Immune System: Components and Function

Immune System Basics

• The immune system protects against infectious agents and harmful substances, often without our awareness.
• It comprises numerous cellular and molecular structures working together to provide immunity.
• Its function is dependent on the specific type of infectious agent encountered.

Infectious Agents

• Infectious agents are organisms causing damage or death to a host organism.
• Pathogenic is the term if these agents cause harm.
• The five major categories are bacteria, viruses, fungi, protozoans, and multicellular parasites.

Leukocytes: Immune Cell Overview

• Leukocytes, or white blood cells, are formed in the red bone marrow.
• Granulocytes: neutrophils, eosinophils, and basophils.
• Monocytes become macrophages once they reside in tissues.
• Lymphocytes include B-lymphocytes, T-lymphocytes, and NK (natural killer) cells.

Structures Housing Immune Cells

• Immune system cells are primarily located outside the bloodstream.
• Lymphatic system structures (lymph nodes, spleen, tonsils, lymphatic nodules) house T- and B-lymphocytes, macrophages, and NK cells.
• Macrophages reside in select organs: alveolar macrophages in the lungs, microglia in the brain, and can be fixed or free.
• Dendritic cells are located in epithelial and mucosal membranes.
• Mast cells reside in connective tissue.

Cytokine Characteristics and Functions

• Cytokines are small, soluble proteins produced by both innate and adaptive immune systems.
• They are released from one cell and bind a specific receptor on a target cell, with actions similar to hormones.
• Cytokines can act on the cell that released it (autocrine), local cells (paracrine), or circulate in the blood to act systemically (endocrine).
• They have a short half-life and regulate/facilitate immune system activity.
• Cytokines are a key means of communication between cells, controlling the behavior of effector cells.
• They regulate inflammatory responses, serve as weapons, and influence non-immune cells like those of the nervous system.

Innate vs. Adaptive Immunity

• The immune system has two categories: innate and adaptive immunity
• They are organized based on the type of immunity provided and work together against harmful agents.
• They differ in cells involved and the specificity of cell response.
• Both differ in mechanisms to eliminate harmful substances, and amount of time for response.

Innate Immunity (Non-Specific Defenses)

• Innate immunity protects against numerous different substances
• It is present from birth and includes barriers like skin and mucosal membranes, as well as nonspecific cellular and molecular internal defenses.
• Innate immunity does not require previous exposure and responds immediately.

Adaptive Immunity (Specific Defenses)

• Adaptive immunity involves T- and B-lymphocytes that respond to different foreign substances.
• It provides powerful means of eliminating foreign substances like a particular lymphocyte responding to chickenpox virus.
• It takes several days to be effective.

Structures of Innate Immunity

• Structures include those that prevent entry of potentially harmful substances,.
• Structures respond nonspecifically to wide range of harmful substances.
• The first line of defense is skin and mucosal membrane.
• The second line of defense is internal processes, activities of neutrophils, macrophages, NK cells, chemicals, and physiological processes.

The Physical Barrier of Skin

• The skin, formed by the epidermis and dermis, acts as a physical barrier.
• Few microbes are able to penetrate it.
• The skin releases antimicrobial substances and hosts normal flora, where nonpathogenic microorganisms residing help prevent pathogenic microorganism growth.

Mucosal Membrane Barrier

• Mucosal membranes line body openings and produce mucin.
• They are lined by harmless bacteria.
• The bacteria suppress the growth of more virulent types.

Barrier Defenses

• Barrier defenses are usually successful.
• Barriers may be penetrated if compromised or if many microbes are present.
• Internal processes of innate immunity are activated if so.
• Adaptive immunity can also be activated.

