Microbiology 532:

Microbiology 532:
Immunology
Immunology
Dennis E. Lopatin, Ph.D. Dennis E. Lopatin, Ph.D.
Dept. of iologic an! Materials "ciences Dept. of iologic an! Materials "ciences
#2$% Dental uil!ing #2$% Dental uil!ing
&'ce (ours by )ppointment &'ce (ours by )ppointment
Phone: *#+,3%-2 Phone: *#+,3%-2
Electronic mail: lopatin.umich.e!u Electronic mail: lopatin.umich.e!u

(elpful (ints
(elpful (ints

/ea!ings in te0t are bene1cial /ea!ings in te0t are bene1cial

I I e0pect e0pect you to rea! the rele2ant chapters in 3ester. you to rea! the rele2ant chapters in 3ester.

4n!erstan!ing the 4n!erstan!ing the concepts concepts is not optional is not optional

5hin6 5hin6, rather than memori7e , rather than memori7e

5est 8uestions are base! on 5est 8uestions are base! on concepts concepts

)s6 8uestions )s6 8uestions

Don9t :ait until the last minute to stu!y Don9t :ait until the last minute to stu!y

;hec6 the :ebsite ;hec6 the :ebsite

Lecture 1
Lecture 1
Immunology
Immunology
Introduction & Innate immunity
Introduction & Innate immunity

<hy Does a Dentist 3ee! to
<hy Does a Dentist 3ee! to
4n!erstan! Immunology=
4n!erstan! Immunology=

Many of the oral !iseases ha2e an immune Many of the oral !iseases ha2e an immune
component component

Perio!ontal !isease Perio!ontal !isease

;aries ;aries

">?gren9s "yn!rome ">?gren9s "yn!rome

;urrent an! future therapeutics a@ect the immune ;urrent an! future therapeutics a@ect the immune
system an! oral health system an! oral health

"ystemic an! &ral !iseases are interrelate! "ystemic an! &ral !iseases are interrelate!

;ooperation :ith other health care professional ;ooperation :ith other health care professional
re8uires a common language re8uires a common language

<hat is immunity=
<hat is immunity=

A
A
ProtectionB from infection, tumors, etc.
ProtectionB from infection, tumors, etc.

Innate immunity is al:ays a2ailable

Innate immunity is al:ays a2ailable

)!apti2e immunity !istinguishes AselfB

)!apti2e immunity !istinguishes AselfB
from Anon,selfB an! in2ol2es immune
from Anon,selfB an! in2ol2es immune
system Ae!ucationB
system Ae!ucationB

/esponses that may result in host

/esponses that may result in host
tissue !amage
tissue !amage

5:o types of immunity
5:o types of immunity

Innate immunity Cnot antigen,speci1cD Innate immunity Cnot antigen,speci1cD

)natomical barriers )natomical barriers

Mechanical Mechanical

iochemical iochemical

3on,speci1c Ceg. Lo: p( in stomachD 3on,speci1c Ceg. Lo: p( in stomachD

/eceptor,!ri2en Ceg. P)MP,recognitionD /eceptor,!ri2en Ceg. P)MP,recognitionD

)!apti2e immunity Cantigen,speci1cD )!apti2e immunity Cantigen,speci1cD

/eceptor,!ri2en /eceptor,!ri2en

Pre,e0isting clones programme! to ma6e a speci1c Pre,e0isting clones programme! to ma6e a speci1c
immune response ChumoralEcellularD immune response ChumoralEcellularD

)ntigen
)ntigen

) substance CantigenD that is capable of

) substance CantigenD that is capable of
reacting
reacting
:ith the pro!ucts of a speci1c
:ith the pro!ucts of a speci1c
immune response, e.g., antibo!y or
immune response, e.g., antibo!y or
speci1c sensiti7e! 5,lymphocytes.
speci1c sensiti7e! 5,lymphocytes.

) AselfB component may be consi!ere! an

) AselfB component may be consi!ere! an
antigen e2en though one !oes not
antigen e2en though one !oes not
generally ma6e immune responses
generally ma6e immune responses
against those components.
against those components.

;haracteristics of )!apti2e
;haracteristics of )!apti2e
Immunity
Immunity

Immune response is highly speci1c for the antigen that Immune response is highly speci1c for the antigen that
triggere! it. triggere! it.

