Unit 2 Material

Microbio

what is one role of the immune system when discussing microbes

preventing pathology (disease) caused by these microbes

how can a pathogen cause disease?

• gain access to the body either by penetrating the skin or entering through an alternate portal of entry

• bind and enter into cost cells or tissue

• evade the host defense systems long enough to cause harmful changes

what has the immune system developed the ability to do?

the ability to distinguishing healthy self from non-self and infected or damaged self

what is the immune system

a complex organization of cells, tissues, and chemicals regulated by checks, balances, back ups and fail safes to kill invaders and prevent harm to healthy self.

• organized in a tissue specific manner optimized to prevent invasion of pathogenic organism

• also has a diverse range of functions that are highly specialized to be effective against given type of microbe.

what is the first line of defense of the immune system?

barrier to invasion

what is a barrier

a group of tissues/cells/etc that exist at the interface between an individual and the outside world.

what are examples of mechanical barriers

Skin:

• epithelial cells joined by tight junctions

• Longitudinal flow of air or fluid

Gut:

• epithelial cells joined by tight junctions

• Longitudinal flow of air or fluid

Lungs:

• epithelial cells joined by tight junctions

• movement of mucus by cillia

Eyes/Nose:

• epithelial cells joined by tight junctions

• tears

• nasal cillia

what are examples of chemical barriers

Skin:

• fatty acids

• antibacterial peptides

Gut:

• Low pH

• Enzymes (pepsin)

• antibacterial peptides

Lungs:

• antibacterial peptides

Eyes/Nose:

• Enzymes in tears (Lysozyme)

what are examples of microbiological barriers?

Skin:

• normal flora

Gut:

• normal flora

Lungs: N/A

Eyes/Nose: N/A

what happens when the first lines of defense break down or is compromised?

the second and third line of defense [made up of antimicrobial chemicals and immune cells] provide the next layer of protection

what is the lymphatic system?

• home of the 2nd and 3rd line of defense

• circulatory system of chemicals, cells, and tissue

what are the functions of lymphoid organs

optimized to promote efficient immune activation and regulation

important parts of the lymph node to know

• primary lymphoid follicle (mostly B cells)

• paracortical area (T cells)

• germinal center

what are the cells of the immune system?

Leukocytes (white blood cells)

what are adaptive immune cells

B cells and T cells

what are lymphocytes

plasma cells (effector B cells)

activated T cells

what is the function of Neutrophils & Polymorphonuclear cells (PMN):

phagocyte and secretion of the inflammatory mediators and reactive oxygen species

what is the function Dendritic Cells (DC):

THE professional antigen presentation cell, phagocyte, and secretion cytokines

what is a macrophage:

the professional phagocyte, antigen presentation, secretion cytokines and healing

whta are the 3 adaptive immune system cells

1) B Cells

2) T Cells

3) NK cell

what is immunochemistry?

molecules that activate, communicate, and direct immune responses

what are chemical mediatiors of inflammation

“early warning system” that initiate, regulate, and resolve the inflammatory response

what are interleukins?

a chemical system of “cellular” communication

what are chemokines?

a chemical system of “traffic control”

what are the 4 classes of pathogens the immune system protects against

1) extracellular bacteria, parasites, fungi

2) intracellular bacteria and parasites

3) viruses (intracellular)

4) parasitic worms (extracellular)

what is the chronological step by step process of an immune response

1) infection

2) innate recognition of the pathogen

3) activation of innate effectors

4) inflammation (cell and chemically induced)

5) changes in microvasculature

6) recruitment cells to the sight of infection

7) transport of antigen to LN

8) Recognition of pathogen

9) proliferation and differentiation of lymphocytes

10) traffic to sight of infection

11) utilize effector functions

12) amplify steps 2 and 3

13) pathogen clearance and long-term memory

14) Healing

15) and they lived “Happily Ever After”

what is an immune response?

a complex interplay of cells and chemicals of the innate and adaptive immune systems that is coordinate in space in time to eliminate infection

process of an innate immune response

1) production of IFN-a, IFN-B, TNF-a, and IL-12

2) NK-cell-mediated killing of infected cells

3) T-cell- mediated killing of infected cells

process of an adaptive immune response

1) NK-cell-mediated killing of infected cells

2) T-cell- mediated killing of infected cells

what are the two types of Host Defense Mechanisms?

