Pathogens and Immunity

Edward Jenner

• Edward Jenner discovered vaccination in the late 18th century
• Jenner's work involved the inoculation of cowpox to protect against smallpox

Robert Koch

• Robert Koch proved that infectious diseases are caused by microorganisms

Commensal Microorganisms

• More than 1000 different species live in the healthy adult human gut
• Commensal microorganisms "eat at the same table"
• Animals are tolerant of and dependent upon their commensal species
• The colon is colonized by large numbers of commensal bacteria
• Oral antibiotics disrupt the natural ecology of the colon, killing beneficial bacteria
• Destruction of the beneficial bacteria allows pathogenic strains to populate and cause disease

Pathogens

• Pathogens are infectious organisms that cause disease
• The four kinds include bacteria, viruses, fungi, and internal parasites
• Pathogens evolved special adaptations to invade their hosts, replicate, and get transmitted

Body Barriers Against Infection

• Skin is a tough, impenetrable barrier of epithelium protected by keratinized cells
• Skin serves as the body's first defense against infection
• Physical damage, such as wounds, burns, or surgical procedures, can violate the skin
• Mucosae lining the respiratory, gastrointestinal, and urogenital tracts are other epithelia

Innate Immune Response

• The Innate immune response causes inflammation at sites of infection
• Consists of recognition via soluble or surface-bound receptor proteins (mainly phagocytes)
• Consists of the recruitment of effector mechanisms to kill and eliminate the pathogen

Recognition of Pathogens

• Pathogen destruction is illustrated by a fundamental process
• Serum proteins of the complement system are activated in the presence of a pathogen
• A complement tags the pathogen as dangerous
• A soluble complement fragment binds to a receptor on the surface of a phagocytic WBC
• Binding summons the WBC to the site of complement activation
• The receptor and its ligand are taken up into the cell by phagocytosis

Inflammation

• Inflammation is characterized by heat, pain, redness, and swelling
• Heat – calor; pain – dolor; redness – rubor; and swelling – tumor
• Inflammation results from the immune system's response to a pathogen
• Inflammation is caused by bacteria activating resident effector cells that secrete cytokines
• The cytokines cause vasodilation and increased vascular permeability, which allows fluid, protein, and inflammatory cells to leave the blood and enter tissue

Adaptive Immune Response

• Adaptive immunity adds onto the ongoing innate immune response
• Adaptive immunity is not deployed without the preceding innate response
• A primary infection is cleared from the body via the combined effects of both adaptive and innate immunity
• Innate immunity is faster, fixed, has limited specificities, and is constant during its response
• Adaptive immunity is slower, variable, has numerous selective specificities, and improves during the response

Medical Practice

• Medical practice is concerned with infections that innate immunity fails to terminate

Hematopoietic Stem Cells

• Immune system cells with different functions all derive from hematopoietic stem cells

Human Hematopoiesis

• Blood cells are first made in the yolk sac of the embryo
• Next, blood cells start being made 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 aids in the production of antibodies (B cells) and cytotoxic and helper functions (T cells)
• Plasma cells are fully differentiated form of B cells that secrete antibodies
• Natural killer cells kill cells infected with certain viruses
• Neutrophils perform phagocytosis and killing of microorganisms
• Monocytes are a circulating precursor cell to macrophages
• Macrophages perform phagocytosis and killing of microorganisms and activate T cells and initiate immune responses
• Dendritic cells activate T cells and initiate adaptive immune responses
• Mast cells assist with the expulsion of parasites from the body through the release of granules containing histamine and other active agents
• Eosinophils assist with the killing of antibody-coated parasites through the release of granule contents
• Basophils control immune responses to parasites
• Megakaryocytes assist with platelet formation and wound repair
• Erythrocytes engage in oxygen transport

Leukocytes

• Neutrophils comprise 40-75%
• Lymphocytes comprise 20-50%
• Monocytes comprise 2-10%
• Eosinophils comprise 1-6%
• Basophils comprise <1%

Neutrophils

• Neutrophils are stored in the bone marrow and released when needed to fight infection
• Once released, neutrophils move to the site of infection where they engulf and kill bacteria
• After ingestion/killing, neutrophils die and are engulfed/degraded by macrophages
• Pus is composed of dead neutrophils

Macrophages

• Macrophages respond to pathogens by using different receptors
• They use receptors to stimulate phagocytosis and cytokine secretion

Lymphocyte Receptors

• Immunoglobulins and T-cell receptors are the diverse lymphocyte receptors of adaptive immunity

