Anatomy and Physiology - Immune System

Immune system

Not composed of organs, but cellular and molecular structures located throughout the body

• Function: provide immunity, or protection from harm

• Infectious agents (pathogens) can damage or kill a host: bacteria, viruses, fungi, protozoans, and multicellular parasites

Prokaryotic cells

Simple, small cells that lack a nuclear envelope (and so do not have a distinct nucleus); free-floating circular DNA

• No membrane-bound organelles

• Typically have a cell wall

• Prokaryotes are always unicellular

Eukaryotic cells

Complex, large cells with linear DNA stored in the nucleus

• Have membrane-bound organelles

• May or may not have a cell wall

• Eukaryotes can be multicellular or unicellular

Bacteria (pathogen)

Prokaryotes, unicellular microbes—some have a sticky polysaccharide capsule and/or hairlike pili; some produce enzymes and/or toxins

• Enclosed by a cell wall

Viruses (pathogen)

Pieces of DNA or RNA in a protein shell (capsid); some are membrane-enclosed

• Viruses are not cells—they cannot reproduce by themselves and are much smaller; only about one-hundredth of a micrometer

Are obligate intracellular parasites: must enter a cell to reproduce → direct infected cell to make copies of nucleic acid and capsid → the virus or immune response may kill the host cell

Fungi (pathogen)

Eukaryotic cells with membrane and cell wall

• Include molds, yeasts, multicellular fungi that produce spores

• Release proteolytic enzymes, inducing inflammation

Protozoans (pathogen)

Eukaryotic cells without a cell wall that interfere with normal cellular functions

• Those that cause disease are called unicellular parasites

• Disease examples: malaria and trichomoniasis

Parasitic worms (pathogen)

Nonmicroscopic multicellular parasites (eukaryotes)

• Take nourishment from host they live in to grow in size

• Ex: tapeworm

Prion

Fragments of infectious proteins

• Neither cells nor viruses

• Cause disease in nervous tissue

• For example, Variant Creutzfeldt-Jakob disease (“mad cow disease”) can be spread from cows to humans by consuming infected meat

Immune response

Collective term for all physiologic processes of the immune system components

Can be innate or adaptive, depending on the type of immunity

Primary location of immune cells

• Blood: all 5 leukocytes circulate here

• Secondary lymphoid structures (ex: lymph nodes, spleen, tonsils): T-cells, B-cells, macrophages, dendritic cells, NK cells

• Select organs (ex: lungs): macrophages

• Skin and mucosal membranes (ex: respiratory tract): dendritic cells

• Connective tissue throughout body: mast cells

Cytokines

Small proteins that regulate immune activity, produced by cells of innate and adaptive immune system

• Chemical messengers released from one cell that bind to receptors of target cells: can act on cell that released it (autocrine); on local cells (paracrine); or on distant cells after circulating through blood (endocrine)

• Have short biological half-life

• The means of communication and weapons available to fight infection

Interleukin (cytokine)

IL-#

Regulates immune cells

Source:

• T-lymphocytes

• Macrophages

• Endothelial cells

• Other various cells

Tumor necrosis factor (cytokine)

TNF-(Greek letter)

Destroys tumor cells; may have other functions as well

Source:

• T-lymphocytes

• Macrophages

• Mast cells

• Dendritic cells

Colony-stimulating factor (cytokine)

(First letter of cell(s) it regulates)-CSF

Stimulates leukopoiesis in bone marrow to increase synthesis of a specific type (colony) of leukocytes

Source

• T-lymphocytes

• Monocytes

Interferon (cytokine)

IFN-(Greek letter)

“Interferes with” replication of pathogens that enter cells (intracellular pathogens)

Source:

• Infected cells

• NK cells

• T-lymphocytes

Innate immunity

Born with this, no previous exposure, immediate response

• Provided by multiple components that protect against a wide array of substances

• Recognize microbes as foreign because of receptors; pattern recognition receptors (TLRs, or toll-like receptors) are proteins on immune cell surface that bind to common microbe surface patterns (PAMPS, or pathogen-associated molecular patterns)

Innate immunity components

Skin and mucosal membranes: prevent entry

Nonspecific internal defenses

• Most immune cells (ex: macrophages, NK cells)

