Immunology Test One

The Immune System

protects the body against disease

Immunology

the study of all aspects of the immune system that protect the body from invading organisms

Commensal Organisms

• microorganisms that normally colonize the healthy human body

• do NOT normally cause disease

Microbiota/Microflora

• the microbial community that inhabits a particular site

  • i.e., intestinal microbiota/microflora

Beneficial Commensal Organisms

aid in:

• metabolic functions

• protective functions

• immune system development

Opportunistic Pathogens

• some commensals

• don’t normally cause disease, but have the potential to if:

  • an individual is immunocompromised, or the body’s defenses are compromised

  • and/or the microbe grows beyond its typical load or gains access to a site that it doesn’t normally colonize

Pathogens

organisms that cause disease

4 Groups of Pathogens

• bacteria

• viruses

• fungi

• parasites

Gram-Positive Bacteria

cell wall contains lipoteichoic acid (LTA), teichoic acid (TA) and peptidoglycan

Gram-Negative Bacteria

outer membrane contains lipopolysaccharide (LPs)

Genetic Material (DNA)

is highly conserved among bacteria

Viruses

the genetic material (DNA or RNA) is surrounded by outer capsid proteins with or without a lipoprotein bilayer envelope

Fungi

• eukaryotic organisms and include yeasts and molds

• ubiquitous in the environment, but only a limited number of fungi cause severe infections (usually in the immunocompromised)

• cell wall contains repetitive carbohydrates, such as ß-glucans, chitin, and mannans added to fungal proteins

• genetic material (DNA) is highly conserved

Protozoan Parasites

single-celled eukaryotes

Antigen

a structure that binds to an immune system receptor (i.e. to activate an immune response)

• typically not part of the human body

Pathogen Associated Molecular Patterns

• antigens that are highly conserved within a pathogen group

• activate the innate immune response

• recognized by pattern recognition receptors (PRRs)

Helminths (worms)

large, multicellular eukaryotes

Innate Response Speed

fast acting, immediate, within hours

Adaptive Response Speed

takes time to develop, at least five days for an initial response (faster for memory response)

Innate Response Specifity

• fixed number of receptors recognize conserved antigens called PAMPS

• response is non-specific, e.g., produces a response to ”bacteria”

Adaptive Response Specifity

• receptors re-arrange to produce an infinite number of receptor specifies that recognizes complex structures

• response is highly pathogen specific, e.g., produces a response to “S. pneumoniae” or “S. pyogenes”

Innate Response Strength

strength of response is constant

Adaptive Response Strength

response gets stronger during on infection

Innate Memory Response

none

Adaptive Memory Response

memory responses are faster, stronger, and more effective than primary responses

The Innate Immune Response

• effectively clears most early infections before symptoms develop

• also necessary for activation of the adaptive response

If the Innate Immune Response cannot clear the infection,

it holds it in check until the stronger adaptive immune response develops

Hematopoiesis

• development of blood cells

  • following birth, it takes place in the bone marrow

Blood Cells

arise from the hematopoietic stem cell (HSC) in the bone marrow

Hematopoietic Stem Cells

differentiate to myeloid and lymphoid precursors

Lymphoid Lineage

T cells, B cells, and innate lymphoid cells (which include natural killer cells) are of _____________ ______________

Red Blood Cells

carry oxygen around the body

Platelets

clot blood after damage to blood vessels

White Blood Cells

• cells of the immune system

  • also called leukocytes

Mast Cells

• important in defense against parasites

• responsible for type 1 allergic reactions

Eosinophils

• involved in defense against parasites

• contribute to type 1 allergic reactions

Basophils

• rare immune cells

• involved in defense against parasites

• contribute to type 1 allergic reactions

Neutrophils

• specialized for the phagocytosis and killing of microbes

• most abundant leukocyte in the blood

Monocytes

• phagocytes

• blood precursors to macrophages

• differentiate to macrophages upon leaving blood and entering tissues

Macrophages

• circulate in tissues and detect invading microbes

• phagocytosis of microbes and general debris

• initiate an innate immune response

Conventional Dendritic Cells

• professional antigen presenting cell (APC)

• picks up antigens in tissues and moves to secondary lymphoid tissues to present antigen to T cells to activate T cells and initiate adaptive immune responses

Plasmacytoid Dendritic Cells

secrete large amounts of type 1 interferons (IFN⍺ and IFNβ)

B cells

differentiate into plasma cells that secrete antibodies

T cells

involved in almost all aspects of adaptive immunity

• 2 types: CD8 T cells and CD4 T cells

Plasma Cells

differentiate from B cells

• secrete antibodies

Innate Lymphoid Cells

kill host (body) cells infected with an intracellular pathogen (most often a virus) as well as early tumor cells (parallel the function of CD8 T cells, which function during the adaptive immune response)

