Exam 3 - 9.1 -9.3

Body's Defense: Leukocytes, Macrophages, and Inflammation

• The body combats infectious agents using blood leukocytes and tissue cells derived from leukocytes.
• The body defeats infections by direct phagocytosis or by forming antibodies and sensitized lymphocytes.

Leukocytes (White Blood Cells)

• Leukocytes are mobile units of the body’s protective system.
• Neutrophils, eosinophils, basophils, monocytes, lymphocytes, and plasma cells are the six types of WBCs usually present in the blood.
• Platelets are also present and are fragments of megakaryocytes.
• Granulocytes include neutrophils, eosinophils, and basophils

Functions of Leukocytes

• Granulocytes and monocytes protect against invading organisms through phagocytosis.
• Granulocytes and monocytes protect against invading organisms though the release antimicrobial or inflammatory substances.
• Lymphocytes and plasma cells mainly function in connection with the immune system.
• Platelets activate the blood-clotting mechanism.

Concentrations of Different White Blood Cells in Blood

• An adult human has about 7000 WBCs and 5 million RBCs per microliter of blood.
• Normal percentages of WBC types:
  • Neutrophils: 62.0%
  • Eosinophils: 2.3%
  • Basophils: 0.4%
  • Monocytes: 5.3%
  • Lymphocytes: 30.0%
• The normal platelet count is 150,000 to 450,000 per microliter of blood, averaging about 300,000.

Genesis of White Blood Cells

• WBCs are formed partially in the bone marrow (granulocytes, monocytes, and some lymphocytes) and partially in the lymph tissue (lymphocytes and plasma cells).
• Myelocytic lineage forms granulocytes and monocytes.
• Lymphocytic lineage forms lymphocytes.
• Granulocytes and monocytes are formed only in the bone marrow.
• Lymphocytes and plasma cells are produced mainly in lymphogenous tissues, like lymph glands, spleen, thymus, tonsils, and lymphoid tissue in bone marrow and Peyer’s patches.
• WBCs formed in the bone marrow are stored there until needed, with about a 6-day supply stored.
• Lymphocytes are mostly stored in lymphoid tissues.
• Megakaryocytes are formed in the bone marrow and fragment to produce platelets, crucial for blood clotting.

Life Span of White Blood Cells

• Granulocytes released from bone marrow typically live 4-8 hours in circulating blood and another 4-5 days in tissues.
• In serious tissue infections, granulocytes life span can be shortened to a few hours.
• Monocytes have a short transit time of 10-20 hours in the blood before becoming tissue macrophages.
• As tissue macrophages, monocytes can live for months unless destroyed by phagocytosis.
• Lymphocytes circulate continuously through the blood and tissues, with varying life spans of weeks or months.
• Platelets in the blood are replaced about once every 10 days.

Neutrophils and Macrophages Defend Against Infections

• Neutrophils and tissue macrophages are the primary cells that attack and destroy invading harmful agents.
• Neutrophils are mature cells that can attack and destroy bacteria even in the circulating blood.
• Macrophages originate as blood monocytes that are immature in the blood.
• Once macrophages are in the tissues, they swell significantly (up to fivefold) to become highly capable.

Movement of White Blood Cells to Inflamed Areas

• Diapedesis (Extravasation) is when neutrophils and monocytes squeeze through gaps between endothelial cells of blood capillaries and postcapillary venules.
• Ameboid Motion is how neutrophils and macrophages move through tissue spaces.
• Chemotaxis attracts WBCs to inflamed tissue areas by chemical substances. 
• Chemotactic substances include bacterial toxins, degenerative products of inflamed tissues, complement complex reaction products, and plasma clotting reaction products.
• Chemotaxis is effective up to 100 micrometers.

Phagocytosis

• Phagocytosis is the cellular ingestion of an offending agent, a major function of neutrophils and macrophages.
• Phagocytes are selective.
• Surface Roughness: Rough surfaces are more likely to be phagocytized.
• Protective Coats: Natural body substances have protective protein coats that repel phagocytes, while dead tissues and foreign particles lack these coats.
• Opsonization: Antibodies adhere to bacteria, making them more susceptible to phagocytosis and involves the C3 product of the complement cascade.
• Mature neutrophils can immediately begin phagocytosis upon entering tissues.
• Single neutrophils typically phagocytize 3 to 20 bacteria before inactivation and death.
• Activated macrophages can engulf up to 100 bacteria and even larger particles like whole RBCs.
• Macrophages can also extrude residual products and survive for many more months.