B-cell receptor

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

Plasma cell receptor

• Secreted soluble antibody (Ab) lacking transmembrane tail
• Otherwise identical to B cell receptor (BCR)

T-cell receptor

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

Activated T-cells

• Cytotoxic T cells: Tc
• Helper T cells: TH

TH Cells

• Subset that activates B cells
• This leads to antibody (Ab)-secreting plasma cells

Antibodies

• Antibodies bind to pathogens and cause their inactivation or destruction
• The main function of antibodies is to facilitate engulfment and destruction of foreign bodies by phagocytes
• Abs Neutralize toxins by binding to them to prevent their interaction with receptors on cells
• IgG opsonizes bacteria/coats bacterium via binding with the variable region
• The macrophage recognizes the constant region of the antibody, leading to phagocytosis

Lymphoid Tissues

• Most lymphocytes are present in specialized lymphoid tissues
• The Primary lymphoid tissues are the sites of development and maturation of lymphocytes, including the BM and thymus
• The Secondary lymphoid tissues are the sites of stimulation in response to pathogens

Secondary Lymphoid Tissues

• Includes all lymphoid tissues aside the BM and thymus

Lymphocyte Recirculation

• Lymphocytes continually recirculate through the blood and lymph

Adaptive Immunity

• Adaptive immunity initiation occurs in the secondary lymphoid tissues

Lymph Node Architecture

• Kidney-shaped organs composed of a cortex and medulla
• The lymph nodes are where bloodborne lymphocytes respond to lymphborne pathogens
• They contain packed lymphocytes, macrophages, and cells of the immune system
• Lymph nodes are structured in layers of percolating lymph including the myeloid sinus, T-cell area, germinal center and marginal sinus

Lymph Node

• Free pathogens and debris are removed by macrophages
• Dendritic cells become lymph node residents and move to T-cell areas to stimulate lymphocyte division and differentiation
• Some helper T cells and cytotoxic T cells leave in the efferent lymph and travel to infected tissue
• Some helper T cells remain in the lymph node and stimulate B cell division and differentiation into plasma cells
• Plasma cells move to the medulla to secrete pathogen-specific Abs which circulate in the efferent lymph and blood to the BM

The Spleen

• The spleen provides adaptive immunity to blood infections
• It resides in the upper left part of the abdomen
• It weighs approximately 150 grams
• The spleen serves as filter for the blood removing aged RBCs defending the body against blood-borne pathogens
• Asplenia is the case of being born without a spleen

Spleen Structure

• Nodule of white pulp comprises a central arteriole surrounded by a sheath of lymphocytes – periarteriolar lymphoid sheath (PALS)
• Lymphocytes closest to the arteriole are mostly T cells, while B cells are placed more peripherally
• Lymphoid follicles consist of a germinal center, B-cell corona, and a marginal zone, which hosts macrophages and differentiating B cells
• Follicles and PALS are surrounded by a perifollicular zone that abuts the red pulp and contains erythrocytes, macrophages, T cells, and B cells

Mucosa-Associated Lymphoid Tissue (MALT)

• 2 types named according to location – gastrointestinal and respiratory tracts
• GALT occurs in the GI tract, including the tonsils, adenoids, appendix, and Peyer's patches
• BALT occurs in the respiratory tract

Gut Associated Lymphoid Tissue (GALT)

• Has a similar structure as the lymph node and spleen’s white pulp
• M cells in the gut epithelium deliver pathogens from the gut lumen to the lymphoid tissue within the gut wall

Commensal Microorganisms

• Mammalian babies do not have commensal microorganisms before birth
• Via family and pets, commensals populate the skin and mucosal surfaces after birth
• Microbiota influences and shapes the development of the immune system

Epithelia

• Epithelia prevent pathogens by crossing and from colonizing tissues
• Epithelia provide mechanical, chemical, and microbiological barriers against infection

Pathogens

• Extracellular pathogens live/replicate in the spaces between cells
• Extracellular pathogens are accessible to the immune system's soluble/secreted molecules
• Intracellular pathogens live/replicate inside cells
• Host cells must be eliminated to allow soluble immune system molecules to get to intracellular pathogens

Complement Systems

• Complement systems mark pathogens via plasma proteins for destruction
• Soluble proteins present in the blood, lymph, and ECF
• Many are proteases that circulate as inactive "zymogens"
• They are activated upon infection
• Complement proteins activate each other in cascade via proteolytic cleavage

C3b

• Key products of complement activation
• A large fragment that is chemically reactive and becomes covalently attached/fixed to the pathogen's surface
• C3b marks the pathogen as dangerous