• innate

• adaptive

what is an innate host defense mechanism?

• in born, native, inherent

• common to all individuals ina species

what is an adaptive host defense mechanism?

• acquired, flexible, and adaptive

• specific to an individual based on antigenic experience

what is innate immunity?

• immediate response with broad specificity

• Operate continuously from the time of infection, through the incubation period and until the infection ends

what is adaptive immunity?

• takes time to develop but is highly specific to its target

• becomes apparent toward the end of the prodromal phase and is maintained long after the infection clears (memory and long-term protective immunity)

how is innate and adaptive immunity different?

Time:

• innate: seconds/minutes/hours

• Adaptive: days

Specificity:

• innate: recognition of microbial patterns

• Adaptive: highly specific for single pathogen

Memory:

• innate: no memory

• Adaptive: has a memory

ways of defense:

• innate: Antimicrobial peptides and phagocytic cells

• Adaptive: Antibodies and Lymphocytes

BOTH are chemical mediators of inflammation and killing

what are the two modes of innate function?

Direct action (immediate) and Indirect Action (immediate and delayed)

what is Direct action?

• prevent the entry/proliferation of pathogens

• directly kill invading pathogens

• localize damage

• induce inflammation

what is indirection action?

• induce inflammation

• establish/determine/regulate the type of immune response

• activate the appropriate adaptive immune response

• Activate healing response

what is the functions of Innate Host defense mechanisms

TISSUE SPECIFIC EFFECTOR FUNCTIONS

• mechanical and physical barriers to invasions

• chemical factors: inflammatory and anti-microbial

• microbial antagonism

• fever

• the inflammatory response

• phagocytic white blood cells

what are the structures of the skin?

-Outer Layer: largely made up of dead cells (physical barrier)

-Oils and pH (chemical barriers) and tight junctions (physical barriers)

-Specialized immune cells reside in follicles (2nd and 3rd line of defense)

components of the Gut Epithelium and Mucosa

• Antibodies and antimicrobial chemicals (act directly on invading pathogens)

• Mucous and tight junctions (Serve as barriers)

What are Chemical barriers to infection?

• Acidid pH (low pH): lethal to most bacteria

• Lysozyme (enzyme in tears): degrade the cell walls of Gram-positive bacteria

• Superoxide radicals (lactoperoxidase/nitrous oxide/ hypochlorite): kill pathogenic bacteria

• Defensins (small cationic peptides): function as antibiotics and are important components of innate immunity. 

why do we need back up systems?

the cells and chemicals of the second (innate) and third (adaptive) lines of defense save us with their effector functions

what is the second line of defense?

• activated (induced) when pathogens suceed in penetrating the skin or mucous membranes

• Composed of:

  • tissue resident

  • blood borne cells

  • soluble proteins that are not part of a physical cells 

Chemical and Protein pathways in serum:

Pathways:

• Kinin pathway: vasodilation plus

• Thrombin: clotting, cross talk with others.

• Complement: 3 distinct anti-microbial functions

• Arachidonic acid: inflammation and healing

Chemicals:

• Cytokines: specific signals to cells

• Chemokines: tells cells where to go

• Inflammatory mediators: activate inflammation

• Reactive oxygen species: directly kill pathogens

what happens when the Arachidonic acid pathway is paired with the Clotting and Kinin cascades

together these pathways activate inflammation and healing

what are the 3 ways complement pathway is activated?

