Chapter 14 Host Defenses: Innate Immunity

Host Defense Mechanisms

• Innate, natural defenses are present at birth and provide nonspecific resistance to infection.
• Adaptive immunities are specific and must be acquired.

General Features of Host Defenses

Defense Mechanisms of the Host

• The immune system protects the body against pathogens through a multilevel network.
  • Physical barriers
  • Immunologically active cells
  • Variety of chemicals
• First line of defense:
  • Any barrier that blocks invasion at the portal of entry.
  • Nonspecific.
• Second line of defense:
  • Protective cells and fluids; inflammation and phagocytosis.
  • Nonspecific.
• Third line of defense:
  • Acquired with exposure to foreign substance.
  • Produces protective antibodies and creates memory cells.
  • Specific.
• The lines of defense do not work separately, most overlap and are redundant in some of their effects.

1st Line of Defense: Barriers at the Portal of Entry

• Defenses are a normal part of the body’s anatomy and physiology.
• Inborn (innate), nonspecific defenses.
• Divided into three categories:
  • Physical or anatomical barriers at the body surface.
  • Chemical defenses.
  • Genetic resistance to infection.
• Block the entry of not only microbes but any foreign agent (living or not).

Physical or Anatomical Barriers

• Built-in defenses in skin
  • Outermost layer of skin with epithelial cells cemented together, and impregnated with keratin.
  • Flushing effect of sweat
• Mucous membranes
  • Coating of digestive, genitourinary, and respiratory tracts
  • Blinking and tear production
  • Flow of saliva
  • Flushing effect of urination, defecation, vomiting
• Mucous coat impedes attachment and entry of bacteria
• Ciliary defense of respiratory tree: nasal hair traps larger particles

Nonspecific Chemical Defenses

• From skin and mucous membranes
  • Sebaceous secretions
  • Antimicrobial secretions from specialized glands (meibomian glands)
• Other defenses in tears, saliva, and skin:
  • Lysozyme, an enzyme that hydrolyzes the cell wall of bacteria
  • Defensins, peptides that lyse bacteria and fungi
  • High lactic acid and electrolyte concentration in sweat
  • Skin’s acidic pH
• Hydrochloric acid in the stomach
• Digestive juices and bile of intestines
• Semen contains an antimicrobial chemical
• Vagina has an acidic pH (maintained by microbiota)

Genetic Defenses

• Some hosts are genetically immune to the diseases of other hosts
  • Humans can’t acquire distemper from cats, and cats can’t get mumps from humans.
  • Viruses have great specificity for their host receptors.
• Some genetic differences in susceptibility exist for other pathogens, including differences within members of the same species.
  • Humans carrying a gene or genes for sickle-cell anemia are resistant to malaria

Structure and Function of the Organs of Defense and Immunity

• Immunology: study of the body’s 2nd and 3rd lines of defense
• Primary functions of a healthy immune system:
  • Surveillance of the body
  • Recognition and differentiation of normal versus foreign material
  • Attack against and destruction of entities deemed to be foreign
• White blood cells (leukocytes) – innate capacity to recognize and differentiate any foreign material
  • Nonself – foreign material
  • Self – normal cells of the body
• Pathogen-associated patterns (PAMPs) – molecules shared by microorganisms
• Pathogen recognition receptors (PRRs) – receptors on WBCs for PAMPs

Origin, Composition, and Functions of Blood

• Whole blood: plasma and formed elements (blood cells)
  • Serum: liquid portion of blood after a clot has formed (minus clotting factors)
  • Plasma – 92% water, metabolic proteins, globulins, clotting factors, hormones, and other chemicals and gases to support normal physiological functions

A Survey of Blood Cells

• Hemopoiesis (or hematopoiesis) – production of blood cells
• Stem cells – undifferentiated cells, precursor of new blood cells
• Primary cell lines:
  • Platelets (thrombocytes)
  • Red blood cells (RBCs)
  • Leukocytes or white blood cells (WBCs), responsible for immune function
    • Granulocytes: lobed nucleus
    • Agranulocytes: unlobed, rounded nucleus

Granulocytes

• Neutrophils – 55-90% - lobed nuclei with lavender granules; phagocytes
• Eosinophils – 1-3% - orange granules and bilobed nucleus; destroy eukaryotic pathogens
• Basophils – 0.5% - constricted nuclei, dark blue granules; release potent chemical mediators
  • Mast cells: nonmotile elements bound to connective tissue

Agranulocytes

• Lymphocytes – 20-35%, specific immune response
  • B (humoral immunity): activated B cells produce antibodies
  • T cells (cell-mediated immunity): activated T cells modulate immune functions and kill foreign cells
• Monocytes, macrophages – 3-7% - largest of WBCs, kidney-shaped nucleus; phagocytic
  • Macrophages: final differentiation of monocytes
  • Dendritic cells: trap pathogens and participate in immune reactions