Digestion of Phagocytized Particles

• A phagosome merges with lysosomes and other cytoplasmic granules, forming a digestive vesicle.
• Digestive enzymes and bactericidal agents are released.
• Both neutrophils and macrophages have lysosomes with proteolytic enzymes for digesting bacteria and foreign proteins.
• Macrophages also contain lipases to digest lipid membranes of some bacteria like tuberculosis bacillus.
• Neutrophils and macrophages can kill bacteria through oxidizing agents (superoxide, hydrogen peroxide, hydroxyl ions).
• Myeloperoxidase, a lysosomal enzyme, forms bactericidal hypochlorite from hydrogen peroxide and chloride ions.
• Some bacteria, like the tuberculosis bacillus, resist lysosomal digestion and killing effects.

Monocyte-Macrophage Cell System (Reticuloendothelial System)

• Monocytes attach to the tissues and remain there for months or years, performing local protective functions.
• They retain the ability to become mobile macrophages again when stimulated.
• It is largely synonymous with the reticuloendothelial system.
• The monocyte-macrophage system includes mobile macrophages, fixed tissue macrophages, and specialized endothelial cells in bone marrow, spleen, and lymph nodes.
• This system is crucial in areas where large quantities of particles, toxins, and unwanted substances need to be destroyed.
• Tissue Macrophages (Histiocytes) in Skin and Subcutaneous Tissues: These can divide in situ during local inflammation to combat infection.
• Macrophages in Lymph Nodes: Trap and phagocytize particulate matter, preventing dissemination throughout the body.
• Alveolar Macrophages in Lungs: Phagocytize particles trapped in the alveoli. Indigestible particles may lead to giant cell capsules.
• Macrophages (Kupffer Cells) in Liver Sinusoids: Filter bacteria from the portal blood, preventing their entry into the general circulation.
• Macrophages of Spleen and Bone Marrow: Trap and phagocytize foreign particles that succeed in entering the general circulation.

Inflammation: Role of Neutrophils and Macrophages

• Inflammation is the complex of tissue changes occurring after injury by bacteria, trauma, chemicals, or heat.
• Inflammation is characterized by:
  • Vasodilation of local blood vessels, increasing blood flow.
  • Increased capillary permeability, leading to fluid leakage into interstitial spaces.
  • Clotting of fluid in interstitial spaces due to increased fibrinogen and other proteins.
  • Migration of granulocytes and monocytes into the tissue.
  • Swelling of tissue cells.
• These reactions are caused by tissue products like histamine, bradykinin, serotonin, prostaglandins, complement system reaction products, blood clotting system reaction products, and lymphokines.
• These substances also activate the macrophage system.
• Walling-Off Effect: Inflammation helps to wall off the injured area with fibrinogen clots, delaying the spread of bacteria or toxins.
• The intensity of inflammation is proportional to the degree of tissue injury.

Macrophage and Neutrophil Responses During Inflammation

• Resident macrophages in tissues begin phagocytic action within minutes of inflammation.
• Large numbers of neutrophils invade the inflamed area within the first hour or so.
• Inflammatory cytokines trigger the expression of adhesion molecules on endothelial cells, loosening of intercellular attachments between endothelial cells, and chemotaxis of neutrophils toward the injured tissues.
• The entire process of leukocyte movement from blood to tissues is called extravasation.
• Blood neutrophils, being mature cells, immediately begin their scavenger functions.
• Acute severe inflammation can cause a rapid increase in the number of blood neutrophils (neutrophilia), from a normal of 4,000-5,000/µl to 15,000-25,000/µl.
• This is due to inflammatory products mobilizing stored neutrophils from the bone marrow into circulation.
• Monocytes from the blood also enter inflamed tissue and become macrophages.
• Monocytes require 8 or more hours to mature into fully functional macrophages.
• After several days to weeks, macrophages dominate due to increased bone marrow production.
• Macrophages are more effective phagocytes, capable of ingesting more bacteria and larger particles, and they also initiate antibody development.
• The bone marrow increases production of granulocytes and monocytes due to stimulation of progenitor cells by factors from the inflamed tissue.
• This takes 3-4 days for new cells to leave the marrow.
• If the stimulus persists, production can increase 20-50 times normal for months or years.

Feedback Control of Macrophage and Neutrophil Responses

• The macrophage response to inflammation is controlled by tumor necrosis factor (TNF), interleukin-1 (IL-1), granulocyte-monocyte colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF), and monocyte colony-stimulating factor (M-CSF.
• The colony-stimulating factors mainly drive increased production of granulocytes and monocytes by the bone marrow.
• This combination of factors creates a powerful feedback mechanism to resolve inflammation.