• classical → depends on antibody/adaptive system (immune system)

• Alternative → does not require antibody or immunity (adaptive immunity)

• Lectin → requires the synthesis of mannose binding

what can the complement cascade do

• lyse invading microbes: membrane attack complex (MAC)

• enhance inflammation and recruit immune cells

• enhance phagocytosis through opsonization

how can you regulate the complement pathway

• the host cell surface protein CD59 (protectin)

  • will bind to any C5b-C8 complex trying to form and prevent C9 from polymerizing

• Protein facto H prevents the activation of complement in the absence of infection by binding to host cells and inactivating C3b

• Cytokines stimulate hepatic production of acute-phase reactant proteins such as C-reactive protein, which (activates complement pathway)

what are innate immune cells:

high protective cells with unique effector function

what is the normal and elevated WBC count?

normal: 4,500-11,000

Elevated: 12,000-30,000

describe the steps of phagocytosis of pathogens

1) bacterium binds to the surface of the phagocytic cell. [antibody or complement cain aid binding]

2) Phagocyte pseudopods extend and engulf the organism

3) Invagination of phagocyte membrane traps the organism within a phagosome

4)A lysosome fuses and deposits enzymes into the phagosome. Enzymes cleave macromolecules and generate reactive oxygen, destroying the organism.

what are the oxygen-independent mechanisms of phagocytosis

Lysozome, lactoferrinm defensins

what are the oxygen-dependent mechanisms of phagocytosis

oxygen radicals -superoxide, hydrogen peroxide, hydroxyl radicals and myelperoixdase

what happens when a phagocyte surface binds with the surface of another body cell

the phagocyte becomes temporarily paralyzed so it can evaluate whether the other cell is self or non-self

what is opsonization?

when antibodies bind to bacteria, and the Fc portion of the antibodies bind to receptors on the macrophage surface

how does ingestion work by macrophages

Antibodies link bacteria and macrophage, aiding phagocytosis

what is CD47?

• the dont eat me receptor

• invading bacteria lack the CD47 surface molecules, making them readily engulged

Opnonsonization (coating pathogens with C3b) __________ activation of phagocytosis

enhances

what is the function of Monocyte (blood)?

circulate in the blood and then migrate to tissues where they differentiate into macrophages and dendritic cells

what are macrophages

widely distributed throughout the body and most likely to make first contact with invading pathogens

• can kill invaders directly and can present antigens on their cell surface to T cells

what is the function of M1 macrophages

inflammatory, phagocytosis, and antigen presentation

what is the function of M2 macrophages

tissue repair and healing

what are neutrophils (PMNs)?

• p most frequent type of WBCs in the blood

• “first responders”

• can engulf microbes by phagocytosis

• bactericidal nets

• produce reactive oxide radicals to kill pathogens

• secrete cytokines/chemokines to recruit and activate other immune cells

how have pathogens evolved ways to prevent being killed by phagocytosis

• multicellular organisms are too large to ingest

• intracellular pathogens (cancer) present a special problem for the host

• Natural self-tolerance mechanisms prevent immune activation

what is the function of Eosinophils

• mainly attack parasitic helminths by attatching to their surface

• produce proteins that weaken or kill hte helminth

• Eosionphilla or elevated eosinphil levels, is often indicative of a helminth infection

what do NK cells (Naturual killer lymphocytes) do?

• distinguish normal body cells from virally infected or tumor cells

• recognize and kill virally infected or tumor cells by two different mechanis,

what are the steps of perfornin mediated killing

1) monomers of pefronin are realeased from the NK cell and enter target host cell membranes that lack MHC 1

2) monomers oligomerize to form a pore in the target cell membrane

3) NK cells release cytotoxic proteins such as granzyme that enter target cells through the perforin pores

what is the Missing self method:

when an NK cell binds to MHC1 protein, it will not attack.

HOWEVER if a cell lacks the MHC class I molecules, NK cells will perceive the cell as foreign and insert a pore-forming protein -perforin- into the target cell membrane.

what is the Antibody-dependent cell-mediated cytotoxicity (ADCC) method

NK cells also contain antibody binding Fc receptors on their surface. the Fc receptor on the NK cell links to antibody coated host cell, which is then killed. 

what is the DAMP recognition method

NK cells are activated by molcules unpregulated on damaged or stressed cells.

what is inflammation

the protective response of the microcirculation designed to destroy, dilute or wall-off injurious agents and the damaged tissues. 

what are the five basic symptoms of inflammation?

