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Prof. Ileana Constannescu MD, PhD

Immunology

Fundeni Clinical Instute

[email protected]

www.imunogeneca.ro

mailto:[email protected]://www.imunogenetica.ro/http://www.imunogenetica.ro/mailto:[email protected]

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Course 1: Defniton o general aspecs o immune response

• Immunology• Innate immunity

• Adape !Ac"uired# Immunity

• Clonal selecon• $umoral and Cellular Immunity

• %ymphocyte migraon into lymphoid ssues

• &erminal centers

• Follicular dendric cells

• Mucosal immune system'Course () Immunology, Prof. Ileana Constannescu

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Course () Immunology, Prof. Ileana Constannescu *

Immunology

Immunology) that +ranch of +iomedical science concerned with the response of the

organism to angenic chalenge, the recognion of self and not self, and all the +iological!in io#, serological !in itro# and physical chemical aspects of immune phenomena.

Immunology means the study of the structure and funcon of the immune system

!+asic immunology# immuni-aon, organ transplantaon, +lood +raing and

immunopathology !clinical immunology# la+oratory tesng of cellular and humoral

immune funcon !la+oratory immunology# and the use of angen/an+ody reacons in

older la+oratory tests !serology and immunochemistry#.

Immunological memory

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• 0he innate and adape immune systems

protect us from potenally infecous agents

!iruses, +acteria, etc.# that hae gained accessto our +ody through the sin or the lining of

our internal organs. 1uch systems hae eoled

to protect us from not only intracellular!iruses, some smaller parasites, some

+acteria# and from e2tracellular !most +acteria,

large parasites# pathogens and allergens

!animal hair, pollen, chemicals# +ut also fromourseles in potenally uncontrolled growth

such as malignancy or autoimmune diseases.

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INNATE IMMUNITY

• Innate immunity is a nonspec4c cellular and

humoral response that operates as the 4rst line of

defense against pathogens. 52tracellular

pathogens are immediately taen up and

degraded +y neutrophils and mononuclearphagocytes. %arge parasites are illed +y

eosinophils. 6atural iller lymphocytes ill some

tumor and irally infected cells. Pree2isng

solu+le mediators of innate immunity are natural

an+odies and complement components, which

can also a7ach to the cell mem+ranes of many

pathogens. 8Course () Immunology, Prof. Ileana Constannescu

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Course () Immunology, Prof. Ileana Constannescu 9

0he innate and adape systems

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• 0he main characteriscs and components of innate immunity occur in the in;ammatory response

discussed. If an organism enters the +ody +y +reaing through the +arriers of the sin or mucosa lining

the inner surfaces of the +ody, it comes in contact with phagocyc !neutrophils, eosinophils,

monocytes cells +ecome

plasma cells, they can also help cytoto2ic 0 cells deelop as well as increase macrophage acity.

$oweer, in contrast to > cells, the receptors on the surface of 0 cells can only recogni-e processed

angenic epitopes presented to them in the conte2t of surface M$C. 0he a+ility of 0 cells to see only

foreign angen in the conte2t of self M$C is called MHC restricon and is a crical safeguard for the

adape immune system to only eliminate pathogens and not normal cells. ?Course () Immunology, Prof. Ileana Constannescu

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Course () Immunology, Prof. Ileana Constannescu

Interacons +etween the innate and adape immune systems

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(Course () Immunology, Prof. Ileana Constannescu

0he cells central to adape immune response

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• > cells deelop with their appropriate

receptors for a cognate angenBs epitope 0and without eer seeing that angen +efore,

once encountering that angen and

generang a full immune response to it, they

will remem+er such a 4rst encounter.

• 0hus, when these memory 0 and > cells

encounter that same angen again their

response to that angen is much faster andmore ro+ust.

((Course () Immunology, Prof. Ileana Constannescu

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Course () Immunology, Prof. Ileana Constannescu ('

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(*Course () Immunology, Prof. Ileana Constannescu

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Actvaton o p&agoc#tc cells &roug& 'in%ing o ())s* >inding of Ps to PAMPs on micro+ial cells smulate phagocytes to

+ecome acated, increasing their si-e, phagocyc acity, producon of anmicro+ial su+stances, and producon of cytoines

and chemoines to a7ract and acate other components of the immune system.


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6atural iller !6# cells. !A# 6 cells use a ariety of receptors to idenfy target cells to +e illed. 0hese include Fc

receptors, complement receptors, and receptors that assess the M$C I molecules present on target cells. In addion, 6 cells can in;uence the deelopment of 0 cells in the iniaon of adape immune responses.

