Microbio 3200 Exam 2

pathogen can cause disease if it can:

-gain access to the body, either by penetrating the skin or entering through an alternate portal of entry
-bind to host cells or tissue
-evade the host defense systems long enough to cause harmful changes

immune system has developed

-ability to distinguish healthy self from non-self and infected or damaged self
-activated specific effector functions able block microbes from achieving these pathological events

what is the immune system?

-defense system that protects us
-complex organization of cells, 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 organisms
-has a diverse range of programmable functions that are highly specialized to be effective against a given type of pathogen

first line immune defense

barrier to invasion

skin

mechanical: epithelial cells joined by tight junctions; longitudinal flow of air or fluid

chemical: fatty acids; antibacterial peptides

microbiological: normal flora

gut

mechanical: epithelial cells joined by tight junctions; longitudinal flow of air or fluid

chemical: low pH; enzymes (pepsin); antibacterial peptides

microbiological: normal flora

lungs

mechanical: epithelial cells joined by tight junctions; movement of mucus by cilia

chemical: antibacterial peptides

eyes/nose

mechanical: epithelial cells joined by tight junctions; tears; nasal cilia

chemical: enzymes in tears (lysozyme)

lymphatic system

home of the 2nd and 3rd line of defense

network of chemicals, cell and tissue strategically distributed throughout the body

lymphoid organs

are optimized to promote efficient immune activation and regulation

lymph node

paracortical area (mostly T cells)
germinal center
primary lymphoid follicle (mostly B cells)

immunochemistry

molecules that activate, communicate, and direct immune responses

chemical mediators of inflammation

early warning system

interleukins

a chemical system of cellular communication

chemokines

a chemical system of traffic control;
are proteins that signal the recruitment of leukocytes and regulated inflammation

cells of immune system

often called leukocytes (white blood cells)

lymphocytes

activated NK cell
activated T cell
plasma cell

adaptive immune cells

T cells and B cells

innate immune cells

neutrophils/polymorphonuclear cell (PMN)
dendritic cell (DC)
macrophage

neutrophils/polymorphonuclear cell (PMN)

phagocyte and secretion of inflammatory mediators and reactive oxygen species

dendritic cell (DC)

professional antigen presentation cell, phagocyte and secretion cytokines

macrophage

professional phagocyte, antigen presentation, secretion cytokines and healing

cells of adaptive immune system

B cells
T cells
NK cells

extracellular bacteria, parasites, fungi

streptococcus pneumoniae (pneumonia), clostridium tetani (tetanus), trypanosoma brucei (sleeping sickness), pneumocystis carinii (pneumocystis pneumonia)

intercellular bacteria, parasites

mycobacterium leprae (leprosy), leishmania donovani (leishmaniasis), plamodium falciparum (malaria)

viruses (intracellular)

variola (small pox)
influenza (flu)
varicella (chickenpox)

parasitic worms (extracellular)

ascaris (ascariasis)
schistosoma (schistosomiasis)

basic map of an immune response

1. recognition of the pathogen
2. activation of innate effectors
3. inflammation
4. changes in microvasculature
5. recruitment cells to the sight of infection
6. transport of antigen to LN
7. recognition of pathogen
8. proliferation and differentiation of lymphocytes
9. traffic to sight of infection
10. utilize effector functions
11. amplify steps 2 & 3
12. pathogen clearance and long term memory
13. healing
14. live happily ever after

innate

in born, native, inherent
common to all individuals in a species

nonspecific host defense mechanisms, first line of defense, second line of defense

innate immunity

-non-adaptive, immediate response but with broad specificity
-operates continuously from the time of infection through the incubation period and until the infection ends

innate immunity

-seconds/minutes/hours
-specific for microbial patterns
-germ-line encoded
-no memory
-antimicrobial peptides
-phagocytic cells

two modes of innate function

direct action (immediate)
indirect action (immediate and delayed)

direct action (immediate)

-prevent the entry/proliferation of pathogens
-directly kill invading pathogens
-localize damage
-induce inflammation

indirect action (immediate and delayed)