Neutrophils, Macrophages, Basophils and Mast Cells

• Neutrophils and macrophages are cells of innate immunity.
• Neutrophils are the most prevalent leukocyte in blood and first to arrive during inflammation.
• Macrophages reside in tissues throughout body.
• Macrophages arrive later and stay longer than neutrophils, engulfing unwanted substances through phagocytosis.
• Engulfed substances degrade and release residues
• Basophils and mast cells are proinflammatory chemical-secreting cells.
• Basophils circulate in the blood while mast cells reside in connective tissue, mucosa, and internal organs.
• Both release granules during inflammatory response containing histamine, increasing vasodilation/permeability, and heparin, an anticoagulant.

Natural Killer Cells

• Natural killer (NK) cells destroy a variety of unwanted cells: virus- and bacteria-infected cells, tumor cells, and cells of transplanted tissue.
• NK cells form in bone marrow and circulate in blood, accumulating in secondary lymphatic structures.
• NK cells patrol the body detecting unhealthy cells, termed immune surveillance.
• They destroy unhealthy cells by releasing cytotoxic chemicals, perforin that forms transmembrane pores, and granzymes that initiate apoptosis (cellular death).

Eosinophils

• Eosinophils target parasites.
• They degranulate and release enzymes and other substances.
• They release proteins forming transmembrane pores.
• Eosinophils participate in the immune response of allergy and asthma, and participate in phagocytosis of antigen-antibody complexes.

Interferons

• Interferons are a group of antimicrobial proteins, a class of cytokines released from leukocytes and fibroblasts.
• They provide a nonspecific defense against viral spread
• Interferons released from virus-infected cells.
• They bind to non-infected cells, and interferes with viral replication preventing them from becoming infected.
• Interferons stimulate macrophages and NK cells to destroy virus-infected cells.

Complement System

• The complement system is an important group of antimicrobial proteins composed of at least 30 plasma proteins.
• It works along with antibodies and is especially potent against bacterial infections.
• The complement system mediates opsonization, inflammation, cytolysis, and elimination of immune complexes.
• Opsonization is the binding of a complement protein to a pathogen enhancing phagocytosis.
• Inflammation is increased by complement activating mast cells and basophils to attract neutrophils and macrophages.
• Cytolysis is complement components triggering direct target killing allowing fluid influx and cell lysis.
• Elimination of immune complexes links antigen-antibody complexes to erythrocytes, transports them to the liver and spleen, where macrophages strip and destroy them.

Inflammation: An Innate Response

• Inflammation is an immediate, local, nonspecific response occurring in vascularized tissue against a variety of stimuli like a scratch or overuse.
• It is a major effector response of innate immunity.
• Inflammation helps eliminate infectious agents.
• Within 72 hours, the inflammatory response slows down, with monocytes exiting blood to become macrophages and initiate cleanup.
• Bacteria, damaged host cells, and neutrophils are destroyed.
• Fibroblasts multiply/synthesize collagen, begin tissue repair and may lead to scar tissue.

Cardinal Signs of Inflammation

• Includes redness by increased blood flow.
• Heat comes from increased blood flow and metabolic activity.
• Swelling results from increased fluid loss.
• Pain is from stimulating pain receptors and chemical irritation.
• Loss of function is possible in severe cases.

Fever as Part of Innate Immunity

• A fever is an elevated body temperature of at least 1°C from normal (37°C).
• Fever may accompany inflammatory response
• Increased fluid intake is required to prevent dehydration due to excess fluid loss.
• A fever results from the release of pyrogens, interleukin 1, interferons, toxins from infectious agents, drug reactions, trauma, and brain tumors.
• Benefits are that It inhibits reproduction of bacteria and viruses,promotes interferon activity, increases activity of adaptive immunity, Accelerates tissue repair,increases CAMs on endothelium of capillaries in lymph nodes, and additional immune cells migrating out of blood.
• It’s recommended to leave a low fever untreated.

Fever Risks

• High fevers significant above 100 degrees F.
• High fevers dangerous above 103 in children, slightly lower in adult.
• High fevers may have changes in metabolic pathways and denaturation of proteins.
• High fevers may have possible seizures.
• Irreversible brain damage if sustained at greater than 106.
• Death is likely if temperature greater than 109.