!># 6 cells uli-e iller acaon receptors !As# to recogni-e cells undergoing stress. Ence engaged, As

acate the 6 cell to ill the target. iller inhi+itory receptors !Is# e2amine the target for suGcient leels of

self M$C I molecules. If Is are suGciently engaged, the illing program is terminated. If not, illing of the target

cell proceeds.


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C%E6A% 15%5C0IE6

• =hen angen +inds to either surface

immunoglo+ulin on > cells or its speci4creceptor on 0 cells, these cells are induced to

proliferate rapidly. 0hus, angen selects and

generates speci4c clones that +ind andrespond to it.

• 0his process is called clonal selecton and is an

e2tremely important part of the adapeimmune response.

(9Course () Immunology, Prof. Ileana Constannescu

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$HMEA% A6D C5%%H%A IMMH6I0

• Humoral immunity is mediated +y the an+ody secreted

+y terminally diJerenated > cells, the plasma cells. Cell-mediated immunity inoles 0 cells that recogni-e

angen in an M$C/restricted fashion and either secrete

cytoines !0h cells# or +ecome cytoto2ic cells !0c cells#,

which ill irus/infected cells or a+normal host cells.

• It should +e reali-ed that in many cases a normal

humoral response will not proceed unless there is also a

companion 0h cell response this is +ecause 0h cells

secrete arious cytoines that are necessary for full >

cell maturaon and an+ody class switching.

(?Course () Immunology, Prof. Ileana Constannescu

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Course () Immunology, Prof. Ileana Constannescu (

Introducon to the interacons and funcons of the maKor components of the immune system

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Course () Immunology, Prof. Ileana Constannescu '(

Inducon of cell mediated immunity and an+ody against a iral infecon

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+YM(,-CYTE MI.)ATI-N INT- +YM(,-ID TI//UE/• %ymphocyte migraon into lymphoid ssues inoles a family of adhesion molecules

called selectns, inegrins, and mem+ers of the immunoglobin superfamily.

• >oth naie and memory lymphocytes connue to recirculate +etween +lood andsecondary lymphoid ssue. $oweer, once acated, memory cells tend to recirculate

+ac to the ssue where they were acated. %ymphocytes respond to chemotacc

signals from in;amed ssues or secondary lymphoid organs inially ia surface

glycoproteins called selecns. 5/selecn !5%AM/(# on endothelial cells +inds %/selecn

!%AM/(# on lymphocytes, causing a loose associaton or ehering. Firm adhesion is

mediated +y lymphocyte inegrin proteins such as L%A/3 or %FA/( interacng with theirrespece ligand LCAM or ICAM !mem+er of the immunoglo+in superfamily# on the

surface of endothelial cells.

• 0his adhesie interacon causes an acaon of the lymphocyte to increase e2pression

of integrin molecules, thus strengthening the adhesion. 0he endolhelial cell then directs

the lymphocyte toward its +asal lamina while simultaneously down/regulang ICAM

e2pression. Migrang lymphocytes 4nally diapedese +etween endothelial cells into anorgan or ssue +y up/regulang producon of proteinases.

• Ence a naie lymphocyte is acated, it displays a diJerent density of adhesion

molecules speci4c for the ssue in which it was inially acated, thus allowing it to

repeatedly return to that ssue.

''Course ( / Immunology / Prof. Dr. Ileana Constannescu

.E)MINA+ CENTE)/

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.E)MINA+ CENTE)/

• &erminal centers !&Cs# deelop within primary follicles of lymph nodes and spleen during 0 cell/dependent

immune responses. &Cs are the sites of centro+last clonal e2pansion and L $ region/directed somac

hypermutaon, selecon of high aGnity an+ody/producing centrocytes, deleon of low aGnity centrocytes,

0h(/ and 0h'/directed an+ody class isotype producon and eentual generaon of plasma+lasts or memory

cells.• > cells in lymph nodes and spleen 4rst encounter Ag in the 0 cell/rich areas of the paracorte2 and periarterial

lymphoid sheath !PA%1#, respecely. Ag is presented to them +y dendric cells !DCs#, which e2press high

leels of class II maKor histocompa+ility comple2 !M$C#, adhesion, and co/smulatory molecules. Aer

acaon, and within ' days, these > +lasts produce low aGnity unmutated lg, which is capa+le of forming

Ag/Ig comple2es on follicular dendric cells within primary follicles. Many of these cells die within ( to ('

clays. En the aerage, three > +lasts coloni-e each primary follicle and are then called centroblasts.