-induce inflammation
-establish/determine/regulate the type of immune response
-activate the appropriate adaptive immune response
-activate healing response

effector mechanisms

general in nature and serve to protect the body against MANY harmful substances

innate host defense mechanisms

-mechanical and physical barriers to invasion
-chemical factors: inflammatory and anti-microbial
-microbial antagonism
-fever
-inflammatory response
-phagocytic white blood cells

protection at physical barriers to infection (ex: skin)

-protective shield covered with keratin
-sebum (oily substance)
-slightly acidic pH inhibits bacterial growth
-competition between species limits colonization by pathogens (microbial antagonism)
-skin-associated lymphoid tissue (SALT) recognizes microbes that may slip past the physical barrier
-langerhans cells (specialized dendritic cells) can phagocytize microbes
-tissue specific organization/composition of barrier material and immune cells

structure of skin

-outermost layer is largely made up of dead cells
-oils and pH and tight junctions serve as barriers
-specialized immune cells reside in follicles

gut epithelium and mucosa

-antibodies and anti-microbial chemicals directly act on invading pathogens
-mucous and tight junctions serve as barriers

protection at physical barriers to infection (ex: mucous membranes)

-selectively permeable to nutrients, gasses and waste components but a barrier against invading pathogens
-secreted mucus coats surface and traps microbes
-other secreted compounds within mucus such as lysozyme and lactoperoxidase and anti microbial peptides can kill organisms trapped in mucus
-mucosa-associated lymphoid tissue (MALT) and gut-associated lymphoid tissue (GALT)

MALT and GALT

are distributed along mucosal linings and populated with B and T cells as well as plasma cells and macrophages

MALTs

peyer's patches/follicles
-bridge the outside and inside world and provide protection in the gut

peyer's patches

are aggregations of lymphoid tissues that dot the intestinal surface, along the lower small intestine

M cells

are specialized parts of peyer's patches that are wedged between epithelial cells.

M stands for "microfold" which describes their appearance

-they take up microbes from the intestine and act as a phagocytic filter. essential for the development of mucosal immunity to pathogens

intraepithelial lymphocytes (IEL)

perserve the integrity of the epithelium and prevent damage induced by invading pathogens (protective immunity) or aberrant inflammatory immune responses

tissue specific architecture

requires unique immune cell function and organization

cilia

respiratory mucociliary elevator moves microbes and contaminants out of the lungs, microbes larger of 100 um become trapped by hairs and cilia lining the nasal cavity

sneezing

forceful expulsion of air from the lungs, is designed to clear the organism from the respiratory tract

alveolar macrophages

ingest and kill most bacteria and send out chemical signals to attract other cells of the innate and adaptive immune systems

negative regulation of immune responses

are necessary for lung health

acidic pH of the stomach

lethal to most bacteria

lysozyme (in tears)

degrade the cells walls of gram + bacteria

lactoperoxidase, nitrous oxide and hypochlorite

kill pathogenic bacteria

defensins

small cationic peptides

function as important components of innate immunity

-made by a variety of cells such as skin, lung, genitourinary tract, GI tract
-kill by destroying microbial cytoplasmic membrane
-effective against both gram + and gram -
-bacteria, fungi, and some viruses

if there is a breakdown in the physical or chemical barrier what happens?

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

second line of defense

-activated (induced) when pathogens succeed in penetrating the skin or mucous membranes
-composed of tissue resident and blood borne cells and soluble proteins that are not associated with a physical barrier

chemical/proteins and pathways

arachidonic acid pathway
clotting and kinin cascades
-together these pathways cooperated to activated inflammation and healing

pathways

kinin pathway
thrombin
complement
arachidonic acid

kinin pathway

vasodilation plus

thrombin

clotting, cross talk with others

complement

3 distinct anti-microbial functions

arachidonic acid

inflammation and healing

chemicals

cytokines
chemokines
inflammatory mediators
reactive oxygen species

cytokines

-made and secreted by cells as a way to communicate with other cells
--provides information as to the the type of invading pathogen
--signaling peptides bind to a specific membrane receptors on target cells and have powerful effects on the functions of those cells
-can stimulate expression of specific receptors (selectins) on the endothelial cells