Helper Innate Lymphoid Cells (ILC 1, ILC 2, and ILC 3)

produce cytokines to promote the functions of other cells during the innate immune response

• parallel the functions of CD4 helper T cells, which function during the adaptive immune response

Lymphoid-Tissue Inducer (LTi) cells

facilitate the development of secondary lymphoid tissues

Lymph

formed from extracellular fluid (which in turn, is formed from blood plasma) that is drained into lymphatic vessels

Lymphatic System

• lymphatic vessels

• lymphatic tissues

Lymphatic Vessels

drain lymph through secondary lymphoid tissues and return it to the circulatory system

Primary/Central Lymphoid Tissues

• sites of B cell and T cell development

• bone marrow and thymus

Secondary/Peripheral Lymphoid Tissues

• sites of B cell and T cell activation

• lymph nodes, spleen, Peyer’s patches, tonsils, adenoids, appendix

Spleen

has no direct connections with the lymphatic vessels (it filters blood borne antigens)

B cells and T cells

leave atrial blood and enter secondary lymphoid tissues where they sample antigens that arrive in lymph

If not activated,

B cells and T cells return to the blood via the lymphatics and continue to recirculate between the blood and lymphatic system until they become activated

Complement Proteins

made by the liver and circulate in body fluids (blood plasma, lymph, and extracellular fluid)

• named C1, C2, C3, etc

Complement System Functions

1. production of C3b, which is an opsonin (promotes phagocytosis)

2. production of membrane attack complex (forms a pore in the pathogen membrane)

3. production of the pro-inflammatory cytokines C3a and C5a

Complement System: Alternative pathway

• first to be activated

• environment at the pathogen surface alters C3 conformation to resemble that of activated C3b

Complement System: Lectin Pathway

• second to be activated

• mannose-binding lectin binds to pathogen surface and activates the complement cascade and production of C3b

• initiated by lectins

  • lectins are carbohydrate-binding proteins

  • acute phase proteins

  • function as an opsonin and activate the complement system

Complement System: Classical Pathway

• last to be activated

• c-reactive protein or antibody binds specific antigens on pathogen surface, activating the complement cascade and production of C3b

• initiated by C-reactive protein (CRP)

  • binds to phosphocholine

  • acute phase protein

  • functions as an opsonin and activates the complement system via C1

Cytokines

• proteins released by cells that affect the behavior of other cells

• interleukins (IL) are a group of cytokines e.g., IL-1, IL-18

• interferons (IFN) are generally antiviral cytokines

Chemokines

• cytokines that induce chemotaxis (movement of cells towards the chemokine gradient)

• abbreviated as CC or CXC

Signaling Receptors

• toll-like receptors (TLRs)

• NOD-like receptors (NLRs)

• RIG-I-like receptors (RLRs)

• DNA sensors

Toll-like receptors

• located on the cell surface and in endosomes

• activation results in the production of cytokines

• several different receptors (10) that collectively recognize a range of different PAMPs

• present on various leukocytes and epithelial cells

NOD-like receptors

• located in cytoplasm

• intracellular sensors of bacteria and viruses

RIG-I-like receptors

• located in the cytoplasm

• detect viral RNA

DNA sensors

• located in the cytoplasm

• detect bacterial and viral DNA

Pro-inflammatory cytokines

• act on local blood vessels resulting in:

  • dilation, upregulation of adhesion molecules and increased permeability resulting in movement of fluid and immune cells out of the blood into the tissue

  • causes edema/swelling, pain heat, and redness

Neutrophils Recruited by Chemokines

• function as phagocytes

  • particularly important for extracellular bacterial and fungal infections

  • contain performed granules with various antimicrobial substances

  • phagosome fuses with granules prior to the lysosome

• short-lived

  • form pus upon death

Upon death neutrophils:

• undergo apoptosis

  • then removed by macrophages

OR

• die by netosis

  • produce NETs (neutrophil extracellular traps)

  • composed of a network of chromatin, bactericidal peptides, proteases

  • trap and kill microbes

Inflammatory Cytokines

• act on the hypothalamus to increase body temperature

• increase metabolism of fat and muscle to allow increased body temperature

• promotes decreased pathogen replication

Acute phase proteins

change concentration by more than 25% during infection

Antiviral Interferon Response

can be initiated by macrophages as well as most other cell types in the body— because most cell types can be infected with a virus

Activation of Type 1 Interferons

• detection of viral PAMPs results in _____________________

  • almost all cells can produce an interferon response

  • type 1 interferons produce an interferon response in the infected cell as well as in neighboring cells