Centro+lasts, which are found in the +ase or dar -one of the follicle, down/regulate their surface lg andundergo a clonal e2pansion phase, diiding eery 9 to : h. During proliferaon, they acate a site/speci4c

hypermutaon mechanism that introduces random point mutaons into their lg L$ region genes.

• Centrocytes are the progeny of centro+lasts that migrate apically into the +asal light -one, where they up/

regulate their somacally mutated surface lg !receptors#. $ere, they interact with follicular dendric cells

!FDCs#, which can contain unprocessed Ag in the form of immune !Ag/A+# comple2es on their surface for

months. 0he centrocytes that e2press somacally mutated surface lg receptors with high ! # aGnity for FDC/

+ound Ag up/regulate +cl/' e2pression and are posiely selected !which is opposite to posie selecon of

thymocytes#. 0hese centrocytes interact with 0h' cells and can +ecome either plasma+lasts or memory >

cells, depending on the co/smulatory signals they receie from FDC and 0h( or 0h' cells. $oweer, they also

hae a high propensity to recycle +ac into centro+lasts for further proliferaon and een higher aGnity

maturaon. Centrocytes with low aGnity somacally mutated surface lg !receptors# for FDC/Ag do not up/

regulate +cl/' and die ia apoptosis. 0hus, there is e2tensie 4ne tuning of centrocytes +efore they are

allowed to produce an+ody for e2port.

'*Course ( / Immunology / Prof. Dr. Ileana Constannescu

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&C -ones

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• 0he recom+inaon/acang genes RAG1 and RAG2, which drie genomic L!D#N rearrangements

are also induced to +e ree2pressed in preapoptoc centrocytes of the +asal light -one. 0his

inducon of an immature state in &C centrocytes may +e necessary for further light chain receptor

eding in an eJort to sae these cells.

• 0his eding of L% genes, along with the +cl/'/regulated apoptosis, proides an addionalmechanism for remoing potenally autoreace an+ody/producing cells. 0hus, in &C, there is

an opportunity for angen/dependent secondary L!D#N rearrangements to occur in order to 4ne

tune the speci4city of the peripheral an+ody repertoire.

• Ence centrocytes with high aGnity surface Ig and high e2pression of +cl/' hae passed the

discriminatory enironment of the +asal light -one, they migrate to the apical light -one. $ere A+

class switching and maturaon into plasma+last or memory cells occur. Plasma+lasts migrate intothe medullary cords of lymphnodes and red pulp cord of the spleen, where they terminally

diJerenate intomature plasma cells and secrete their an+odies into the circulaon .

• 1ome acated > cells or plasma+lasts can leae the secondary lymphoid organs, return to the

circulaon, and reappear in the +one marrow and the gut. Memory > cells are found in the areas

surrounding &Cs !follicular mantles# a well as the marginal -one of the spleen.

• Inial proliferaon of centro+lasts gies rise to the 4rst foci in primary folicles within ' days, and

the deelopment of a full dar and light -one &C tae (3 days. 0he deelopment of &Cs re"uires

cluster formaon +etween %FA/( on > cells and ICAM/( on FDCs as well as L%A/3 on acated >

cells and LCAP on FDCs.

• In addion, interleuin/3, /8, and /( must +e elicited from 0h( or 0h' cells in order for an+ody

class switching and full centrocyte deelopment to plasma+lasts or memory cells to occur. &Cs in

spleen and lymph nodes peaat ' wees and +egin to wane aer * wees howeer, &Cs remain

constuely in the gut. '8Course ( / Immunology / Prof. Dr. Ileana Constannescu

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0-++ICU+A) DEND)ITIC CE++/

• FDCs hae long processes and Fc, C, 06F receptors, as well as ICAM/(, and LCAM/(

+ut no M$C/II. 0hey contain Ag/A+ comple2es on their surface for months to years.

• Centrocytes that connue to maintain high leels of +cl/' e2pression can receie

mem+rane/+ound immune comple2es !iccosomes# from FDC and induce the

e2pression of 0 cell/reace surface molecules such as >:.'. 0his resultant interacon

determines whether there is diJerenaon into a mature &C centrocyte or

centro+last recycling. $oweer, the formaon of FDC clusters is crical dependent on

06FO and %0O, since these cytoines are necessary for FDC cluster formaon andconse"uent primary as well as secondary follicles indicang that they hae 06F/(s.