Formation of Pus

• Pus is a mixture found in cavities of inflamed tissues, containing necrotic tissue, dead neutrophils, dead macrophages, and tissue fluid.
• It forms after neutrophils and macrophages engulf large numbers of bacteria and necrotic tissue and subsequently die.
• After infection suppression, the pus undergoes autolysis, and the products are absorbed.

Eosinophils

• Eosinophils constitute about 2% of blood leukocytes.
• Eosinophils are weak phagocytes and exhibit chemotaxis but are likely not significant in typical infections compared to neutrophils.
• In parasitic infections, eosinophils are produced in large numbers and migrate to tissues.
• Eosinophils attach to parasites and release substances that kill them.
• In allergic reactions, eosinophils collect in tissues due to eosinophil chemotactic factor.
• Eosinophils are believed to detoxify inflammation-inducing substances from mast cells and basophils.
• Eosinophils may phagocytize allergen-antibody complexes, limiting the inflammatory process.

Basophils

• Basophils in the circulating blood are similar to tissue mast cells located near capillaries.
• Both release heparin and histamine, as well as smaller amounts of bradykinin and serotonin.
• Mast cells and basophils play a significant role in some allergic reactions because immunoglobulin E (IgE) antibodies have a strong tendency to attach to them.
• Reaction of the specific antigen with the IgE on mast cells or basophils causes the release of histamine, bradykinin, serotonin, heparin, slow-reacting substance of anaphylaxis (leukotrienes), and lysosomal enzymes, mediating many allergic manifestations.

Leukopenia

• Leukopenia is a clinical condition where the bone marrow produces very few WBCs, leaving the body unprotected against invading bacteria and other agents.
• A decrease in WBCs allows resident bacteria to invade adjacent tissues.
• Within 2 days of halted WBC production, ulcers in the mouth and colon or severe respiratory infections can develop, leading to rapid bacterial invasion of tissues and blood.
• Without treatment, death can occur within a week.
• Causes include irradiation, exposure to drugs/chemicals with benzene or anthracene nuclei, and some medications like chloramphenicol and thiouracil.
• Moderate bone marrow injury may allow regeneration with supportive treatment over weeks to months.

Leukemias

• Leukemia is caused by cancerous mutation of myelogenous or lymphogenous cells.
• Leukemia leads to uncontrolled production of WBCs and greatly increased numbers of abnormal WBCs.
• Lymphocytic leukemias originate from lymphoid cells, usually in lymph nodes, and spread.
• Myelogenous leukemias start with cancerous production of young myelogenous cells in the bone marrow and then spread.
• With myelogenous leukemia WBCs are produced in extramedullary tissues.
• Myelogenous leukemia can sometimes produce partially differentiated cells (neutrophilic, eosinophilic, basophilic, or monocytic leukemia), but more often the cells are bizarre and undifferentiated.
• More undifferentiated cells usually indicate a more acute leukemia with a shorter lifespan if untreated.
• More differentiated cells can lead to chronic leukemia developing over 10-20 years.
• Leukemic cells, especially undifferentiated ones, are usually nonfunctional for normal protection against infection.

Effects of Leukemia on the Body

• The first effect is metastatic growth of leukemic cells in abnormal areas.
• Leukemia can potentially invade surrounding bone and causing pain and fractures.
• Almost all leukemias spread to the spleen, lymph nodes, liver, and other vascular regions, regardless of origin.
• Common effects include infection, severe anemia, and bleeding tendency due to thrombocytopenia caused by displacement of normal bone marrow and lymphoid cells.
• Excessive use of metabolic substrates by rapidly growing cancerous cells leads to depletion of energy, amino acids, and vitamins, causing patient debilitation and potentially death from metabolic starvation.

Leukocytes, Granulocytes, and Body Defense

• Leukocytes are a crucial part of the hematologic system and play a vital role in the body's defense.
• There are approximately 7,000 white blood cells per microliter of blood.
• They encompass six types: neutrophils, eosinophils, basophils (which are granulocytes), monocytes, lymphocytes, and occasionally plasma cells.
• Granulocytes and monocytes protect the body against invading organisms through phagocytosis or by releasing antimicrobial or inflammatory substances.
• These cells are primarily found in the bone marrow.
• Neutrophils circulate in the blood for about 48 hours and then reside in the tissues for another 4 to 5 days.
• They are one of the main cell types that attack and destroy bacteria, viruses, and other harmful agents.
• They exhibit chemotaxis, moving towards chemical signals.
• Monocytes circulate in the blood for 10 to 20 hours.
• Once monocytes enter the tissues, they swell and become tissue macrophages, where they can remain for months.
• Monocytes perform phagocytosis and provide continued defense against infection.
• Monocytes are immature cells until they transform into highly capable macrophages.
• Lymphocytes continually circulate through the blood and lymph system, with a lifespan of weeks to months.
• Eosinophils are weak phagocytes and are essential in the protection against parasites.
• Eosinophil numbers increase significantly during parasitic infections.
• Basophils liberate heparin into the blood, as well as histamine and serotonin. They function similarly to mast cells.

