Comprehensive Notes on Innate and Adaptive Immunity

Immune System: Innate and Adaptive Immunity

• To microbes, the human body is nutrient-rich.
• Blood, muscles, bones, and organs are generally sterile.
• Skin and mucous membranes prevent entry of microbes.
• Sensor systems detect invaders and mount a response.
• Innate immunity provides routine protection.
• Innate immunity involves pattern recognition of specific molecules, although it is considered non-specific.
• Adaptive immunity develops throughout life.
• Antigens cause a response, and the system produces antibodies to bind to them.
• Adaptive immunity can also destroy host cells.

First-Line Defenses

• First-line defenses are barriers blocking entry.
• If invaders breach, sensor systems detect them and send out signals.
• Innate defenses work to destroy invaders.
• Sentinel cells use Pattern Recognition Receptors (PRRs).

First-Line Defenses: Epithelium

• All exposed surfaces are lined with epithelium.
• Borders are either outside or inside the body.
  • Outside: Skin
  • Inside: Digestive tract, respiratory tract

First-Line Defenses: Physical Barriers (Skin)

• Skin is difficult for microbes to penetrate.
• Epidermis: many layers of epithelial cells
  • Outermost layers are dead and filled with keratin.
    • Keratin repels water and maintains a dry environment.
    • Cells continually slough off along with any attached microbes.
• Dermis: tightly woven fibrous connective tissue

First-Line Defenses: Mucous Membranes

• Mucous membranes line the digestive, respiratory, and genitourinary tracts.
• They are constantly bathed in secretions, such as mucus.
• Peristalsis in the intestines and the mucociliary escalator in the respiratory tract remove microbes.

First-Line Defenses: Antimicrobial Substances

• Protect skin and mucous membranes.
• Salt accumulates from perspiration.
• Lysozyme degrades peptidoglycan.
• Peroxidase enzymes break down hydrogen peroxide.
• Lactoferrin binds iron.
• Antimicrobial peptides (AMPs)
  • Defensins form pores in microbial membranes.

First-Line Defenses: Normal Microbiota (Flora)

• Competitive exclusion of pathogens
  • Cover binding sites, consume available nutrients
• Production of toxic compounds
  • Propionibacterium degrade lipids and produce fatty acids.
  • E. coli synthesizes colicins in the intestinal tract.
  • Lactobacillus in the vagina produces a low pH.
• Disruption of normal microbiota (e.g., antibiotic use) can predispose a person to infections.
  • Clostridium difficile in the intestine.
  • Candida albicans in the vagina.
• Essential to the development of the immune system.

The Cells of the Immune System: Hematopoiesis

• Formation and development are termed hematopoiesis.
• Blood cells originate from hematopoietic stem cells.
• Found in bone marrow.
• Induced to develop by colony-stimulating factors (CSFs).
• Move around the body and travel through circulatory systems.
• Always found in normal blood.
• Numbers increase during infections.
• Some reside in various tissues.
• Three general categories:
  • Red blood cells (erythrocytes) carry O_2. Platelets (from megakaryocytes) are involved in clotting.
  • White blood cells (leukocytes) are important in host defenses.

The Cells of the Immune System: Leukocytes

• Four Types of Leukocytes (White Blood Cells)
  • Granulocytes contain cytoplasmic granules.
    • Neutrophils: highest numbers, engulf and destroy bacteria and other material.
    • Basophils: involved in allergic reactions and inflammation; mast cells are similar and found in tissues.
    • Eosinophils: fight parasitic worms and are also involved in allergic reactions.

The Cells of the Immune System: Mononuclear Phagocytes

• Comprise the mononuclear phagocyte system (MPS).
• Includes monocytes (circulate in blood) and cell types that develop as they leave the bloodstream.
• Macrophages differentiate from monocytes.
• Often named after the location where they are found in the body (e.g., alveolar macrophages).

The Cells of the Immune System: Dendritic Cells and Lymphocytes

• Dendritic Cells
  • Sentinel cells, function as “scouts.”
  • Engulf material in tissues and bring it to cells of the adaptive immune system for “inspection.”
  • Usually develop from monocytes.
• Lymphocytes
  • Responsible for adaptive immunity.
  • B cells and T cells are highly specific in the recognition of antigens.
    • Generally reside in lymph nodes and lymphatic tissues.
  • Natural killer (NK) cells destroy certain types of cells.