Chronic Inflammation

• Chronic inflammation is inflammation continuing for longer than two weeks
• It is characterized by macrophages and lymphocytes (not neutrophils).
• It can occur from overuse injuries.
• It may occur if acute inflammation unable to eliminate pathogen, or due to autoimmune disorder.
• Chronic inflammation can lead to tissue destruction and scar tissue formation

Adaptive Immunity: An Introduction

• Adaptive immunity is initiated upon entry of a foreign substance.
• It takes longer to respond than innate immunity.
• Adaptive immunity involves contact with an antigen, which causes lymphocytes to proliferate and form a specialized "army."
• Lymphocytes and released products are collectively termed the immune response.
• Adaptive immunity is the body's third line of defense.

The Two Branches of Adaptive Immunity

• Cell-mediated immunity involves T-lymphocytes.
• Humoral immunity involves B-lymphocytes that develop into plasma cells to release antibodies.

Antigens

• Antigens are proteins or large polysaccharides.
• Foreign antigens differ in structure from human body's molecules and bind the body's immune components.
• Self-antigens are body's molecules and typically do not bind immune components
• The immune system can distinguish.
• Reactions to self-antigens results in autoimmune disorders.

Antigenic Determinants and Autoimmune Disorders

• An antigenic determinant, or epitope, is the specific site on an antigen recognized by the immune system.
• Each antigenic determinant has a different shape and pathogenic organisms have multiple determinants.
• Autoimmune disorders are caused by the immune system lacking tolerance for specific self-antigens, initiating an immune response.
• They may is due to cross-reactivity, altered self-antigens, or entering areas of immune privilege.
• Such disorders include rheumatic heart disease, type 1 diabetes, and multiple sclerosis- all affecting different body structures.

T- and B-Lymphocytes Overview

• T- and B-lymphocytes have unique receptor complexes, about 100,000 per cell, that bind specific antigens.
• B-lymphocytes make direct contact with antigens.
• T-lymphocytes must have antigens processed and presented in the plasma membrane of another cell.
• T-lymphocytes need additional receptor molecules (coreceptors) to facilitate interaction with cells presenting antigens.
• CD molecules are a significant category of coreceptors differentiated into subtypes based on CD protein.

T-Lymphocyte Subtypes

• Helper T-lymphocytes help activate B-lymphocytes and other immune cells, contain CD4 in their plasma membrane, and are classified as CD4+ cells.
• Cytotoxic T-lymphocytes release chemicals toxic to cells, contain CD8 in their plasma membrane, and are classified as CD8+ cells.

Antigen Presentation

• Antigen presentation display an antigen on a cell's plasma membrane, a process performed by other cells.
• It helps T-lymphocytes "see" the antigen.
• The two categories of cells presenting antigen to T-lymphocytes are all nucleated cells of the body, and antigen-presenting cells (APCs).
• APCs are any immune cell communicating antigen presence to T-lymphocytes, like dendritic cells, macrophages, and B-lymphocytes.
• It requires the physical attachment of an antigen to a transmembrane protein
• The transmembrane protein is major histocompatibility complex (MHC), and is a group of genes coding for MHC molecules in plasma membranes.
• MHC categories are MHC class I found on all nucleated cells, and class II found on APCs (in addition to MHC I).

MHC Class I and II Molecules

• MHC class I molecules are genetically determined glycoproteins unique to an individual.
• They normally display randomly selected self-antigens on cell surfaces, but are ignored by immune system cells.
• During infection, MHCs present foreign antigens, providing means for communicating with cytotoxic T-lymphocytes.
• MHC class II molecules are glycoproteins synthesized/modified by RER.
• Exogenous antigens brought into the cell is done through endocytosis.
• The phagosome merges with a lysosome forming a phagolysosome, and the substance is digested into peptide fragments, and loaded onto MHC class II molecules
• Lastly they merge with the plasma membrane with antigen to signal to helper T-lymphocytes.