Mechanisms of Defense

• Smooth natural structures resist phagocytosis, while rough surfaces increase the likelihood.
• Most natural forces of the body have protective protein coats that resist uptake by phagocytes.
• The body's immune system develops antibodies that adhere to bacteria and increase the likelihood of phagocytosis.
• During phagocytosis, particles are engulfed into the cell within a vesicle, which fuses with lysosomes.
• Lysosomes contain proteolytic lytic enzymes, forming a digestive vesicle to break down the particle.
• Even if lysosomal enzymes fail, neutrophils and macrophages contain bactericidal agents that can kill most bacteria.
• Neutrophils and macrophages can move through the capillary walls by squeezing through gaps smaller than themselves (diapedesis).
• Neutrophils and macrophages move about 40 micrometers per minute by ameboid motion.

Reticuloendothelial System

• The reticuloendothelial system is a network of monocytes, mobile macrophages, fixed tissue macrophages, and specialized endothelial cells in the bone marrow, spleen, and lymph that are involved in killing cells.

Defense at Different Entry Points

• If bacteria enter tissue through the skin, local tissue macrophages initiate the attack and destruction.
• If bacteria bypass tissue macrophages, they enter the lymph flow and travel to the lymph nodes, has a large number of macrophages lining the lymph sinuses.
• Invading organisms entering through the lungs are met by large numbers of tissue macrophages within the alveolar walls.
• A large number of bacteria from ingested food constantly pass through the GI tract and enter the portal blood, which flows through liver sinusoids lined with tissue macrophages called Kupffer cells.
• These Kupffer cells are highly effective in removing bacteria, preventing their entry into systemic circulation.
• Macrophages in the spleen and bone marrow become entrapped in the meshwork of these organs.
• When foreign particles encounter these macrophages, the macrophages' "fingers" attach to them.

Inflammation

• Tissue damage triggers inflammation, causing dramatic changes in the surrounding tissue.
• Inflammation causes vasodilation of local blood vessels, leading to increased blood flow.
• Inflammation causes increased permeability of the capillaries.
• Inflammation causes clotting of fluid in the interstitial space due to increased fibrinogen.
• Inflammation causes aggregation of large numbers of granulocytes and monocytes into the tissue.
• Inflammation causes swelling of tissue cells.
• Various tissue products contribute to or increase these inflammatory reactions, including histamine, bradykinin, serotonin, prostaglandins, and several reaction products of the complement system.
• One of the initial responses to inflammation is to wall off the injured area, limiting the spread of bacteria or toxins.
• Within minutes of injury, tissue macrophages begin their action, attracted by inflammatory cytokines.
• Neutrophils start to invade from the blood within the first hour of inflammation, leading to an acute increase in neutrophil count in the blood (neutrophilia), sometimes up to 4 to 5 times normal.
• Monocytes from the blood also enter the inflamed tissues and enlarge to become macrophages.
• The bone marrow stores fewer monocytes than neutrophils, and monocytes are immature, requiring at least eight hours to mature into macrophages.
• Macrophages engulf more bacteria but are slower to respond initially.

Leukemia

• Leukemia is characterized by the uncontrolled production of white blood cells.
• Lymphocytic leukemia is caused by cancers of lymphoid cell production, typically starting in a lymph node or lymphoid tissue and spreading.
• Myelogenous leukemia begins with cancers of young myelogenous cells in the bone marrow; these cells spread and lead to white blood cell production in extra-medullary tissues.
• The acuteness of leukemia depends on the differentiation of the cancerous cells.
• Undifferentiated cells lead to acute leukemia, which can be fatal within months if untreated.
• More differentiated cells result in chronic leukemia, which can develop over 10 to 20 years.
• Decreases in white blood cells can lead to immediate invasion by the numerous bacteria that normally reside on the human body.
• Within a few days of leukemia, ulcers can appear in the mouth and colon, and severe infections can develop.

Body's Defense: Immunity and Allergy

• The human body has an ability to resist almost all types of organisms or toxins that tend to damage tissues and organs.
• Immunity can be broadly classified into innate immunity and acquired immunity.