• 0he fact that FDC can contain Ag for prolonged periods of me is the reason why we

do not need to +e fre"uently immuni-ed with certain angens, since FDCs proide a

connuous depot of Ag een without an e2isng &C. It has recently +een recogni-ed

that the human immunode4ciency irus, upon disappearing from the +lood, can +ese"uestered on the dendric arms of FDC for a num+er of years. 5entually, the FDC

can no longer hold the irus in chec, the irus is released into peripheral +lood, and

the paent enters the lethal stages of AID1.

'9Course ( / Immunology / Prof. Dr. Ileana Constannescu

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MUC-/A+ IMMUNE /Y/TEM• 0he mucosal immune sysem !MI1# consists of lymphoid ssues within and directly +eneath the epithelial lining of

the respiratory, genitourinary, and gastrointesnal tracts as well as +eneath the ductal system of the saliary,

lacrimal, and mammary glands. 0he surface area of mucosal surfaces is oer ( mes greater than that of sin, and

the MI1 contains up to :8 of all the > cells of the +ody. 0he primary product of the MI1 is IgA.

• =ithin the gastrointesnal tract, solu+le angen is taen up +y illus epithelium and parculate angens areprimarily taen up in the ileal poron of the small intesne +y speciali-ed surface lining microfold !M# cells. M cells

internali-e Ag and transport it to underlying lamina propria macrophages, which process it and present it to

surrounding collecons of lymphoid cells forming ileal PeyerBs patches !PPs#.

• PPs contain follicles, similar to lymph nodes and spleen, with high endothelial enules and signi4cant collecons of

0 cells in +etween. 0 and > +lasts acated here go to the nearest mesenteric lymph node for further maturaon,

alpha $ chain class switching, or N chain formaon or deleon. 0hey then enter the thoracic duct and +loodstream,

homing +ac to the same or distant mucosal sites. 0hus, een though much of the processing and reacity to

angen occurs in the ileum, protecon through IgA occurs at many mucosal surfaces.• 1erum IgA is monmeric and represents only (( of all serum immunoglo+ulin. 1ecretory IgA represents oer 8 of

all Ig found in secreons and is primarily dimeric with two monomerlic units coalently Koined +y a N chain. Dimeric

IgA +inds to a polymeric immunoglo+ulin receptor !pI&# on the +asal surface of mucosal epithelial cells. 0his IgA/

pI& comple2 is endocytosed and transported to the apical !luminal# surface of the epithelial cell.

• During this transport process, a small piece of the pI& is cleaed with the remaining component now called the

secreory componen . 0hus, IgA is secreted as dimeric IgA +ound to a secretory component.

• 1ecretory IgA does not acate the complement system +ut coats +acteria and some iruses !polio, co2sacie, rota,and herpes#, thus preenng their adherence to mucosal lining epithelium. Also, some iruses within surface

epithelia can +e neutrali-ed +y pI&/internali-ed IgA. $oweer, it should +e noted that oral immuni-aon with

solu+le Ag does not always generate an immune response and can instead generate unresponsieness.

':Course (' / Immunology / Prof. Dr. Ileana Constannescu

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Ag and cell traGc in gut

'?Course ( / Immunology / Prof. Dr. Ileana Constannescu

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eferences• oi7Bs 5ssenal Immunology, Includes Destop 5dion, ('th 5dion, Peter N. Deles, 1eamus N. Marn,

Dennis . >urton, Ian M. oi7, April '((, =iley/>lacwell

• A++as A, %ichtman A$. &eneral properes of immune responses. In Cellular and molecular immunology,8th ed. Philadephia) => 1aunders Co., '*.

• >er-ofsy NA, >erower IN. Immunogenicity and angen structure. In Paul =5, ed. Fundamental

immunology, 8th ed. Philadelphia) %ippinco7 =illiams Q =ilins, '*.

• Chaplin DD. Eeriew of the immune response. J Allergy Clin mmunol '* ((( )133'.

• Naneway CA, Nr. 5oluon of the immune system. In Naneway CA Nr, 0raers P, =alport M, 1hlomchi P, eds.

mmunobiol-ogy! "#e immune system in #ealt# and disease, 9th ed. Philadephia) &arland Pu+lishing,

'3)998/9?'.• Paul =5. 0he immune system) An introducon. In Paul =5, ed. Fundamental immunology, 8th ed.

