Innate and Adaptive Immunity

• The Immune System, Fourth Edition, Chapter 1 "Elements of the Immune System and their Roles in Defense" study notes:

Edward Jenner and Vaccination

• Edward Jenner discovered vaccination in the late 18th century
• Jenner found that inoculation with cowpox protected against smallpox

Eradication of Smallpox

• Smallpox has been officially eradicated
• Robert Koch determined infectious illnesses are caused by microorganisms

Part 1 Checklist: Topics in the Chapter

• Commensal microorganisms
• Pathogens
• Body barriers against infection
• Inflammation
• Adaptive immunity
• Hematopoietic stem cells

Commensal Microorganisms

• More than 1000 microbial species reside in the healthy adult human gut
• These microorganisms are called "commensal" which means "eat at the same table"
• Animals are both tolerant of and dependent on commensal species

Impact of Antibiotics on Gut Ecology

• Antibiotic treatments can disrupt the natural ecology of the colon
• Antibiotics can destroy beneficial commensal bacteria in the colon
• The destruction of commensal bacteria provides an opportunity for pathogenic strains to colonize and cause disease

Pathogens

• Pathogens: organisms able to inflict disease
• Four kinds of pathogens: bacteria, viruses, fungi, and internal parasites
• Pathogens adapt to invade hosts, replicate, and spread

Types and Routes of Infection for Pathogens

• Fungi can cause Aspergillosis (via Aspergillus species) through inhalation of spores
• Fungi can also cause Athlete's foot (via Tinea pedis) through physical contact
• Protozoan parasites can cause Malaria through the bite of an infected mosquito
• Helminth parasites (worms) can cause Common roundworm (via Ascaris lumbricoides) through oral intake of infected material

Barriers Against Infection

• Skin: acts as the body's initial defense against infection
• The skin consist of a tough, impenetrable barrier of epithelium protected by layers of keratinized cells
• Physical damage, such as wounds, burns, or surgical procedures, can compromise skin
• Other epithelia, such as mucous membranes, line the respiratory, gastrointestinal, and urogenital tracts

Innate Immune Response and Inflammation

• Innate immune response involves: -Recognition via soluble or surface-bound receptor proteins (primitive non-specific recognition: mainly phagocytes) -Recruitment of effector mechanisms to kill and eliminate the pathogen
• Inflammation, characterized by heat, pain, redness, and swelling (calor, dolor, rubor, and tumor, respectively)
• Inflammation is a result of the immune system's response to the pathogen

Comparison of Innate and Adaptive Immunity

• Innate Immunity: -Rapid response (hours)
  -Fixed
  -Limited number of specificities
  -Constant during response
• Adaptive Immunity: -Slow response (days to weeks) -Variable -Numerous highly selective specificities -Improve during response

Benefits of Innate and Adaptive Immunity

• Red Line: uncontrolled infection because adaptive immune response cannot be deployed without a preceding innate response.
• Green Line: infection is initially contained by innate immunity, but cannot be cleared from the body
• Much of medical practice is concerned with the small proportion of infections that innate immunity fails to terminate.

Hematopoiesis

• Blood cells are first made in the yolk sac of the embryo, and later in the embryonic liver and spleen.
• They also start to be made in the bone marrow before birth
• By birth, the BM is the only tissue in which hematopoiesis occurs

Types of Hematopoietic Cells

• Small lymphocyte: Production of antibodies (B cells) or cytotoxic and helper functions (T cells)
• Dendritic cell: Activation of T cells and initiation of adaptive immune responses
• Plasma cell: Fully differentiated form of B cell that secretes antibodies
• Mast cell: Expulsion of parasites from body through release of granules containing histamine and other active agents
• Natural killer cell: Kills cells infected with certain viruses
• Monocyte: Circulating precursor cell to macrophage
• Neutrophil: Phagocytosis and killing of microorganisms
• Macrophage: Phagocytosis and killing of microorganisms/activation of T cells and initiation of immune responses
• Eosinophil: Killing of antibody-coated parasites through release of granule contents
• Basophil: Controlling immune responses to parasites
• Megakaryocyte: Platelet formation, wound repair
• Erythrocyte: Oxygen transport

Leukocyte Proportions and Neutrophil Function

• Leukocyte proportions in human peripheral blood: Neutrophils (40-75%), Eosinophils (1-6%), Basophils (<1%), Monocytes (2-10%), Lymphocytes (20-50%)
• Neutrophils are stored in the bone marrow and move in large numbers to sites of infection, act, and then die
• After one round of bacteria ingestion and killing, a neutrophil dies
• Pus is composed of dead neutrophils