Leukocytes and Their Derivatives

The following table summarizes Leukocytes and Their Derivatives:

• Neutrophils (55-65%): Phagocytosis; release substances that trap and destroy microbial invaders, most abundant leukocyte in blood.
• Eosinophils (2-4%): Release chemicals that destroy eukaryotic parasites. Found mainly in tissues below the mucous membranes.
• Basophils (0-1%), mast cells: Release histamine and other inflammation-inducing chemicals. Basophils are found in blood, whereas mast cells are present in most tissues.
• Monocytes (3-8%): Phagocytosis. Found in blood; they differentiate into either macrophages or dendritic cells when they migrate into tissues.
• Macrophages: Phagocytosis; an important type of sentinel cell. Found in tissues; sometimes known by different names based on the tissue in which they are found.
• Dendritic cells: Collect antigens from the tissues and then bring them to lymphocytes that gather in the secondary lymphoid organs (e.g., lymph nodes, spleen, appendix, tonsils); an important type of sentinel cell.
• B and T cells: Participate in the adaptive responses. Found in lymphoid organs (e.g., lymph nodes, spleen, appendix, tonsils, thymus, bone marrow); also in blood.
• Innate lymphoid cells: Various subsets have different roles and different locations.

Cell Communication

• Communication allows for a coordinated response.
• Surface receptors serve as “eyes” and “ears” of the cell.
  • Usually span the membrane, connecting the outside to the inside.
  • Binding to a specific ligand induces a response.
• Adhesion molecules allow cells to adhere to other cells.
  • For example, endothelial cells can adhere to phagocytic cells, allowing them to exit the bloodstream.
• Cytokines are the “voices” of the cell.
  • Produced by cells, diffuse to others, and bind to appropriate receptors to induce changes: growth, differentiation, movement, cell death.
  • Act at low concentration; effects are local, regional, and systemic.

Cell Communication: Cytokines

• Chemokines: chemotaxis of immune cells.
• Colony-stimulating factors (CSFs): multiplication and differentiation of leukocytes.
• Interferons (IFNs): control of viral infections, regulation of inflammatory response.
• Interleukins (ILs): produced by leukocytes; important in innate and adaptive immunity.
• Tumor necrosis factor (TNF): inflammation, apoptosis.
• Act together to promote response.

Pattern Recognition Receptors (PRRs)

• Pattern recognition receptors (PRRs) detect pathogen-associated molecular patterns (PAMPs) and “see” signs of microbial invasion.
• PRRs are located on the cell surface, on internal membranes, and in the cytoplasm.
• Cell wall components (lipopolysaccharide, peptidoglycan, lipoteichoic acid, lipoproteins), flagellin subunits, and viral RNA molecules.
• May be called MAMPs (for microbe-associated).
• Some are DAMPs (for danger-associated), which indicate host cell damage.

Pattern Recognition Receptors (PRRs): Toll-like Receptors (TLRs)

• Toll-like receptors (TLRs) are anchored in the membranes of sentinel cells.
• Cells “see” PAMPs in the extracellular environment.
• Others are in phagosomal or endosomal membranes of organelles and characterize ingested material.
• Following detection, a signal is transmitted to the nucleus.
• Induces gene expression, inflammatory response, and antiviral response.

Pattern Recognition Receptors (PRRs): NOD-like Receptors (NLRs)

• NOD-like receptors (NLRs) are found in the cytoplasm.
• Detect bacterial components, indicating the cell has been breached; some detect damage.
• Unleash a series of events to protect the host, sometimes at the expense of the cell.
• Some NLRs join cytoplasmic proteins to form an inflammasome.
  • Activates the inflammatory response.

Pattern Recognition Receptors (PRRs): RIG-like Receptors (RLRs)

• RIG-like receptors (RLRs) are found in the cytoplasm.
• Detect viral RNA, indicating infection, and produce interferons.
  • Viral RNA often has 3 phosphates at the 5' end (no capping as in cytoplasmic RNA).
  • Often double-stranded (dsRNA).
• Interferons cause neighboring cells to express inactive antiviral proteins (iAVPs) (protein kinase R, RNase L).
• Activated by dsRNA to degrade mRNA, stop protein synthesis, and undergo apoptosis.

The Complement System

• Complements activities of the adaptive immune system.
• Proteins circulating in blood and bathing tissues.
• Proteins named in order discovered: C1 through C9.
• Can split into fragments; for example, C3 splits into C3a and C3b.
• Activated by three different pathways that lead to the formation of C3 convertase, which splits C3.

The Complement System: Three Pathways

• Alternative pathway: triggered when C3b binds to foreign cell surfaces (C3 unstable, so some C3b is always present).
• Lectin pathway: pattern recognition molecules (mannose-binding lectins, or MBLs) bind to mannose of microbial cells and interact with complement system components.
• Classical pathway: activated by antibodies bound to antigen, which interact with the complement system.

The Complement System: Activation Outcomes

• Opsonization: C3b binds to bacterial cells and foreign particles, promotes engulfment by phagocytes.
• Inflammatory Response: C5a attracts phagocytes to the area; C3a and C5a increase the permeability of blood vessels and induce mast cells to release cytokines.
• Lysis of Foreign Cells: membrane attack complexes (MACs) are formed by proteins C5b, C6, C7, C8, and C9 molecules assembling in cell membranes of Gram-negative bacteria.