Activation of Alternative Pathway

the first to be activated

1. activated by spontaneously tick-over of C3, which changes shape to expose the reactive bond

2. the bond is attacked by water to produce iC3

3. factor B binds iC3 and is then cleaved by factor D to produce Bs (unknown function) and iC3Bb (soluble convertaase)

4. iC3Bb cleaves C3 to produce C3a (inflammatory cytokine) and C3b

5. if a pathogen surface is close by, then C3b becomes fixed

C3b Fixation

factor B also binds to fixed C3b

• factor D then cleaves factor B to form Ba and C3bBb (alternative C3 convertase)

• amplifies complement fixation

Structure of Lectin Pathway

• associates with MASP-1 and MASP-2

• MASP-2 protease is activated when MBL binds pathogen

Structure of C1

• C1 associates with C1r:C1s pairs

• C1r protease activated upon binding to CRP (or antibody) and cleaves C1s

Activated MBL or CI (via CRP)

1. cleaves C4 to C4a and C4b

   • some C4b gets fixed on the pathogen surface

   • C4a is a weak inflammatory mediator (C5a> C3a> C4a)

2. Cleaves C2 to C2a and C2b

   • fixed C4b binds C2a to form the classical C3 convertase (C4b2a)

     • cleaves C3 to C3a and C3b

C3b

is an opsonin that binds to a pathogen surface as well as cellular debris and promotes phagocytosis

Phagocytes have complement receptor 1 (CR1)

binds to C3b, which facilitates phagocytosis of the coated material

Complement Control proteins

prevent the complement system from damaging host tissues

DAF, MCP, factor H, and CR1

disrupt C3bBb on human cell surfaces

• inhibit complement fixation

C5b

initiates formation of the membrane attack complex (MAC)

• forms a pore in microbial cell membranes

Membrane Attack Complex Sequence of Events

• C5b, C6, and C7 associate together sequentially

• C7 then undergoes a conformational change to expose a membrane binding domain which inserts in the membrane

• C8 binds and undergoes a conformational change to expose a membrane-binding domain

• binding of C8 initiates C9 polymerization to form a pore

The Membrane Attack Complex

disrupts microbial cell membranes

Soluble proteins, S protein, clusterin, and Factor J

prevent the C5b67 complex associating with membranes

Homologous Restriction Factor (HRF) and CD59 (protectin)

inhibit binding of C9 to host cell membranes

Paroxysmal Nocturnal Hemoglobinuria

results from complement control protein deficiencies

C3a and C5a

are pro-inflammatory cytokines that act on blood vessels to produce inflammation

Inherited Neutropenia

• affects less than 1 in 200,000

• neutrophil deficiency

• results in frequent infections with extracellular bacteria and fungi

• treatments: antibiotic and anti-fungal drugs, a cytokine (G-CSF) that may stimulate neutrophil production; hematopoietic stem cell transplantation for serious cases

Leukocyte Adhesion Deficiency

• affects 1 in 1,000,000

• deficiency in adhesion molecules necessary for phagocytes to leave the blood and enter tissues

• results in more frequent, often severe, bacterial and fungal infections

• treatment: antibiotic and antifungal drugs, hematopoietic stem cell transplantation for serious cases

Chronic Granulomatous Disease

• affects 1 in 250,000

• phagocytes can’t kill certain bacteria and fungi during phagocytosis

• results in chronic, recurrent, bacterial and fungal infections

• granulomas and abscesses are characteristics

• treatments: antibacterial and antifungal drugs for prevention and treatment, corticosteroids as needed, hematopoietic stem cell transplantation

Stages of an Immune Response

1. epithelial surfaces are effective barriers to infection

2. microbes that cross epithelial surfaces are detected by:

   • macrophages, which initiate an immune response

   • dendritic cells, which traffic to secondary lymphoid tissues

3. innate immune responses are activated

4. a stronger adaptive immune response develops over several days

Antigens

are transported from the site of infection to secondary lymphoid tissues via the lymphatic vessels

Activated B-cells

differentiate into plasma cells that secrete antibody

Activated T-cells

differentiate into one of several subsets (cytotoxic T-cells, helper T-cells or regulatory T-cells)

B-cells and Plasma cells

• have the B-cell receptor on their surface

• plasma cells secrete the receptor as soluble antibody instead of putting the molecule on their surface (i.e., antibodies are a secreted form of the B-cell receptor)

• antibodies bind to antigens

Functions of Antibodies

1. neutralization

2. opsonization

3. activation of the classical complement pathway

4. antibody dependent cell mediated cytotoxicity (ADCC)