and function of immune cells.
• Hormonal changes and stress; short-term stress stimulates immune processes and vice versa.

Specific Immunity Details

• The ability of organisms to quickly identify a pathogen, prepare a response specific to that invader, and remember it for most of life for immunologic memory.
• Responses are slower yet better targeted and are strong.
• It is present only in fish, amphibians, reptiles, birds, and mammals.
• Lymphocytes play a important role, including B-cells that mature in the bone marrow or fetal liver for humoral-mediated responses and T-cells that mature in the thymus gland for cell-mediated responses.

Specific Immune Response to Antigens

• Lymphocytes identifies pathogens by antigens or immunogens.
• Antigens are molecules (proteins or polysaccharides) that induce a specific immune response against themselves by reacting with specific receptors on T and B cells.
• Antigens can be molecules on the surface of a foreign cell, cancer cell, transplanted cell, or a toxin produced by a pathogen.
• The process involves phagocytosis by antigen-presenting cells (APCs), APCs process the antigen and present it on its surface to be recognized through binding a specific T-cell population, and clonal expansion results in antibody-mediated mass production of antibodies and cell-mediated response via cytokine activation of T-cells.

Antigen-Presenting Cells (APC)

• APCs: Macrophages (monocytes), B-lymphocytes, dendritic cells.
• They detect foreign particles and will partially degrade it by proteolytic enzymes within phagolysosomes.
• Subsequently, an antigenic peptide presents on its surface bound to MHC molecule, which stimulates Th-lymphocytes.

Dendritic Cells (DCs)

• DCs serve as antigen-presenting cells.
• They originate from hematopoietic bone marrow progenitor cells.
• DCs are found in the blood immature and mature in the skin, lungs, stomach, and intestines.
• They are messengers between the innate and adaptive immune systems, process antigen material and present it on the cell surface, and can activate a specific immune response or induce immunological tolerance and activation of T-lymphocytes.

Macrophages

• Transformed or developed monocytes and exist in all tissues and organs.
• Subpopulations include Kupffer's cells, histiocytes, alveolar macrophages, microglia, and osteoclasts.
• Functions: phagocytosis, antigen presentation, role in tissue repair, production of pro-inflammatory mediators, and production of the anti-inflammatory cytokine IL-10.

Lymphocyte Activation

• This occurs due to antigen binding to a receptor, prompting antigen recognition and cell division, known as clonal expansion.
• A clone represents the progeny of a single lymphocyte that produces effector and memory cells.
• Autotolerance describes cells ability to tolerate its own tissue.

Effect of Activated Lymphocytes

• Activated effector lymphocytes attack the antigens that initiated stimulation.
• This results in antibody production from B-lymphocytes and direct attack on cells bearing the antigen by cytotoxic T cells.
• Activated cells also undergo apoptosis.
• While the rest undergo homeostatic responses that persist the memory cells.

Characteristics of Specific Immunity

• Includes an ability to recognize and eliminate particular microorganisms, respond to millions of kinds of invaders each recognized by its antigenic markers by a unique antibody producing lymphocyte and to remember antigens it has encountered to react quickly and effectively.
• Self-tolerance refers to destroyed lymphocytes recognizing molecules present in the body itself.

Humoral Immunity Details

• Humoral refers to substances found in the body fluids and in the antibody-mediated system.
• B-lymphocytes and macromolecules in extracellular fluids e.g., complement proteins and antimicrobial peptides are also involved.

B-Lymphocytes

• Produce and develop in bone marrow, making about 25% of circulated lymphocytes.
• Genetically programmed to encode a surface receptor specific for a particular antigen.
• Activation occurs from contact with antigens and will multiply and differentiate into plasma cells that produce large amounts of antibodies specific against the antigen and memory cells.
• Memory cells preserve immunological memory for antigens, restimulating if the antigen is encountered again and give long-term immunity.

Antibody Production

• Primary response occurs on contact with an antigen which involves, antigen binding to a receptor on a specific B lymphocyte activation.
• In this activation B lymphocytes with non-complementary receptors remain inactive, causing proliferation to form a clone and the production of plasma cells and memory cells.
• Secondary response occurs on repeated contact with the same antigen years later, the antigen binds to a receptor on a memory B cell.
• Which forms a clone of cells identical to ancestral cells.