1) Redness (rubor)

2) Heat (calor)

3) swelling (tumor)

4) Pain (dolor)

5) Loss of function (functio laesa)

what are triggers of acute inflammation

• infections and microbial toxins

• trauma

• physical and chemical agents

• tissue necrosis

• foreign bodies

• immune reactions

what initiates the acute inflammatory response

Basoactive factors released by macrophages

what is vasodilation

slows blood flow and as a result increases blood volume in the affected area.

• the more permeable vessels allows the scape of plasma into the tissues

what does inflammation allow for

chemical stimulus which recruits and activates immune cells

how does inflammation end?

Neutrophils are loaded with destructive enzymes and signal molecules. Neutrophils trigger programmed cell death (apoptosis).

• accumulation of dead cells seen as puss

• Long lived phagocytes remove the dead neutrophils by engulfing them.

how does the body know what tyme of immune response will be the best?

it is based off the signals leading to inflammation (MAMPS or PAMPS)

what are MAMPS (microbe-associated molecular patterns)

bacteria and viruses contain unique structures such as peptidoglycan, flagellin, dsRNA and etc that are not expressed on mammalian cells.

what are PRR (pattern recognition receptors)

Nod-like receptors present on/in various host cells which recognize MAMP

• once pound the TLR sends a signal to the interior of the cell to start making interferon and pro-inflammatory cytokines and direct the inflammatory response

why are there different types of TLRs

so different stimulus and messengers can activate different responses and different signal pathways that stimulate the production of cytokines by the TLR.

what are cytokines?

ways to communicate information to other cells, and the type of cytokine provides information as to the type of invading pathogen

what do chemokines do?

direct cells to traffic to a specific area. they can also work with cytokines to activate endothelial cells to up-regulate molecules that provide leukocytes an “address” for the site of infection.

what are INterferons and INterleukins (IL)

cytokines produced by eukaryotic cells in response to infection, that signal among leukocytes.

what is a tumor necrosis factor (TNF)

kills tumor cells and regulates immune responses

what are chemokines?

proteins that signal the recruitment of leukocytes and regulate inflammation. 

what is a type 1 interferon?

binds to specific receptors of uninfected host cells and induce the synthesis of DsRNA and Protein kinases that phosphorylate and inactive elF2

what is a type 2 interferon

activates various white blood cells to increase the number of Major Histocompatibility Complex antigens on their surface.

what are the goals of an adaptive immune response?

• provide a diverse pathogen specific response

• Generation of long term memory

what are the two types of adaptive immunity?

Humoral and Cellular

what is important about Humoral Immunity

• most effective against extracellular microorganisms

• B Lymphocyte → produce antibodies

what is important about Cellular immunity

most effective against intraceulluar organisms

T lymphocytes → produce cytokines or kill infected/tumor cells

key thing to know about lymphocytes

each class of lymphocyte has a unique…

• method of antigen recognition

• effector function

receptors on lymphocyte surfaces bind to _____.

specific foreign antigen to activate protective immunity

what is the CD8 T cell used for

Killing

what is burnets theory of clonal activation and selection (1957)

it explains the activation, function, and selection of lymphocytes able to respond to specific foreign antigens and with no response to self.

• Activation

  • single type of receptor with a unique specificity

• Selection

  • those lymphocytes bearing receptors for self molecules will be clonally deleted at an early stage

clonal selection in response to antigen

Clonal selection is the process by which a specific lymphocyte (B or T cell) with a receptor matching an invading antigen is activated, causing it to proliferate and differentiate into a large population of identical effector and memory cells. This ensures a targeted immune response and long-term protection against that antigen.

what is an antigen?

describes anything that can elicit an immune response

what is an epitope?

a specific binding site of an antigen