• Antimicrobial proteins (ex: interferon, complement)

• Physiologic responses (ex: inflammation, fever)

Adaptive immunity

Provided by lymphocytes that are activated to replicate and respond when stimulated by a specific antigen; response takes days

• T-cells: cell-mediated immunity

• B-cells: antibody-mediated immunity → become plasma cells: synthesize and release antibodies

Antigen

Unique molecule (such as a protein or polysaccharide) able to bind to a component of the adaptive immune system

• Examples: virus capsids, cell walls of bacteria or fungi, bacterial toxins, tumor antigens of cancer cells

• Lymphocytes able to distinguish foreign vs. self-antigens (those of a person’s own body)

T-lymphocytes or antibodies contact a region of the antigen called the antigenic determinant (epitope)

Immunogens

Antigens that induce an immune response (i.e., is immunogenic)

• Immunogenicity affected by how foreign it is, its size, complexity, and quantity

Hapten

Small substance that attaches to another molecule to initiate an immune reaction

Too small to function as an antigen alone

• Can become immunogenic when attached to a molecule in the host

• May trigger an immune response, such as a hypersensitivity reaction to certain drugs or chemicals

Skin barriers (1st line of defense - preventing entry)

Few microbes can penetrate intact skin

Physical barriers of epidermis and dermis

• Epidermis: keratinized stratified squamous epithelium; exfoliates to remove potential pathogens

• Dermis: connective tissue contains hyaluronic acid in dermis, which limits microbe spread

Skin secretions (1st line of defense - preventing entry)

Skin releases antimicrobial substances from sweat and sebaceous glands

• Sweat helps wash away microbes; contains dermcidin, lysozyme, defensins

• Sebum is low in pH (acidic) and interferes with microbial growth; contains lactate and fatty acids

Mucous membranes (1st line of defense - preventing entry)

Line body openings

• Produce mucus, containg antimicrobial substances (defensins, lysozyme, IgA)

• Cilia in respiratory tract sweep/remove trapped microbes

• GI tract utilizes saliva and stomach acid to kill ingested microbes

• Urinary tract flushes microbes away

• Reproductive tract contains acidic secretions

Microbiome (1st line of defense - preventing entry)

Commensal microbiota; are microorganisms that reside on body surfaces (ex: skin, mucous membranes like on GI tract)

• Nonpathogenic

• Interfere with attachment of potentially pathogenic organisms

Phagocytic cells (2nd line of defense - nonspecific internal defenses)

Engulf unwanted substances by phagocytosis

TLRs on cell surface bind to PAMPS

• Macrophages

• Neutrophils

• Dendritic cells

Neutrophils and macrophages (2nd line of defense - nonspecific internal defenses)

Phagocytic; destroy engulfed particles

• Intake vesicle (phagosome) fuses with lysosome = phagolysosome

• Digestive enzymes break down the unwanted substances

• Respiratory burst produces reactive oxygen-containing molecules that help destroy the microbes

• Degraded residue is released by exocytosis

• Macrophages can also perform antigen presentation

Dendritic cells (2nd line of defense - nonspecific internal defenses)

Phagocytic; destroy engulfed particles and then present fragments

• Antigens are presented on dendritic cell surface to T-lymphocytes

• Necessary for initiating adaptive immunity

Proinflammatory chemical-secreting cells (2nd line of defense - nonspecific internal defenses)

Basophils and mast cells (resemble basophils; found in connective tissue, close to small blood vessels)

• Release histamine → arteriole vasodilation and ↑ capillary permeability (classic allergy symptoms)

• Release heparin → anticoagulant

• Release eicosanoids (ex: leukotrienes) → ↑ venule inflammation

Apoptosis-initiating cells (2nd line of defense - nonspecific internal defenses)

NK (natural killer) cells destroy unhealthy/unwanted cells by initiating apoptosis (programmed cell death, not pathologic death)

• Form in bone marrow, circulate in blood, and accumulate in secondary lymphoid structures