Philadelphia) %ippinco7 =illiams Q =ilins, '*.

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5dion, '(.

• Callaghan, C. N., and >radley, N. A., Current status of enal 0ransplantaon Cpt. ( in 0ransplantaon

Immunology Methods and Protocols edited +y Philip $ornicl2, Marlene ose, $umana Press Inc. '9.

• Camp+ell, .D. and 0rowsdale, N. Immunology 0oday (?, 3*, (:.

• Ceca, N.M. and eed F.5., $istocompa+ility 0esng, Cross/Matching, and Allocaon of idney 0ransplants

in $and+oo of indey 0ransplantaon, Fourth 5dion, &a+riel M. Danoitch, '8 +y %ippinco7 =illiams

Q =ilins.

Course (/ Immunology / Prof. Ileana Constannescu'

http://eu.wiley.com/WileyCDA/Section/id-302479.html?query=Peter+J.+Delveshttp://eu.wiley.com/WileyCDA/Section/id-302479.html?query=Seamus+J.+Martinhttp://eu.wiley.com/WileyCDA/Section/id-302479.html?query=Seamus+J.+Martinhttp://eu.wiley.com/WileyCDA/Section/id-302479.html?query=Dennis+R.+Burtonhttp://eu.wiley.com/WileyCDA/Section/id-302479.html?query=Ivan+M.+Roitthttp://eu.wiley.com/WileyCDA/Section/id-302479.html?query=Ivan+M.+Roitthttp://www.ashi-hla.org/http://www.ashi-hla.org/http://eu.wiley.com/WileyCDA/Section/id-302479.html?query=Ivan+M.+Roitthttp://eu.wiley.com/WileyCDA/Section/id-302479.html?query=Ivan+M.+Roitthttp://eu.wiley.com/WileyCDA/Section/id-302479.html?query=Dennis+R.+Burtonhttp://eu.wiley.com/WileyCDA/Section/id-302479.html?query=Seamus+J.+Martinhttp://eu.wiley.com/WileyCDA/Section/id-302479.html?query=Seamus+J.+Martinhttp://eu.wiley.com/WileyCDA/Section/id-302479.html?query=Peter+J.+Delves

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• Ceca, N.M., 0he role of $%A in renal transplantaon. $uman Immunology 89) 9/(9,

(:.

• Chua, M.1., 1arwal, M. Microarrays) 6ew tools for transplantaon research. Pediatric

6ephrology, (?)*(/*':, '*.

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• De Meester, N., PersiKn, &.&., Claas, F.$.N., Frei, H) In the "ueue for a cadaer donor

idney transplant) new rules and concepts in the 5urotransplant Internaonal

Foundaon. 6ephrology Dialysis 0ransplantaon (8,*, ***/**?, '.

• 5uropean >ioinformacs Instute, h7p)

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• Nerius, N. 0., 0aylor, . N., Murillo, D., and %eone, N. P. Dou+le renal transplants from marginal donors) '/year results. Nournal of

Hrology, (9*, 3'*/3'8, '.

• Nohnson, A.$., atoich, $urley. C., $art-man, .N., =ade, N.A., $uman %eucocyte Angen ) 0he MaKor $istocompa+ility Comple2

of Man, 3, ':/39, in Clinical Diagnosis and Management +y %a+oratory Methods, Nohn >ernard $enry, M.D., '(, 1aunders,

0weneth 5dion.

• %i7le, A/M., Parham, P) Polymorphism and eoluon of class I and class II genes and molecules. eiews in Immunogenesc,

(S(8/('*, (.

• %ucas, D.P., Paparounis, M.%., Meyers, %., Mart, N.M., Tachary, A.A.,) Detecon of $%A class I speci4c an+odies +y the Rui1creen

5n-yme/%ined Immunosor+ent Assay. Clin %a+ Diagn %a+ Immunol, (:3)'8'

• %umine2 Corporaon, (?/'. %umine2 ( Hser Manual Lersion (.: e >.

• Marsh, 1.&.5., Parham, P. >ar+er., >ar+er %.D., 0he $%A Facts>oo, Academic Press, '.

• Moore, 1.>., Ploeger, 6.A., De&oey, 1..,) $%A an+ody screening) Comparison of a solid phase en-yme/lined immunoassay with

anglo+ulin augmented lymphocytoto2icity. 0ransplantaon (: 93)(9(:.