Innate Immunity (Natural Immunity)

• Innate immunity does not develop until after the body is first attacked by a specific organism or toxin.
• Key aspects of innate immunity include:
  • Phagocytosis of bacteria and other invaders by white blood cells and tissue macrophages.
  • Destruction of swallowed organisms by stomach acid and digestive enzymes.
  • Resistance of the skin to invasion by organisms.
• The presence in the blood of certain chemicals and cells that attach to and destroy foreign organisms or toxins, including:
  • Lysozyme: A mucolytic polysaccharide that attacks and dissolves bacteria.
  • Basic polypeptides: React with and inactivate certain gram-positive bacteria.
  • The complement complex: A system of about 20 proteins activated to destroy bacteria.
  • Natural killer lymphocytes: Recognize and destroy foreign cells, tumor cells, and some infected cells.
• Innate immunity provides resistance to certain animal diseases.

Acquired (Adaptive) Immunity

• Acquired immunity is the ability to develop extremely powerful specific immunity against individual invading agents.
• It is caused by a special immune system that forms antibodies and/or activated lymphocytes that attack and destroy the specific invader.
• Immunization is a crucial process for protecting against diseases and toxins.
• Two basic types of acquired immunity exist:
  • Humoral immunity (B-cell immunity): the development of circulating antibodies (globulin molecules in blood plasma) produced by B lymphocytes.
  • Cell-mediated immunity (T-cell immunity): Achieved through the formation of large numbers of activated T lymphocytes in the lymph nodes that directly destroy foreign agents.
• Both antibodies and activated lymphocytes are formed in the lymphoid tissues of the body.

Antigens: Initiators of Acquired Immunity

• Acquired immunity develops after invasion by a foreign organism or toxin, necessitating a recognition mechanism.
• Each toxin or organism contains specific chemical compounds different from the body's own, called antigens.
• Antigens are generally proteins or large polysaccharides.
• For a substance to be antigenic, it usually needs a high molecular weight (8000 or more) and regularly recurring molecular groups on its surface called epitopes.

Lymphocytes

• Acquired immunity is the product of lymphocytes.
• Lymphocytes are located extensively in lymph nodes and other lymphoid tissues like the spleen, submucosal areas of the gastrointestinal tract, thymus, and bone marrow.
• The distribution of lymphoid tissue allows for interception of invading organisms or toxins before widespread spread.
• Lymphocytes are divided into two major populations: T lymphocytes (for cell-mediated immunity) and B lymphocytes (for humoral immunity).
• Both T and B lymphocytes originate from multipotent hematopoietic stem cells in the embryo, which form common lymphoid progenitor cells.
• Lymphoid progenitor cells destined to become T lymphocytes migrate to and are preprocessed in the thymus gland.
• Lymphoid progenitor cells destined to become B lymphocytes are preprocessed in the liver during mid-fetal life and in the bone marrow in late fetal life and after birth.

Preprocessing of T and B Lymphocytes

• Lymphocyte stem cells cannot directly form activated T lymphocytes or antibodies.
• Thymus Preprocessing of T Lymphocytes:
  • T lymphocytes migrate to the thymus, divide rapidly, and develop extreme diversity for reacting against different specific antigens.
  • Each thymic lymphocyte develops specificity against a single antigen.
  • The thymus ensures released T lymphocytes will not react against the body's own tissues (self-antigens).
  • T lymphocytes that react with self-antigens are destroyed.
  • Most T lymphocyte preprocessing occurs before and shortly after birth.
• Liver and Bone Marrow Preprocessing of B Lymphocytes:
  • B lymphocytes are preprocessed in the liver (mid-fetal life) and bone marrow (late fetal life and after birth).
  • B lymphocytes differ from T lymphocytes in that they secrete antibodies as their reactive agents.
  • B lymphocytes differ from T lymphocytes in that they have even greater diversity, forming millions of antibody types with different specificities.
  • After preprocessing, both T and B lymphocytes migrate to lymphoid tissue throughout the body.

Lymphocyte Clones and Antigen Specificity

• When specific antigens contact T and B lymphocytes in lymphoid tissue, some become activated.
• Millions of different types of preformed B and T lymphocytes, each capable of forming a highly specific antibody or T cell, are stored in lymphoid tissue.
• Each preformed lymphocyte can only form one type of antibody or T cell with a single specificity and is activated only by its specific antigen.
• Upon activation, a specific lymphocyte reproduces wildly, forming a clone of identical lymphocytes.
• B lymphocyte clones secrete specific antibodies, while T lymphocyte clones differentiate into specific sensitized T cells.
• The diversity of lymphocyte clones arises from the random recombination of gene segments during preprocessing.
• Each mature lymphocyte has a gene structure coding for a single antigen specificity.
• Each lymphocyte clone is responsive to only a single type of antigen (or very similar antigens) due to specific antibody molecules on the surface of B cells and T-cell receptors on T cells.