C3a

• Key products of complement activation
• Recruits phagocytic cells to the site

Complement Activation Pathways

• Three include alternative, lectin, and classical pathways

Alternative Pathway

• First to be activated
• Part of innate immunity
• Initiated by direct interaction with pathogen

Lectin Pathway

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

Classical Pathway

• Initiation by the binding of C-reactive protein to pathogen surfaces is part of innate response
• Initiation by the binding of Abs to pathogen surfaces is part of adaptive response

Alternative Activation

• Constituent bacterial changes induce change in the local environment
• This triggers hydrolysis of serum that gives C3(H2O), also called iC3
• iC3 binds to inactive complement factor B as factor B is cleaved by a protease
• A protease gives iC3Bb, which is a soluble C3 convertase cleaves C3 into C3a and C3b
• The fragments covalently attach to the pathogen surface

C3 Converted

• The alternative C3 convertase C3bBb functions at the pathogen’s surface
• It also functions like soluble iC3Bb but is pathogen-bound, so cannot diffuse away
• Some molecules cleave more C3 molecules and fix more C3at surface
• This assembly of even more convertase leads to rapid coding and a positive feedback loop with C3b

Complement Control Proteins

• Determine C3b deposition extent/site and formation
• Factor P extends lifetime on a microbial surface
• Factor I cleaves and inactivates C3bBb using Factor H

Human Cell Surface

• DAF and MCP are regulators
• They disrupt C3bBb on the human cell surface

Macrophages

• Form a first line of cellular defense against invading microbes
• Mature forms of circulating monocytes
• Monocytes leave the blood to reside in tissues
• They are prevalent in connective tissues, GI and respiratory tracts, and the liver
• Participate in innate and adaptive immunity

Phagocytes

• Complement receptors trigger the uptake and breakdown of C3b-coated pathogens
• CR1 on macrophage surfaces recognize CR1-coated pathogens
• Upon recognition/interaction, intracellular signals generate and enhance phagocytosis and phagosome fusion with lysosomes

The Terminal Complement

• Terminal complement proteins cause lysis of pathogens by generating membrane passages known as membrane attack complex
• C5 converts to C5b during activation
• C5b initiates the MAC
• C5b stabilizes C5b
• MAC causes destruction of bacterial cells and eurkaryotic cells.
• Polymerization on the C5b678 complex forms the membrane-spanning channel that disrupts the cell's integrity, killing it
• CD59 prevents MAC assembly on the C5b678 complex and forms the pore

Small Peptides

• Small peptides released activate complement locally to induce inflammation
• Fragments induce anaphylactic shock (aka acute inflammatory reaction): called anaphylatoxins
• Some small peptides have mast cells, endothelial, and phagocyte receptors

Role Of Inflammation

• Increase blood flow
• Increase vascular permeability
• Serve as chemoattractants (C5a)

Plasma Proteins

• Limit the spread of infection:
• The coagulation system comprises plasma enzymes forming blood clots and immobilized pathogens to contain
• The kinin system comprises plasma proteins that cause vasodilation to increase supply of innate immunity components
• Protease inhibitors work by inhibiting pathogenic cell-surface or secreted proteases

Proteases

• Alpha a-Macroglobulins inhibit microbial proteases by trapping the protease a bait region
• They bind the protease covalently through activation of the thioester group and restrict other protein submissions

Antimicrobial Peptides (Defensins)

• Kill pathogens by perturbing their membranes
• Is amphipathic with charged or hydrophobic residues
• It leads to the formation of pours or a loss in membrane integrity

Defensins

• Short segments of a helix that rest against three strains of antiparrallel
• Interacts with charged cell surface membranes and inserts into the lipid layer
• Beta and short peptides can interact with charged surfaces of cell membranes and insert into the lipid layer forming pores and compromise membrane integrity
• Produced by Penth cells in the small intestine
• Include HD5 and HD6
• Secrete lysozyme and phospholilipase A2
• Epithelial cell origin and considered as part of the immune system
• It is not a hemopoetic
• The defensins are variable antimicrobial peptides

Pentraxins

• Pentraxins are plasma proteins of innate immunity that bind microorganisms target them to phagocytes
• They play a role similar to that or antibodies
• Serum amyloid P component is short pentraxin that is produced by the liver
• PTX3 is a long pentraxin that is produce by monoocytes macrophages etc.
• Serum C - reactive protein is a principal member of the pentraxin family
• These have bacteria viruses fungin and parasites as ligands