/eceptors on surface of immune cells ha2e same speci1city as the /eceptors on surface of immune cells ha2e same speci1city as the
antibo!yEe@ector acti2ity that :ill be generate! antibo!yEe@ector acti2ity that :ill be generate!

E0posure to antigen creates an immunologic Amemory.B E0posure to antigen creates an immunologic Amemory.B

Due to clonal e0pansion an! creation of a large pool of cells Due to clonal e0pansion an! creation of a large pool of cells
committe! to that antigen committe! to that antigen

"ubse8uent e0posure to the same antigen results in a rapi! an! "ubse8uent e0posure to the same antigen results in a rapi! an!
2igorous response 2igorous response

;omponents of the
;omponents of the
immune system
immune system

Cells
Cells
involved
involved
in
in
immunity
immunity
platelets platelets
megakaryocyte megakaryocyte
eosinophil eosinophil
neutrophil neutrophil
basophil basophil
mast cell mast cell
common common
myeloid myeloid
progenitor progenitor
monocyte monocyte
macrophage macrophage
Natural Natural
Killer cell Killer cell
plasma cell plasma cell
B Lymphocyte B Lymphocyte
T Lymphocyte T Lymphocyte

common common
lymphoid lymphoid
progenitor progenitor
Pluripotent Pluripotent
hematopoietic hematopoietic
stem cell stem cell

Blood
Blood
Serum or Serum or
Plasma Plasma
Leukocytes, Leukocytes,
Platelets and RBC Platelets and RBC
Serum Proteins Serum Proteins
Mononuclear Mononuclear
Cells Cells
Polymorphonuclear Polymorphonuclear
leukocytes (or leukocytes (or
Granulocytes) Granulocytes)

Immunoglobulins Immunoglobulins

Complement Complement

Clotting factors Clotting factors

Many others Many others

Neutrophils Neutrophils

Eosinophils Eosinophils

Basophils Basophils

Lymphocytes Lymphocytes
(T cells, B cells (T cells, B cells
& NK cells) & NK cells)

Monocytes Monocytes
<here is that stu@=
<here is that stu@=

Lymphoi! &rgans
Lymphoi! &rgans

Primary or central lymphoi! organs

Primary or central lymphoi! organs

bone marro: an! thymus bone marro: an! thymus

:here lymphocytes are generate! :here lymphocytes are generate!

"econ!ary or peripheral lymphoi! organs

"econ!ary or peripheral lymphoi! organs

:here a!apti2e immune responses are :here a!apti2e immune responses are
initiate! initiate!

Distribution of Lymphoi! 5issues
Distribution of Lymphoi! 5issues

Response to Initial Infection
Response to Initial Infection

Stages of Response to Infection
Stages of Response to Infection

Course
Course
of Typical
of Typical
Acute
Acute
Infection
Infection

Innate Host Defense Mechanisms
Innate Host Defense Mechanisms

Anatomic Factors
Anatomic Factors

Mechanical Factors
Mechanical Factors

Biochemical Factors
Biochemical Factors

Skin
Skin

Stratified and cornified epithelium provides a

Stratified and cornified epithelium provides a
mechanical barrier
mechanical barrier

Indigenous microbiota competes with pathogens

Indigenous microbiota competes with pathogens

Acid pH inhibits growth of disease producing

Acid pH inhibits growth of disease producing
bacteria
bacteria

Bactericidal long chain fatty acids in sebaceous

Bactericidal long chain fatty acids in sebaceous
gland secretions
gland secretions

Respiratory Tract
Respiratory Tract

Upper Respiratory Tract Upper Respiratory Tract

Nasal hairs induce turbulence Nasal hairs induce turbulence

Mucous secretions trap particles Mucous secretions trap particles

Mucous stream to the base of tongue where material is swallowed Mucous stream to the base of tongue where material is swallowed

Nasal secretions contain antimicrobial substances Nasal secretions contain antimicrobial substances

Upper respiratory tract contains large resident flora Upper respiratory tract contains large resident flora

Lower Respiratory Tract Lower Respiratory Tract

Particles trapped on mucous membranes of bronchi and bronchioles Particles trapped on mucous membranes of bronchi and bronchioles