Macrophage Response to Pathogens

• Macrophages respond to pathogens using different receptors to stimulate phagocytosis and secrete cytokines

Adaptive Immunity

• Immunoglobulins and T-cell receptors are the diverse lymphocyte receptors of adaptive immunity
• Encountering their specific antigen, B cells and T cells differentiate into effector cells
• Antibodies inactivate or destroy pathogens
• Lymphocytes are present in specialized lymphoid tissues
• Adaptive immunity is initiated in secondary lymphoid tissues
• Spleen provides adaptive immunity to blood infections
• Secondary lymphoid tissue is associated with the gut

B-cell Receptor

• Y-shaped immunoglobulin (glycoprotein)
• Membrane-bound, anchored by a transmembrane tail
• Contains two identical Ag-binding sites

Plasma Cell Receptor:

• Soluble Ab secreted with no transmembrane tail
• Otherwise identical to BCR

T-cell receptor:

• Membrane-bound protein with no secreted form
• Only one Ag-binding site

Types of T-cells

• Cytotoxic T cells (Tc)
• Helper T cells (TH)
• A subset of TH cells activate B cells that become Ab-secreting plasma cells

Antibody Function

• Antibody-mediated killing of pathogens involves facilitating the engulfment/destruction of foreign bodies through phagocytes
• Abs combat infection through neutralization of toxins and opsonization of bacteria where IgG can coat the bacterium
• The constant region of the Ab is recognized by receptors on a macrophage, leading to phagocytosis

Types of Lymphoid Tissues

• Primary lymphoid tissues: BM and thymus -Sites of development and maturation of lymphocytes
• Secondary lymphoid tissues: All other lymphoid tissues -Sites of stimulation in response to pathogens

Lymphocyte Recirculation

• Lymphocytes recirculate between blood and lymphoid tissues

Adaptive Immunity Initiation

• Adaptive immunity is initiated in secondary lymphoid tissues

Lymph Node Architecture

• Small kidney-shaped organs
• Composed of a cortex and a medulla
• Blood-borne lymphocytes respond to lymph-borne pathogens in the lymph node
• Lymph node is packed with lymphocytes, macrophages, and other cells of the IS, between which the lymph percolates

Cells in Lymph Node

• Free pathogens and debris are removed by macrophages
• Dendritic cells become resident in the lymph node, specifically stimulating the division and differentiation of small lymphocytes into effector lymphocytes in T-cell areas
• Some helper T cells and cytotoxic T cells leave in the efferent lymph to the infected tissue
• Some helper T cells remain in the lymph node and stimulate the division and differentiation of B cells into plasma cells
• Plasma cells move to the medulla of the lymph node and secrete pathogen-specific antibodies
• The efferent lymph and blood carries antibodies the to the site of infection
• BM is the final destination of some plasma cells where they continue to secrete antibodies

Spleen

• Large lymphoid organ in the upper left of the abdomen weighing abut 150 grams
• Functions: -Remove damaged or senescent RBCs (red pulp) -Act as a secondary lymphoid organ by defending the body against blood-borne pathogens (white pulp)
• Spleen contains central arteriole surrounded by sheath of lymphocytes: periarteriolar lymphoid sheath (PALS).
• Lymphocytes close to the arteriole are mostly T cells (blue region), while B cells are placed more peripherally (yellow regions)
• Lymphoid follicles comprise a germinal center, a B-cell corona, and a marginal zone containing macrophages and differentiating B cells
• Follicles and PALS are surrounded by a perifollicular zone abutting the red pulp that contains a variety of cells, including erythrocytes, macrophages, T cells, and B cells

Mucosa-Associated Lymphoid Tissue (MALT)

• Gastrointestinal and respiratory tracts are invested with secondary lymphoid tissue, for example, Gut-Associated Lymphoid Tissue (GALT) and Bronchial-Associated Lymphoid Tissue (BALT)
• GALT: in the GI tract, includes the tonsils, adenoids, appendix, and Peyer's patches
• BALT: in the respiratory tract
• GALT is organized similarly to the lymph node and the white pulp of the spleen
• M cells in the gut epithelium deliver pathogens from the gut lumen to the lymphoid tissue within the gut wall

Physical Barriers and Commensal Microorganisms

• Mammalian babies have no commensal microorganisms before birth
• After birth, commensals from the environment colonize the skin and mucosal surfaces
• Microbiota is an integral part of a healthy human body; it influences and shapes the development of the IS

Surface Epithelia Protection

• Surface epithelia provide mechanical, chemical and microbiological barriers to infection