• Perform immune surveillance—patrol body, detect unhealthy cells

How NK cells initiate apoptosis

1. Release cytotoxic chemicals (perforin and granzymes)

2. Perforin forms a transmembrane pore (perforating the cell)

3. Granzymes enter cell through pores → apoptosis (shriveling)

Parasite-destroying cells (2nd line of defense - nonspecific internal defenses)

Eosinophils degranulate, releasing enzymes and other cytotoxic substances, including proteins that form transmembrane pores in parasite

• Participate in immune responses of allergy and asthma

• Engage in phagocytosis of antigen-antibody complexes

Interferons (2nd line of defense - nonspecific internal defenses)

Antimicrobial proteins

A class of cytokines that nonspecifically interferes with spread of intracellular pathogens (for example, viruses, intracellular bacteria)

IFN-α and IFN-β produced by leukocytes and virus-infected cells

• Bind to neighboring cells and prevent their infection by triggering synthesis of enzymes that destroy viral nucleic acids → synthesis of viral proteins inhibited

• Stimulate NK cells to destroy virus-infected cells (killing itself)

IFN-g produced by T-lymphocytes and NK cells

• Stimulates macrophages to destroy virus-infected cells

Interferon pathway of a virus-infected cell

1. Body cell is infected with a virus

2. Virus-infected cell releases IFN-α and IFN-β

3. a. IFNs alert neighboring body cells to synthesize enzymes that interfere with viral replication, protecting them from infection

3. b. IFNs also stimulate NK cells to destroy virus-infected cells by apoptosis, killing the original infected cell that released them

4. NKs release IFN-g that stimulates macrophages to eliminate the infected cell

Complement system (2nd line of defense - nonspecific internal defenses)

Antimicrobial proteins

Group of over 30 plasma proteins identified as “C#”

• Work along with (“complement”) antibodies

• Synthesized by liver, continuously released in inactive form

• Activation occurs by enzyme cascade

• Complement activation follows pathogen entry; 3 pathways

Classical pathway (complement activation)

Antibody attaches to foreign substance, then complement binds to antibody

Alternative pathway (complement activation)

Complement binds to polysaccharides of bacterial or fungal cell wall

Mannose-binding lectin pathway (complement activation)

Lectin protein binds to carbohydrate on some microbes, and complement binds to the lectin

Complement system functions

• Increases inflammation by activating various cells (mast cells, basophils, neutrophils, macrophages)

• Opsonization: complement protein (opsonin, or “red flag”) binds to pathogen to enhance likelihood of phagocytosis

• Eliminates immune complexes: complement links immune (antigen-antibody) complexes with erythrocytes, which are later stripped of these by macrophages within the liver and spleen

• Induces cytolysis: collectively, complement proteins form a protein pore in the microbe’s plasma membrane (called membrane attack channels/MAC) → fluid enters → cell lyses/bursts

Inflammation (2nd line of defense - nonspecific internal defenses)

An immediate, local, nonspecific response of vascularized tissue to injury and infection

1. Release of inflammatory and chemotactic factors

2. Vascular changes result, including arteriole vasodilation, ↑ in capillary permeability, and stimulation of capillary endothelium of injured tissue to display cell-adhesion molecules (CAMs)/selectins

3. Recruitment of leukocytes through margination, diapedesis, and chemotaxis

4. Delivery of plasma proteins to site, including antibodies, complements, clotting proteins, kinins

5. Exudate is formed when increased fluid, immune cells, and proteins leave blood capillaries and enter the interstitial space, helping to “wash” the area of injurious or infectious agents

Chemotaxis (recruitment of leukocytes)

Migration of immune cells along a chemical gradient/in response to a chemical

Diapedesis (recruitment of leukocytes)

Leukocytes (amassed by margination) squeeze out thru endothelial cells of the vessel to site of infection/injury

• Aided by vasodilation

Margination (recruitment of leukocytes)

CAMs on leukocytes adhere to CAMs on capillary endothelium

• First neutrophils, then macrophages

Exudate (product of inflammation)

Mix of fluid, immune cells, and proteins; ex: pus

1. Exudate leaves the blood

2. Circulates through the infected/injured interstitial tissue, picking up infectious agents, dead cells, and cellular debris

3. Increased interstitial HP pushes it into lymphatic capillaries, becoming new lymph

4. Filters through lymph nodes