chemokines

tells cells where to go

inflammatory mediators

activate inflammation

reactive oxygen species

directly kill pathogens

pathways of complement activation

classical
alternative
lectin

classical

depends on antibody/adaptive immune system

alternative

does not require antibody or adaptive immunity

lectin

requires the synthesis of mannose-binding lectin in response to cytokines released from macrophage

complement cascade can (no matter how it is started)

-lyse invading microbes: membrane attack complex (MAC)
-enhance inflammation and recruit immune cells
-enhance phagocytosis through opsonization

regulating complement activation

- the host cell surface protein, CD59 (protectin), will bind to any C5b-C8 complex trying to form and prevent C9 from polymerizing.
-protein factor 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.

cells of innate immunity

-neutrophils
-eosinophils
-monocytes
-macrophages
-dendritic cells
-mast cells
-natural killer cells
-T cells
-B cells

blood counts as a

diagnostic

white blood cell differential

-is the total number and identity of white blood cells in a patient
-these numbers can provide a clinician with important clues about the cause of a patient's illness

elevated total WBC

indicates infection or allergy

elevated neutrophils

suggest bacterial infection

elevated lymphocytes

suggest viral infection

increased eosinophils

suggest intestinal parasites or blood parasites or allergies

monocytes

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

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

monocyte activation leads to extravasation and effector function

macrophage

M1

inflammatory; phagocytosis, inflammation, antigen presentation

M2

tissue repair and healing

neutrophils (PMNs)

-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 recruit and activate other immune cells

how phagocytes kill

-During phagocytosis, the intracellular phagosome is formed and subsequent phagosome-lysosome fusion (phagolysosome) permits both oxygen-independent (anaerobic) and oxygen-dependent (aerobic) killing pathways.
-Oxygen-independent mechanisms:
--lysozyme, lactoferrin, defensins
-Oxygen-dependent mechanisms:
--oxygen radicals such as superoxide ion and hydrogen peroxide, hydroxyl radicals, and myeloperoxidase
-Reactive nitrogen intermediates:
--nitric oxide, nitrite/nitrate ions

phagocytosis of pathogens by neutrophils an MO

1. bacterium binds to the surface of the phagocytic cell. antibody or complement can 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

opsonization

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

ingestion by macrophage

antibodies link bacteria and macrophage, aiding phagocytosis

dendritic cell

phagocytosis, antigen processing and presentation to T cells

-can take up small soluble antigens from the surroundings as well as phagocytizing whole bacteria
-once activated, they traffic from various tissue to the spleen and lymph nodes and present antigens on their cell surface to T cells

phagocytosis: self non-self discrimination

•Fail-safe controls built into our immune defenses prevent Phagocytes from killing host cells in the absence of infection
•For phagocytosis to proceed, macrophages and
neutrophils must first "see" the surface of a particle as being foreign.
•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.

phagocytes express receptors

that bind the bad guys

CD47

"don't eat me receptor"

because invading bacteria lack CD47 surface molecule, they can be readily engulfed

phagocytes express numerous receptors that directly recognize

MAMPs and enhance phagocytosis

opsonization - the coating of pathogens with

C3b or antibodies, enhances activation of phagocytosis

basophils and eosinophils

do not phagocytize microbes but release products that are toxic to the mircobes and chemical mediators of inflammation

mast cells

contain many granules rich in inflammatory mediators such as histamine and heparin.

reside in connective tissues and mucosa and do not circulate in the bloodstream

eosinophils

-mainly attack parasitic heminths (worms) by attaching to their surface
-produce proteins that weaken or kill the helminth
-eosinophilia, or elevated eosinophil levels, is often indicative of a helminth infection

intracellular pathogens

can hide from the humoral immune system
-antibodies and complement do not enter cells