Types of Pathogens

• Extracellular pathogens accessible to soluble, secreted molecules of the IS (live and replicate in the spaces between human cells)
• Intracellular pathogens require host cells to be killed to expose pathogens to the soluble IS molecules (live and replicate inside human cells)

Complement System

• The complement system's proteins are made by the liver
• Consist of soluble protein that mark pathogens for destruction
• Circulate as proteases and inactive "zymogens"
• Activated by infection

Complement Activation

• C3 cleavage produces C3b and C3a fragments
• Activation results in covalent attachment of C3b to a pathogen's surface, marking it dangerous
• At the same time, C3a recruits phagocytic cells to the site of infection
• There are three complement activation pathways: Alternative, Lectin, and Classical

Complement Activation Pathways

• Alternative: The first pathway to be activated; part of innate immunity, initiated by direct interaction with pathogen

• Lectin: Initiated by mannose-binding lectin in plasma; Part of innate immunity

• Classical: Initiated in the innate response by the binding of C-reactive protein to pathogen surfaces; Initiated in the adaptive response by the binding of antibodies to pathogen surfaces

Alternative Pathway

• Constituents of bacterial surfaces induce changes in the local physiochemical environment
• These changes trigger the hydrolysis of serum C3, giving C3(H2O) (aka iC3)
• iC3 binds to the inactive complement factor B.
• Cleavage of the bound factor B by a protease (factor D) gives iC3Bb, a soluble C3 convertase: cleaves C3 into C3a and C3b
• C3b fragments covalently attach to the pathogen surface
• The alternative C3 convertase C3bBb works at the surface of the pathogen. It functions similarly to the soluble iC3Bb, but is pathogen-bound so is unable to diffuse away from the pathogen

Regulatory Proteins and C3b Deposition

• Complement control proteins determine formation and stability of C3bBb on the cell surface: -Factor P: extends lifetime on microbial surface
  -Factor I: cleaves and inactivates C3bBb (assisted by Factor H)
  -DAF and MCP: disrupt C3bBb on human cell surface

Phagocytosis by Macrophages

• Mature circulating monocytes that have left the blood to take up residence in the tissues are prevalent in connective tissues, GI and respiratory tracts, and liver (Kupffer cells)
• Macrophages participate in both innate and adaptive immunity
• CR1 generates intracellular signals that enhance phagocytosis, and fusion of the phagosome with lysosomes
• C3b fragments covalently attach to the pathogen surface

The terminal complement attacks

• The terminal complement proteins lyse pathogens by forming membrane pores

Terminal Complement Components

• C5 concentration in serum (µg/ml): 85; function is to activate and initiate assembly of membrane-attack complex in solution
• C6 60: binds to and stabilized C5b
• C7 55: exposure to hydrophobic region that enables cell membrane atachment
• C8 55: inserts into the cell membrane and binds to C5b67
• C9 60: polymerization to form spanning channel to upset integrity in cell death

C5 Activation

• Binding of C3b to creates C3b2Bb: alternative C5 convertase cleaves C5 into C5a and C5b

Membrane Attack Complex

• Initiated by C5b formation of membrane-attack complex (MAC) to create holes in cell membranes of bacterial pathogens and eukaryotic cells

The MAC Attack

• Prevents CD59 assembly made on human cells on CD59
• Prevents C9 from assembling so the complex and polymerizing isn't created

Complement Activation Effects

• Small C3a, C3b fragments are inflammation-inducing, anaphylactic shock-inducing shock and increase blood flow/permability as chemoattractants for C5a

Plasma

• Plasma enzymes create coating to stop pathogens from entering bloodstream
• Plasma enzymes that create vasodilation to the site increased immunity
• Inhibits pathogenic cell-surface proteases with the help of proteases

Production of Membrane Peptides

• In the small intestine crypt, Defensins are released, including lysozyme + phospholipase A2
• Although epithelial-derived and not hematopoietic in orgin, these paneth cells that release A2 and lysozymes are linked to Immunity
• Human defensins are diverse transmembrane peptides used as immunity

Innate Immunity and Defense Pathways

• Defensins can contact charged area and bind to the barrier with pores

Plasma Defence Pathways

• Similar functions to the role of antibodies
• Pentaxins assist like the antibody, 2 types
• CRP is known as the Principal Protein (C-reactive protein)

Explore the complex interplay between commensal microorganisms, innate immunity, and adaptive immunity. Questions cover from the effects of antibiotics on bacterial communities to the crucial role of the skin and mucosal surfaces in defending against infection. Delve into the process of hematopoiesis and how the body responds to primary infections.