Mechanism of Lymphocyte Clone Activation

• Macrophages play a crucial role in antigen presentation.
• Macrophages phagocytize and partially digest invading organisms, releasing antigenic products.
• Macrophages present these antigens directly to lymphocytes, leading to the activation of specific clones.
• Macrophages also secrete interleukin-1, which further promotes growth and reproduction of specific lymphocytes.
• T-helper cells are also involved in activating B lymphocytes for B cell activation and antibody production.

B-Lymphocyte System: Humoral Immunity and Antibodies

• Dormant B lymphocyte clones are activated upon entry of a foreign antigen.
• Macrophages present the antigen to B lymphocytes and T cells.
• Activated T-helper cells also contribute to B lymphocyte activation.
• B lymphocytes specific for the antigen enlarge into lymphoblasts, which then differentiate into plasmablasts (precursors of plasma cells).
• Plasmablasts undergo rapid division and mature into plasma cells, which produce gamma globulin antibodies at an extremely rapid rate.
• Antibodies are secreted into the lymph and circulate in the blood, continuing for several days or weeks until plasma cell exhaustion.
• Some lymphoblasts do not become plasma cells but form memory cells, which are long-lived B lymphocytes.
• Memory cells circulate and populate lymphoid tissue but remain dormant until re-exposed to the same antigen.
• Subsequent exposure to the same antigen triggers a much faster and more potent secondary antibody response due to the presence of a larger number of memory cells.
• Activated B lymphocytes differentiate into short-lived and long-lived plasma cells.
• Long-lived plasma cells reside in tissues like bone marrow and gut-associated lymphoid tissue and can continue producing antibodies for many years, providing lifelong immunity.

Nature of Antibodies (Immunoglobulins)

• Antibodies are gamma globulins called immunoglobulins (Igs), constituting about 20% of plasma proteins.
• Immunoglobulins are composed of light and heavy polypeptide chains.
• Each heavy chain is paralleled by a light chain at one end, forming heavy-light pairs.
• Each chain has a variable portion and a constant portion.
• Light and heavy chains are held together by noncovalent and covalent bonds.
• Specificity of antibodies results from the unique amino acid arrangement in the variable portions of the light and heavy chains, creating a specific steric shape.
• Binding between antibody and antigen is rapid, tight, and strong.
• IgG antibodies have two variable antigen-binding sites, making them bivalent.
• Five General Classes of Antibodies: IgM, IgG, IgA, IgD, and IgE.
• IgG constitutes about 75% of antibodies.
• IgE is especially involved in allergies.
• IgM has 10 binding sites.

Mechanisms of Action of Antibodies

• Antibodies protect the body in two main ways: Direct attack on the invader and activation of the complement system.
• Direct Action of Antibodies: Due to their bivalent nature and multiple antigen sites on invaders, antibodies can cause agglutination, precipitation, neutralization, and lysis
• These direct actions are often amplified by the complement system.

Complement System for Antibody Action

• The complement system enhances antibody and phagocytic cell actions in neutralizing pathogens, removing damaged cells, and promoting inflammation.
• It consists of about 20 proteins, many as enzyme precursors, including 11 principal proteins present in plasma and tissue spaces.
• The enzyme precursors are normally inactive but can be activated by the classical pathway, initiated by an antigen-antibody reaction.
• Antibody binding to antigen triggers a cascade of amplified enzymatic reactions with important effects.
• Opsonization and phagocytosis: C3b strongly activates phagocytosis by neutrophils and macrophages, enhancing bacterial engulfment.
• Lysis: The membrane attack complex inserts into cell membranes, creating pores and causing osmotic rupture of bacteria and other invaders
• Agglutination: Complement products change invader surfaces, promoting clumping.
• Neutralization of viruses: Complement can attack viral structures, rendering them nonvirulent.
• Chemotaxis: C5a initiates migration of neutrophils and macrophages to the antigenic site.
• Activation of mast cells and basophils: C3a, C4a, and C5a trigger release of histamine, heparin, and other substances.
• Inflammatory effects: Complement products further increase blood flow, capillary leakage, and coagulation of interstitial fluid proteins, hindering invader movement..