Beating action of cilia causes mucociliary stream to flow up into the pharynx Beating action of cilia causes mucociliary stream to flow up into the pharynx
where it is swallowed where it is swallowed

90% of particles removed this way. Only smallest particles (<10 in diameter) 90% of particles removed this way. Only smallest particles (<10 in diameter)
reach alveoli reach alveoli

Alveoli Alveoli

Alveolar macrophage rapidly phagocytize small particles Alveolar macrophage rapidly phagocytize small particles

Alimentary Tract
Alimentary Tract

General defense mechanisms General defense mechanisms

Mucous secretions Mucous secretions

Integrity of of mucosal epithelium Integrity of of mucosal epithelium

Peristaltic motions of the gut propel contents downward Peristaltic motions of the gut propel contents downward

Secretory antibody and phagocytic cells Secretory antibody and phagocytic cells

Stomach Stomach

Generally sterile due to low pH Generally sterile due to low pH

Small Intestine Small Intestine

Upper portion contains few bacteria Upper portion contains few bacteria

As distal end of ilieum is reached flora increases As distal end of ilieum is reached flora increases

Colon Colon

Enormous numbers of microorganisms Enormous numbers of microorganisms

50-60% of fecal dry weight is bacteria 50-60% of fecal dry weight is bacteria

Genitourinary Tract
Genitourinary Tract

Male Male

No bacteria above urethrovesicular junction No bacteria above urethrovesicular junction

Frequent flushing action of urine Frequent flushing action of urine

Bactericidal substances from prostatic fluid Bactericidal substances from prostatic fluid

pH of urine pH of urine

Bladder mucosal cells may be phagocytic Bladder mucosal cells may be phagocytic

Urinary sIgA Urinary sIgA

Female (Vagina) Female (Vagina)

Large microbial population (lactobacilli) Large microbial population (lactobacilli)

Microorganisms produce low pH due to breakdown of glycogen produced by Microorganisms produce low pH due to breakdown of glycogen produced by
mucosal cells mucosal cells

Eye
Eye

Flushing action of tears which drain through the

Flushing action of tears which drain through the
lacrimal duct and deposit bacteria in nasopharynx
lacrimal duct and deposit bacteria in nasopharynx

Tears contain a high concentration of lysozyme

Tears contain a high concentration of lysozyme
(effective against gram positive microorganisms
(effective against gram positive microorganisms

/eceptors
/eceptors

)lmost all of biology occurs because

)lmost all of biology occurs because
recognition
recognition

En7ymatic action En7ymatic action

Interactions bet:een cells Interactions bet:een cells

CcooperationEacti2ationD CcooperationEacti2ationD

;ommunication bet:een cells ;ommunication bet:een cells

Innate an! a!apti2e immunity re8uires it

Innate an! a!apti2e immunity re8uires it

Innate Immune /ecognition
Innate Immune /ecognition

)ll multi,cellular organisms are able to

)ll multi,cellular organisms are able to
recogni7e an! eliminate pathogens
recogni7e an! eliminate pathogens

Despite their e0treme heterogeneity,

Despite their e0treme heterogeneity,
pathogens share highly conser2e! molecules,
pathogens share highly conser2e! molecules,
calle! Apathogen,associate! molecular
calle! Apathogen,associate! molecular
patternsB C
patternsB C
P)MPs
P)MPs
D
D

(ost cells !o not share P)MPs :ith pathogens

(ost cells !o not share P)MPs :ith pathogens

P)MPs are recogni7e! by innate immune

P)MPs are recogni7e! by innate immune
recognition receptors calle! pattern,
recognition receptors calle! pattern,
recognition moleculesEreceptors C
recognition moleculesEreceptors C
P/MsEP//s
P/MsEP//s
D
D