Characteristics of Leukocytes

Erythrocytes and Platelet Lines

• Erythrocytes: develop from bone marrow stem cells, lose nucleus, simple biconcave sacs of hemoglobin
• Platelets: formed elements in circulating blood that are not whole cells

Lymphatic System

• Provides an auxiliary route for return of extracellular fluid to the circulatory system
• Acts as a drain-off system for the inflammatory response
• Renders surveillance, recognition, and protection against foreign material

Lymphatic Fluid

• Lymph is a plasma-like liquid carried by lymphatic circulation
• Formed when blood components move out of blood vessels into extracellular spaces
• Made up of water, dissolved salts, 2-5% proteins
• Transports white blood cells, fats, cellular debris, and infectious agents

Lymphatic Vessels

• Lymphatic capillaries permeate all parts of the body except the CNS, bone, placenta, and thymus
• Thin walls easily permeated by extracellular fluid which is then moved through contraction of skeletal muscles
• Functions to return lymph to circulation; flow is one-direction – toward the heart – eventually returning to blood stream

Classification of Lymphoid Organs and Tissues

• Primary organs
  • Sites of lymphocytic origin and maturation
  • Thymus gland
  • Bone marrow
• Secondary organs and tissues
  • Circulatory-based locations
    • Lymph nodes
    • Spleen
• Collections of cells distributed throughout skin and mucous membranes
  • MALT—mucosal-associated lymphoid tissue
  • SALT—skin-associated lymphoid tissue
  • GALT—gut-associated lymphoid tissue (Peyer’s patches)

Lymphoid Organs

• Thymus
  • High growth and activity until puberty, then begins to shrink
  • Site of T-cell maturation
• Lymph nodes
  • Small, encapsulated, bean-shaped organs along lymphatic channels and large blood vessels of the thoracic and abdominal cavities
• Spleen
  • Nestled below the diaphragm and left of the stomach
  • Structurally similar to lymph node; filters circulating blood to remove worn out RBCs and pathogens

Second-Line Defenses: Inflammation

• Mechanisms that play important roles in host defenses:
  • Recognition
  • Inflammation
  • Phagocytosis
  • Interferon
  • Complement
• Nonspecific in their effects but they support and interact with specific immune responses

Inflammatory Response

• Reaction to any traumatic event in the tissues that attempts to restore homeostasis
• Helps to clear away invading microbes and cellular debris left by immune reactions
• Signs and symptoms:
  • Redness – increased circulation and vasodilation in response to chemical mediators
  • Warmth – heat given off by the increased blood flow
  • Swelling – increased fluid in the tissue as blood vessels dilate – edema; WBC’s, microbes, debris, and fluid collect to form pus; prevents spread of infection
  • Pain – stimulation of nerve endings

Major Inflammatory Events

• Injury/Immediate Reactions: Blood vessels narrow (vasoconstriction); blood clots; and mast cells release chemokines and cytokines into injured area.
• Vascular Reactions: Nearby blood vessels dilate; increased blood flow; increased vascular permeability; increased leakage of fluid forms exudate.
• Edema and Pus Formation: Collection of fluid; edema/swelling; infiltration by neutrophils and formation of pus.
• Resolution/Scar Formation: Macrophages lymphocytes, and fibrolasts migrate in; initiate immune response and repair of injury; scar and loss of normal tissue.

Chemical Mediators of Inflammatory Response

• Formation of a Blood Clot: fibrinogen converted to fibrin (white strands)

Unique Characteristics of Leukocytes

• Diapedesis – migration of cells out of blood vessels into the tissues
• Chemotaxis – migration in response to specific chemicals at the site of injury or infection

Fever: An Adjunct to Inflammation

• Initiated by circulating pyrogens which reset the hypothalamus to increase body temperature; signals muscles to increase heat production and vasoconstriction
  • Exogenous pyrogens – products of infectious agents; endotoxin
  • Endogenous pyrogens – liberated by monocytes, neutrophils, and macrophages during phagocytosis; interleukin-1 (IL-1) and tumor necrosis factor (TNF)
• Benefits of fever:
  • Inhibits multiplication of temperature-sensitive microorganisms
  • Impedes nutrition of bacteria by reducing the available iron
  • Increases metabolism and stimulates immune reactions and protective physiological processes

Second-Line of Defenses: Phagocytosis

• General activities of phagocytes:
  • To survey tissue compartments and discover microbes, particulate matter, and dead or injured cells
  • To ingest and eliminate these materials
  • To extract immunogenic information from foreign matter
• Major categories of phagocytes:
  • Neutrophils – general-purpose; react early to bacteria and other foreign materials, and to damaged tissue
  • Eosinophils – attracted to sites of parasitic infections and antigen-antibody reactions
  • Macrophages – derived from monocytes; scavenge and process foreign substances to prepare them for reactions with B and T lymphocytes