Organ Transplants and MHCs

• An organ transplant is the transfer of an organ from one individual to another.
• Individuals are tested for MHC antigens and ABO groups prior to donation.
• No two individuals, except identical twins, have the same MHC molecules
• Innate and adaptive immune systems attempt to destroy transplanted tissue.
• The recipient's immune system is suppressed with drugs.

Life Events of Lymphocytes

• The three events in life of a lymphocyte are the formation and maturation of lymphocytes, their activation, and the effector response.
• Formation and maturation occur within primary lymphatic structures of red bone marrow and thymus to recognize foreign antigens.
• Activation of lymphocytes is done by secondary lymphatic structures once exposed to an antigen.
• The lymphocytes become activated and replicate to form identical lymphocytes, their effector response.
• Effector response is action of T-lymphocytes and B-lymphocytes to eliminate antigen
• T-lymphocytes migrate to site of infection.
• B-lymphocytes remain in secondary lymphatic structures and synthesize/release antibodies, enter into blood and lymph and are transported to site.

Immunocompetent Lymphocytes

• Immunocompetent lymphocytes can bind antigen and respond, this ability gets tested.
• This happens primarily during development and after birth in primary lymphatic structures

Antigen Challenge

• The antigen challenge is the first encounter between an antigen and lymphocyte
• This usually occurs in secondary lymphatic structures.
• It comes from antigen in blood, or antigen penetrating skin transported to lymph node or from respiratory, GI tracts in tonsils or MALT

Helper T-Lymphocyte Activation

• Activation of helper T-lymphocytes requires activation prior to immune functions.
• First stimulation requires direct physical contact between APC and helper T-lymphocyte and an antigen is engulfed.
• Next the APC gets presents surface with MHC class II, and the helper T-lymphocyte binds to inspect.
• If no recognition occus, it will disengage.
• If the T-lymphocyte does recognize the antigen, there will be contact for several hours.
• In the second stage of stimulation, the helper T-lymphocyte divides to form activated and memory helper T-lymphocytes.

Cytotoxic T-Lymphocyte Activation

• Activation of cytotoxic T-lymphocytes occurs in stages like: direct contact by Cytotoxic T-lymphocyte and the peptide
• Like the previous stage peptide and MCH I molecule must bind (on infected cell). Second stimulation occurs, and the cytotoxic T-lymphocytes divide.
• They will form into activated cytotoxic T-lymphocytes and memory cytotoxic T-lymphocytes ready to activate upon re-exposure to same antigen.

B-Lymphocyte Activation

• Intact antigen binds to B-lymphocyte during first stimulation.
• The stimulated B-lymphocyte then engulfs antigens.
• The antigens are presented to helper T-lymphocytes that recognize the antigen leading into second stimulation.
• Lastly there is an activated Helper T-Lymphocyte which turns the B-lymphcyte to divide and form Plasma Cells (produce antibodies) and memory B-lymphocytes remain for RE-exposure, long lifespan.

Lymphocyte Recirculation

• Lymphocytes only temporarily in secondary lymphatic structure and exit after period of time.
• Lymphocytes circulate through blood and lymph every several days.
• This makes it more likely to encounter antigen (if present).

Effector Response: Cytotoxic T-Lymphocytes

• Cytotoxic T-lymphocytes destroy unhealthy cells by apoptosis.

Effector Response of Cytotoxic T-Lymphocytes

• Activated and memory cytotoxic T-lymphocytes leave to secondary lymphatic structure and migrate to the site of infection.
• Physical contact made between cytotoxic cell and unhealthy or foreign cell so that It can recognizes antigen.
• If cytotoxic T-lymphocyte recognizes antigen that it will destroy by releasing Perforin channels.

B-Lymphocytes

• Plasma cells form antibodies (the effectors of humoral immunity) and remain in the lymph nodes.
• Plasma cells produce millions of antibodies during a 5 day life span.
• Antibodies circulate through body, lymph and blood come in contact with antigen where they ultimately come in contact with antigen.
• Antibody concentration is circulating blood concentration of antibody against specific antigen