5ypical P)MPs
5ypical P)MPs

Lipopolysacchari!es
Lipopolysacchari!es

Pepti!oglycans
Pepti!oglycans

;ertain nucleoti!e se8uences uni8ue to

;ertain nucleoti!e se8uences uni8ue to
bacteria
bacteria

&ther bacterial components

&ther bacterial components

En!ogenous "ignals In!uce! by P)MPs
En!ogenous "ignals In!uce! by P)MPs

Me!iate inFammatory cyto6ines

Me!iate inFammatory cyto6ines

)ntigen,presenting cells recogni7e

)ntigen,presenting cells recogni7e
P)MPs
P)MPs

"ame )P; processes pathogens into speci1c "ame )P; processes pathogens into speci1c
pathogen,!eri2e! antigens an! presents them pathogen,!eri2e! antigens an! presents them
:ith M(; enco!e! receptors to 5,cells :ith M(; enco!e! receptors to 5,cells

5,cell respon!s only :hen presente! :ith both 5,cell respon!s only :hen presente! :ith both
signals signals

Di@erent E@ector ;yto6ines in /esponse to Di@erent Di@erent E@ector ;yto6ines in /esponse to Di@erent
Pathogens C5h- 2s. 5h2D Pathogens C5h- 2s. 5h2D

)ntimicrobial
)ntimicrobial
Pepti!esEDefensins
Pepti!esEDefensins

Gour hun!re! pepti!es !escribe! to !ate Gour hun!re! pepti!es !escribe! to !ate

Defensins C3, 5,6D, four families in eu6aryotesD Defensins C3, 5,6D, four families in eu6aryotesD

,!efensins Cneutrophils an! intestinal Paneth cellsD ,!efensins Cneutrophils an! intestinal Paneth cellsD

,!efensins Cepithelial cellsD ,!efensins Cepithelial cellsD

Insect !efensins Insect !efensins

Plant !efensins Plant !efensins

Defensins appear to act by bin!ing to outer Defensins appear to act by bin!ing to outer
membrane of bacteria, resulting in increase! membrane of bacteria, resulting in increase!
membrane permeability. membrane permeability.

May also play a role in inFammation an! :oun! May also play a role in inFammation an! :oun!
repair repair

;omplement "ystem
;omplement "ystem

5hree path:ays no: 6no:n

5hree path:ays no: 6no:n

;lassical ;lassical

)lternati2e )lternati2e

Lectin or ML path:ay Cbin!ing to mannose, Lectin or ML path:ay Cbin!ing to mannose,

containing carbohy!ratesD containing carbohy!ratesD

(ost cells ha2e complement regulatory

(ost cells ha2e complement regulatory
proteins on their surface that protect them
proteins on their surface that protect them
from spontaneous acti2ation of ;3 molecules
from spontaneous acti2ation of ;3 molecules

InFammatory Me!iators in Innate
InFammatory Me!iators in Innate
Immunity
Immunity

;yto6ines secrete! by phagocytes in response to ;yto6ines secrete! by phagocytes in response to

infection inclu!e: infection inclu!e:

IL,- IL,-

acti2ates 2ascular en!othelium an! lymphocytes acti2ates 2ascular en!othelium an! lymphocytes

Increases a!hesi2eness of leu6ocytes Increases a!hesi2eness of leu6ocytes

IL,* IL,*

In!uces ,cell terminal maturation into Ig,pro!ucing plasma cells In!uces ,cell terminal maturation into Ig,pro!ucing plasma cells

IL,H IL,H

In!uces e0pression of b2 integrin a!hesion molecules on neutrophils, In!uces e0pression of b2 integrin a!hesion molecules on neutrophils,
lea!ing to neutrophil migration to infection site lea!ing to neutrophil migration to infection site

IL,-2 IL,-2

)cti2ates 3I cells an! in!uces 5h-,cell !i@erentiation )cti2ates 3I cells an! in!uces 5h-,cell !i@erentiation

IL,-H IL,-H

53G, 53G,

)cti2ates 2ascular en!othelium an! increases 2ascular permeability, )cti2ates 2ascular en!othelium an! increases 2ascular permeability,
lea!ing to accumulation of Ig an! complement in infecte! tissues lea!ing to accumulation of Ig an! complement in infecte! tissues

&ther Me!iators an! Molecules
&ther Me!iators an! Molecules

Phagocytes Phagocytes

5o0ic o0ygen ra!icals 5o0ic o0ygen ra!icals

Pero0i!es Pero0i!es

3itric o0i!e C3&D 3itric o0i!e C3&D

Lipi! me!iators of inFammation Lipi! me!iators of inFammation

Prostaglan!ins Prostaglan!ins

L5# L5#

Platelet acti2ating factor Platelet acti2ating factor

;omplement component ;5a ;omplement component ;5a

"timulates mast cells to release histamine, serotonin an! L5# "timulates mast cells to release histamine, serotonin an! L5#