Development of Monocytes and Macrophages

• After leaving the bloodstream and entering the tissue, monocytes are transformed by inflammatory mediators into macrophages or dendritic cells
• Macrophage and dendritic cells can remain nomadic or take up residence in a specific organ

Phagocytic Recognition

• Protein receptors within the cell membrane of macrophages, called Toll-like receptors (TLRs)
• Detect foreign molecules and signal the macrophage to produce chemicals to stimulate an immune response

Mechanisms of Phagocytosis

• Chemotaxis, binding, and ingestion
  • Phagocytes migrate to inflammation following a gradient of stimulant products
  • Using TLRs they bind pathogen-associated molecular pattern (PAMPs) receptors
• Phagolysosome formation
  • Phagocyte extends pseudopods that enclose the pathogen in a vacuole called a phagosome
  • In a short time, lysosomes with antimicrobial substances fuse with the phagosome to form a phagolysosome and digest the pathogen
• Destruction and elimination
  • Oxygen-dependent system (respiratory burst)
  • Liberation of lactic acid, lysozyme, and nitric oxide
  • Undigestible debris are released from the macrophage by exocytosis

Interferon

• Small protein produced by certain WBCs and tissue cells
• Three major types of IFNs:
  • Interferon alpha – product of lymphocytes and macrophages
  • Interferon beta – product of fibroblasts and epithelial cells
  • Interferon gamma – product of T cells
• All produced in response to viruses, RNA, immune products, and antigens
• All three types bind to cell surfaces and induce expression of antiviral proteins and inhibit expression of cancer genes
• IFNs alpha and beta stimulate phagocytes
• IFN gamma is an immune regulator of macrophages and T and B cells

Complement

• Consists of 26 blood proteins that work in concert to destroy bacteria and viruses
• Complement proteins are activated by cleavage (cascade reaction)
• Pathways
  • Classical – activated by the presence of antibody bound to the microorganism
  • Lectin pathway – nonspecific reaction of a host serum protein that binds mannan
  • Alternative – begins when complement proteins bind to normal cell wall and surface components of microorganisms

Complement System

• Classical Pathway: Complement-fixing antibodies $C1q, C1r, C1s$, Factors $C4, C2, C3$. Rapid and Specific effects.
• MB-Lectin Pathway: Mannose-binding Lectin (MBL) binds mannose on pathogen surfaces and nonspecific for bacteria and viruses (MBL, MASP-1, MASP-2, Factors $C4, C2, C3$)
• Alternative Pathway: Molecules on surfaces of bacteria, viruses and parasites. Nonspecific (Factors B, D, $C3$)
• $C3$ Convertase: Converts the $C3$ molecule to an activator of cascade $C3b$.
• $C5$ Factor is acted on by $C3b$, which converts it to $C5b$.
• $C5b$ becomes bound to the membrane and serves as the starting molecule for the chain of events that assemble the complex in the last two steps of the pathway.
• Two products of the cascade reaction—$C3a$ and $C5a$—have additional inflammatory functions. Both molecules stimulate mast cell degranulation, enhance chemotaxis of white blood cells, and act as inflammatory mediators.

Membrane Attack Complex (MAC)

• $C5b$ is a reactive site for the final assembly of an attack complex. In series, $C6$, $C7$, and $C8$ aggregate with $C5b$ and become integrated into the membrane. They form a substrate upon which the final component, $C9$, can bind. Up to 15 of these $C9$ units ring the central core of the final membrane attack complex (MAC).
• Insertion of MACs produces hundreds of tiny holes in the cell membrane. This can cause lysis and death of eukaryotic cells and many gram-negative bacteria.

Overview of the Major Host Defenses

• Innate, nonspecific
  • First line of defense
    • Physical barriers
    • Chemical barriers
    • Genetic barriers
  • The first line of defense is a surface protection composed of anatomical and physiological barriers that keep microbes from penetrating sterile body compartments.
• Second line of defense
  • Inflammatory response
  • Interferons
  • Phagocytosis
  • Complement
  • The second line of defense is a cellular and chemical system that comes immediately into play if infectious agents make it past the surface defenses. Examples include phagocytes that destroy foreign matter, and inflammation which holds infections in check.
• Acquired, specific
  • Third line of defense
    • B and T lymphocytes, antibodies, cytotoxicity
  • The third line of defense includes specific host defenses that must be developed uniquely for each microbe through the action of specialized white blood cells. This form of immunity is marked by its activity toward specific pathogens and development of memory.