T-Lymphocyte System: Activated T Cells and Cell-Mediated Immunity

• Upon antigen exposure, specific T lymphocyte clones proliferate and release large numbers of activated, specifically reacting T cells into the lymph, similar to antibody release by B cells.
• Whole activated T cells circulate throughout the body for months or even years.
• T-lymphocyte memory cells are also formed in the lymphoid tissue, enhancing the T cell population.
• Subsequent exposure to the same antigen results in a much faster and more powerful release of activated T cells.
• T cell responses are highly antigen-specific and crucial for defense.
• T lymphocytes respond to antigens only when bound to MHC proteins on the surface of antigen-presenting cells (APCs) in lymphoid tissues.
• Major types of APCs are macrophages, B lymphocytes, and dendritic cells (most potent).
• Interaction of cell adhesion proteins is critical for T cells to bind APCs long enough for activation.
• MHC proteins bind peptide fragments of degraded antigen proteins inside APCs and transport them to the cell surface.
• MHC I proteins present antigens to cytotoxic T cells, while MHC II proteins present antigens to T-helper cells.
• Antigens on APC surfaces bind to receptor molecules on T cell surfaces (T-cell receptors), with each T cell having up to 100,000 receptor sites.

Different Types of T Cells and Their Functions

• Three major groups of T cells exist: T-helper cells, cytotoxic T cells, and regulatory T cells each with distinct functions.
• T-Helper Cells: most numerous T cells that serve as major regulators of virtually all immune functions by forming lymphokines.
• Naïve CD4+ T-helper cells can differentiate into subsets that produce different lymphokines and trigger different immunological reactions.
• Absence of T-helper cell lymphokines paralyzes the rest of the immune system.
• HIV inactivates or destroys T-helper cells, leading to AIDS and severe immunodeficiency.
• Specific regulatory functions include stimulation of growth and proliferation of cytotoxic T cells and regulatory T cells, especially via interleukin-2.
• T-Helper Cells stimulate of B-cell growth and differentiation into plasma cells and antibody secretion, especially via interleukins 4, 5, and 6, activate the macrophage system, and feedback stimulatory effect on T-helper cells, especially via interleukin-2.
• Cytotoxic T Cells directly attack cells capable of killing microorganisms and some of the body's own cells.
• Receptor proteins on CD8+ cytotoxic cells bind tightly to target cells with the appropriate antigen.
• Cytotoxic T Cells kill by secreting perforins into the target cell membrane and releasing cytotoxic substances directly into the cell, detaching and kill multiple cells.
• Cytotoxic T Cells are crucial for destroying virus-infected cells, cancer cells, and foreign tissue cells (e.g., transplants).
• Regulatory T Cells are capable of suppressing the functions of both cytotoxic and T-helper cells.
• CD4+ regulatory T cells are believed to prevent excessive immune reactions by cytotoxic cells.

Tolerance of Acquired Immunity System to the Body's Own Tissues

• The immune system normally recognizes the body's own tissues as distinct and forms few antibodies or activated T cells against self-antigens.
• Most tolerance develops during the preprocessing of T lymphocytes in the thymus and B lymphocytes in the bone marrow (clone selection).
• Introducing a strong antigen into a fetus during lymphocyte preprocessing prevents the development of lymphocyte clones specific for that antigen.
• Failure of the tolerance mechanism causes autoimmune diseases.
• Examples of autoimmune diseases
  • Rheumatic fever
  • Glomerulonephritis
  • Myasthenia gravis
  • Multiple sclerosis
  • Systemic lupus erythematosus (SLE)

Immunization by Injection of Antigens

• Immunization is used to produce acquired immunity against specific diseases.
• Methods include injecting:
  • Dead organisms with intact antigens
  • Chemically treated toxins (toxoids) with destroyed toxicity but intact immunizing antigens
  • Live, attenuated organisms that can no longer cause disease but still carry necessary antigens
• Immunization often involves multiple doses to enhance the secondary immune response.

Passive Immunity

• Passive immunity provides temporary immunity by infusing antibodies or activated T cells from another immunized individual or animal, without injecting any antigen into the recipient.
• Transfused antibodies last for 2-3 weeks.
• Transfused T cells last for a few weeks if from another person but only hours to days if from an animal.

Allergy and Hypersensitivity

• An undesirable side effect of immunity is the development of allergy or other immune hypersensitivity under certain conditions.
• Several types of allergy and hypersensitivity exist, some occurring only in individuals with a specific allergic tendency.