The Complement System: Regulation

• Regulation prevents host cells from activating the complement system.
• Molecules in host cell membranes bind regulatory proteins that inactivate C3b, preventing opsonization or triggering of the alternative pathway.

Phagocytosis

• Phagocytes engulf and digest material and pathogens.
• Chemotaxis: phagocytes are recruited by chemoattractants (products of microorganisms, phospholipids from injured host cells, chemokines, C5a).
• Recognition and Attachment: direct (receptors bind mannose) and indirect (binding to opsonins).
• Engulfment: pseudopods surround and form a phagosome.
• Phagosome Maturation and Phagolysosome Formation: endosomes fuse, lower pH; lysosomes bring enzymes.
• Destruction and Digestion: toxic ROS and nitric oxide are produced; pH decreases; enzymes degrade; defensins damage the membrane of the invader; lactoferrin ties up iron.
• Exocytosis: a vesicle fuses with the cytoplasmic membrane and expels remains.

Phagocytosis: Macrophages

• Macrophages are scavengers and sentinel cells.
• Phagocytize dead cells, debris, and destroy invaders.
• Live weeks or months; regenerate lysosomes.
• Always present in tissues; can call in reinforcements.
• TLRs on surfaces and in phagosomes detect invaders.
• Cytokines are produced in response.
• Can become activated macrophages to increase their power.
• If insufficient, can fuse to form giant cells.
• Macrophages, giant cells, and T cells form granulomas, which wall off and retain organisms or material resistant to destruction.
  • Prevent escape but interfere with normal tissue function.
  • Occurs in tuberculosis and other diseases.

Phagocytosis: Neutrophils

• Specialized attributes of neutrophils.
• Neutrophils: rapid response; move into the area and eliminate invaders.
• Critical role in early stages of inflammation.
• First to be recruited from the bloodstream to the site of damage.
• More powerful than macrophages, but have a short life span of 1–2 days in tissues.
  • Die once granules are used.
• Kill microbes via phagocytosis and release of granule content.
• Can release DNA to form neutrophil extracellular traps (NETs), catching microbes, and allowing enzymes and peptides from granules to destroy them.

The Inflammatory Response

• Tissue damage results in inflammation.
• The purpose is to contain the site of damage, localize the response, eliminate the invader, and restore tissue function.
• Results in swelling, redness, heat, pain, and sometimes loss of function.
• Pattern recognition receptors (TLRs, NLRs) trigger inflammation.
  • Detect PAMPs and DAMPs.
• Host cells release inflammatory mediators (cytokines, histamine; TNF acts on the liver to release acute-phase proteins).
• Inducers include microbes and tissue damage.
  • Blood vessel damage starts two enzymatic cascades; leads to coagulation and increased permeability.

The Inflammatory Response: Process

• Inflammatory process involves a cascade of events.
• Dilation of small blood vessels.
  • Greater blood flow (heat, redness); slower flow rate.
  • Leakage of fluids (swelling, pain).
• Migration of leukocytes from the bloodstream to tissues.
  • Endothelial cells “grab” phagocytes and slow them down.
  • Phagocytes squeeze between cells of the vessel (diapedesis).
• Clotting factors wall off the site of infection.
• Dead neutrophils and tissue debris accumulate as pus.

The Inflammatory Response: Acute vs. Chronic

• Acute inflammation is short-term, mainly involving neutrophils; macrophages clean up damage by ingesting dead cells and debris.
• If acute inflammation fails, chronic inflammation results; macrophages and giant cells accumulate, and granulomas form.

The Inflammatory Response: Damaging Effects

• The process can be likened to a fire sprinkler system: prevents spread but damages the building.
• Enzymes and toxic compounds from phagocytic cells are released, damaging tissues.
  • If limited (e.g., a cut on the finger), then damage is minimal.
  • If in a delicate system (e.g., membranes surrounding the brain or spinal cord), then it can be severe or even life-threatening.
• Cell Death and the Inflammatory Process
  • Apoptosis: programmed cell death; does not trigger an inflammatory response.
  • Pyroptosis: if pattern recognition receptors are triggered, the cell may undergo cell death with an inflammatory response.

Fever

• Fever is an important host defense mechanism.
• A strong indicator of infectious disease, especially bacterial.
• The temperature-regulation center in the brain normally holds at 37° C but raises during infection in response to pyrogens.
• Cytokines produced by macrophages following detection of microbial products by TLRs are endogenous pyrogens.
• Exogenous pyrogens are produced by microbes.
• The growth rates of bacteria optimized for 37° C typically drop sharply above the optimum, allowing more time for defenses.
• A moderate temperature rise increases the rates of enzymes.
• Enhances the inflammatory response, phagocytic killing, multiplication of lymphocytes, release of attractants for neutrophils, production of interferons and antibodies, and release of leukocytes from bone marrow.