Immunoglobulins

• Antibodies are immunoglobulins and proteins or gamma globulins.
• They are produced by plasma cells responding to a specific antigen stimulating able to bind the antigen stimulating.
• All immunoglobulins have at least two identical antigen binding sites.

Mechanisms of Action of Antibodies

• Antibodies can directly attack the invader, which involves agglutination via multiple large particles with antigen that are bound together.
• It involves precipitation which forms a molecular complex of soluble antigen turns insoluble.
• Also, neutralization occurs when antibodies cover the toxic sites of the antigenic agent (IgA) or indirectly lysis through rupturing of pathogens.
• Or, activation the complement system becomes more effective, forming MAC and causing pathogen cell lysis.
• It all leads to phagocytosis, inflammation and cell lysis.

Antibody Classes

• IgG which exist as a monomer is present in serum, give naturally acquired passive immunity, neutralize bacterial toxins, participate in complement fixation and increase phagocytosis.
• IgG's also cross the placental barrier.
• IgM represents the first antibody secreted after B-cell activation, indicating a new infection.
• IgM's are secreted as pentamers and are involved in agglutination as well as complement fixation.
• IgA are found in serum as a monomer and secretory are found as a dimer, protect mucosal surfaces, neutralize the antigen; however, this does neutralize, do not activate complement.
• IgA's exist as the major antibodies found within milk.
• IgD which exist as a monomer, involve in B-cell maturation to plasma cells, exist in the serum in small amounts, and the function in serum is currently unknown.
• IgE exist as a monomer and binds to mast cells and basophils.
• IgE's involved in allergic reactions and reactions against parasites.

Humoral Immunity Types

• Active (own antibodies) are natural when you have exposure to an infectious agent.
• An artificial active source of own antibodies is from immunization.
• Passive (ready-made antibodies) can occur naturally through maternal antibodies.
• Passively and artificially you can become immune from a transfer of antibodies from other sources.

Cell-Mediated Immunity

• Cell-mediated involves the activation of phagocytes and antigen-specific cytotoxic T-lymphocytes.
• Also, the release of various cytokines responds to an antigen.

Mechanisms of Cellular Immunity

• T cells activating causes apoptosis of body cells displaying epitopes of foreign antigen on their surface e.g., virus-infected cells, cells with intracellular bacteria, cancer cells.
• Macrophages and NK cells activating destroys pathogens.
• Secretion of a variety of cytokines influence other cells involved in adaptive and innate immune responses.

T-Lymphocytes

• The t-lymphocytes are found in the blood, lymph nodes and spleen, making of 70 percent of peripheral lymphocites.
• Made out of millions of different T cell populations, each expressing a TCR that differs in its variable domain.
• Each single T cell will express thousands of identical copies of one specific TCR variant on its cell surface.
• T cell combines with the complex of a specific antigen bound to MHC.
• The three types of cells that can stimulate the immune system are helper cells, cytotoxic cells, and regulatory cells.

T-Helper Cells

• Master regulators of immunity, the most numerous mature T-cells, about 70% of the T lymphocytes.
• T Helper cells could recognize peptides presented on MHC molecules found on APCs.
• B-cells and cytotoxic T-cells cannot function adequately without stimulation by cytokines from T-helper cells.

T-Cytotoxic Cells

• Also known as attack cells or CTLs.
• They account for 30% of T-cells.
• Must enter the blood to seek out targets cells and bind to MHC molecules.
• Provide response to cancerous or cells infected by intracellular pathogen (virus, bacteria, parasite).

T-Regulatory Cells

• Also known as Tregs or suppressor T-cells.
• Regulate or suppress T-helpers and T- cytotoxic cells.
• Produce immunosuppressive cytokines and gives role in limiting the ability of the immune system to attacks their own tissues.

Immune Tolerance

• Refers to self-tolerance or autotolerance.
• It prevents harmful reactivity against the body's own tissue.
• The immune system randomly generates vast diversity of antigen-specific receptors, and will some of them self-reactive, they are then eliminated.
• There are T-cell and B-cell deletion steps.
• T-cell deletion mainly in the thymus, causes the deletion of all T-cells recognizing intrathymic self antigens.
• B-cell deletion occurs in bone marrow, which differentiating B-cells expressing immunoglobulin receptors with high binding affinity to self membrane bound antigens are deleted.