Allergy Caused by Activated T Cells: Delayed-Reaction Allergy

• Caused by activated T cells, not antibodies.
• Involves substances like poison ivy toxin that cause formation of activated helper and cytotoxic T cells upon repeated exposure.
• Release of toxic substances from activated T cells and macrophage invasion can cause serious tissue damage.

Atopic Allergies Associated with Excess IgE Antibodies

• Occur in people with a genetic allergic tendency with large quantities of IgE antibodies
• IgE antibodies have a strong propensity to attach to mast cells and basophils.
• When an allergen binds to several IgE antibodies on a mast cell or basophil, it causes an immediate change in the cell membrane, leading to rupture or release of special agents.
• Released agents include histamine, protease, slow-reacting substance of anaphylaxis (leukotrienes), eosinophil and neutrophil chemotactic substances, heparin, and platelet-activating factors.
• These substances cause local blood vessel dilation, attraction of eosinophils and neutrophils, increased capillary permeability, and smooth muscle contraction.
• Anaphylaxis is a widespread allergic reaction occurring when a specific allergen is injected directly into circulation.
• Urticaria (Hives) are localized anaphylactoid reactions in specific skin areas upon antigen entry.
• Hay Fever is an allergen-reagin reaction in the nose.

Innate and Acquired Immunity

• Two main types of immunity are innate and acquired.
• Innate immunity is present from birth and includes non-specific defense mechanisms, like phagocytosis of bacteria, stomach acid, complement complex, and natural killer lymphocytes.
• Acquired immunity develops throughout an individual's life in response to exposure to foreign substances.
• Acquired immunity is characterized by specificity and memory.
• Humoral Immunity involves the production of antibodies (immunoglobulins) in the blood plasma, which are gamma globulins (20% of all plasma proteins).
• Each antibody is specific for a particular antigen (unique structural organization).
• There are five general classes of antibodies: IgM, IgG, IgA, IgD, and IgE.
• Antibodies protect the body through direct attack on the invader or by activating the complement system.
• B lymphocytes are responsible for humoral immunity.
• B lymphocytes remain dormant in lymphoid tissue until exposure to a specific antigen, later enlarging and differentiating into plasma blasts that produce antibodies.
• Some activated B lymphocytes become memory cells, leading to a faster/potent secondary immune response and potentially lifelong immunity.
• Cell-Mediated Immunity involves the formation of activated T lymphocytes in the lymph nodes that directly destroy a foreign agent.
• T lymphocytes are responsible for cell-mediated immunity.
• T lymphocytes originate in the bone marrow and migrate to the thymus gland.
• Helper T cells (75%) secrete protein mediators that help other parts of the immune system function.
• Helper T cells are the primary target of HIV.
• Lymphocytes are located in the lymph nodes, spleen, gastrointestinal tract, thymus, and bone marrow.
• Born without lymphocytes, an individual will die shortly after birth from severe bacterial infections.
• Activated by antigens, T and B lymphocytes proliferate extensively, forming specialized lymphocytes that persist in the body for months to years.
• Acquired immunity can target an individual's own body tissues.
• Tolerance to self-antigens develops during the processing of lymphocytes in the bone marrow for B cells and thymus for T cells.
• Autoimmune diseases occur when an individual loses tolerance to their own tissues.
• Immunization is used to induce acquired immunity against specific diseases.
• Passive immunity can be achieved by infusing antibodies or activated T cells, but is temporary (2-3 weeks).
• Hypersensitivity reactions and allergies are inappropriate/excessive immune responses, either like delayed reaction allergies (poison ivy) or Atopic allergies (excess IgE antibodies).
• Anaphylaxis is a severe, widespread allergic reaction that has led to a release of histamine and other substances from mast cells.

Immunity and Inflammation: Hypersensitivity and Deficiency

• Hypersensitivity is an altered immunologic response to an antigen that results in disease or damage to the host.
• Hypersensitivity reactions can be classified by the source of the antigen into allergy, autoimmunity, and alloimmunity.
• Allergy reactions are a deleterious effect of hypersensitivity to environmental antigens.
• Autoimmunity is a disturbance in the immunologic tolerance of self-antigens.
• Alloimmunity is an immune response directed against beneficial foreign tissues.
• Hypersensitivity reactions are classified by the mechanism that causes disease into four types: I, II, III, and IV.

Mechanisms of Hypersensitivity

• Type I: IgE-Mediated Hypersensitivity Reactions: Mediated by antigen-specific IgE and the products of tissue mast cells.
• Most common allergies are type I reactions and occur against environmental antigens.
• Sensitization usually requires repeated exposure to the antigen to elicit enough IgE.
• IgE binds to high-affinity