IL,-, IL,* an! 53G, IL,-, IL,* an! 53G,

In!uce acute,phase response in li2er In!uce acute,phase response in li2er

In!uce fe2er In!uce fe2er

IL,- an! IL,-H signaling path:ays acti2ate 3G, IL,- an! IL,-H signaling path:ays acti2ate 3G, , important in , important in
innate immunity innate immunity

Immune ;ells an! Innate Immunity
Immune ;ells an! Innate Immunity

Phagocytes Phagocytes

3eutrophils 3eutrophils

MoncyteEmacrophage MoncyteEmacrophage

Eosinophils Cto a lesser e0tentD Eosinophils Cto a lesser e0tentD

3I cells 3I cells Clarge granular lymphocytesD Clarge granular lymphocytesD

)ntibo!y,!epen!ent cell,me!iate! cytoto0icity )ntibo!y,!epen!ent cell,me!iate! cytoto0icity

C)D;;D C)D;;D

(a2e t:o ma>or functions (a2e t:o ma>or functions

Lysis of target cells Lysis of target cells

Pro!uction of cyto6ines CIG3, Pro!uction of cyto6ines CIG3, an! 53G, an! 53G, D D

)ct against intracellular pathogens )ct against intracellular pathogens

(erpes2iruses (erpes2iruses

Leishmania Leishmania

Listeria monocytogenes Listeria monocytogenes

)ct against proto7oa )ct against proto7oa

Toxoplasma Toxoplasma

Trypanasoma Trypanasoma

Immune ;ells an! Innate Immunity Ccont9!D
Immune ;ells an! Innate Immunity Ccont9!D

E E 5 cells 5 cells

5:o types of 5 cell receptors 5:o types of 5 cell receptors

&ne compose! of &ne compose! of an! an! chains Cbasic 5 cell antigen receptorD chains Cbasic 5 cell antigen receptorD

&ne compose! of &ne compose! of an! an! chains Cminor population of 5 cellsD chains Cminor population of 5 cellsD

5:o groups of 5:o groups of E E 5 cells 5 cells

&ne group foun! in lymphoi! tissues &ne group foun! in lymphoi! tissues

&ne group locate! in paracellular space bet:een epithelial cells &ne group locate! in paracellular space bet:een epithelial cells

/ecogni7es unprocesse! target antigen in absence of )P; help /ecogni7es unprocesse! target antigen in absence of )P; help

,- cells Cminor fraction of cells, !o not re8uire 5,cell helpD ,- cells Cminor fraction of cells, !o not re8uire 5,cell helpD

Mast cells Mast cells

Locate! in serosa, un!er epithelial surfaces an! a!>acent to bloo! Locate! in serosa, un!er epithelial surfaces an! a!>acent to bloo!
2essels, ner2es an! glan!s 2essels, ner2es an! glan!s

;apable of phagocytosis ;apable of phagocytosis

Process an! present antigen using M(; class I or II receptors Process an! present antigen using M(; class I or II receptors

LP" can !irectly in!uce release of mast cell me!iators LP" can !irectly in!uce release of mast cell me!iators

;omplement C;3a an! ;5aD in!uce mast cells to release me!iators ;omplement C;3a an! ;5aD in!uce mast cells to release me!iators

;hemota0is, complement acti2ation, inFammation ;hemota0is, complement acti2ation, inFammation

53G, 53G, secrete! by mast cells results in neutrophil inFu0 into infecte! secrete! by mast cells results in neutrophil inFu0 into infecte!
site site

"ummary of Innate Immunity
"ummary of Innate Immunity

E0ternal an! mechanical barriers

E0ternal an! mechanical barriers

/eceptors for pathogen motifs

/eceptors for pathogen motifs

"oluble antimicrobial proteins

"oluble antimicrobial proteins

Pattern of cyto6ines pro!uce!

Pattern of cyto6ines pro!uce!
inFuences a!apti2e response
inFuences a!apti2e response