• 6y+erg, 1. %., Matas, A. N., remers, =. ., et. al. Improed scoring system to assess adult donors for cadaer renal transplantaon.

American Nournal of 0ransplantaon. *, :(8/:'(, '*.

• hodes, D.A., 0rowsdale, N.) &enecs and molecular genecs of the M$C. eiews in Immunogenecs, ()'(/*(, (.

• odey &lenn 5. $%A >eyond 0ears. De 6oo, Inc. ''(*.

• 1anger Centre, h7p)

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Course : -rigin" %estnaton an% srucure o cells an% tssues o &e

immune s#sem

• >one Marrow

• 1tem Cells

• 5rythropoiesis

• &ranulolcytopoiesis

• 5osinophils

• >asophils

• 6eutrophls

• %ymphopoiesis

• 6atural iller Cells

• Monocytes

• Dendric Cells

• 0hymus

• %ymph 6odes

• 1pleen

• Mucosal Associated %ymphoid 0issue !MA%0#

• Circulaon and ecirculaon

**Course ') Immunology, Prof. Ileana Constannescu

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>E65 MAE=

• 0he +one marrow constutes almost 8 of

total +ody weight and is responsi+le for the

formaon of all +lood !&emopoiesis# in

adults.

• It also proides a microenironment necessary

for > lymphocyte maturaon and formaon of

pre/0 cells $lymphopoiesis%.

*3Course ') Immunology, Prof. Ileana Constannescu

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105M C5%%1

• All of these cells originate from undiJerenated

pluripotenal hemopoiec sem cells !P$1C#, which can +e

found 4rst in the mammalian em+ryo within the lier then

spleen.

• 1Cs are pluripotenal CD23 and represent less than .( &

of all cells in adult marrow. 1Cs hae limited proliferae

capacity and e2hi+it the potenal to diJerenate ino all

cells of the m#eloi% !erythrocytes, granulocytes, monocytes,

and platelets# or l#mp&oi% !0 and > cells# lineage. =hen 1Csdiide, the two daugher cells $'Cs% can either connue as

1Cs or proceed into any of the diJerenaon pathways


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Cells of the immune system / hematopoiesis

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*:Course ') Immunology, Prof. Ileana Constannescu

Cells and growth factors in hemopoiesis

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• If a DC !daughter cell# proceeds into the diJerenaon pathway,

it +ecomes a diiding mulpotenal colon# orming uni4spleen

5C0U4/# or CFH !colon# orming uni4l#mp&oi% #!C0U4+##

progenitor cell and then a progressiely maturing unipotenalprecursor cell for any of the mature cells of peripheral +lood. 0he

precursor cell gradually loses its a+ility to self/renew and then

diide as it approaches its mature phenotype.

• /Cs not only depend on a speci4c microenironment for their

maturaon, they also depend on numerous gl#coproein gro6&

acors that act at diJerent stages to control the cell #pe as well

as rae o cell ormaton. 1ome of these growth factors such as

sem cell acor 5/C07 and interleuin !I%/:# are secreted +y

marro6 sromal cells, +ut most others are produced elsewhereand transported to the marrow +y the +lood stream !en%ocrine7*

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50$EPEI51I1

• Erythropoiesis occurs 2hen a "0- cell !ies rise to burst-forming units -

erythrocyte (BFU-E) and then colony-forming units-erythrocyte (CFU-E)

all under the in8luence of erythropoietin (EPO) 8rom the 3idney corte as

2ell as IL-3 and granulocyte-macrophage colony-stimulating factor (G-

C!F)"

• CFU-E 8orm the precursor o8 erythrocytes, the proerythroblast. 0nder normal

conditions, #"$ % &' 77 erythrocytes are prouce each ay" roerythro

blast *+ basophilic erythroblast *+ polychromatophilic erythroblast

*, ortho-chromatophilic erythroblast * reticulocyte * erythrocyte

is the se9uence o8 eents in maturation. Durin! this se9uence, the nucleus is

condensed and then lost as the cell becomes 1-4 micro.

• &hese maturation eents occur around macrophages, 2hich pha!ocytose the

etruded nuclei as 2ell as proide some !ro2th 8actors.

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&A6H%EC0EPEI51I1

• &ranulocytopoiesis is the generaon of three

types of granulocytes !neutrophils,

eosinophils, +asophils# from CFH/1.

• Mature cells are named +ecause of staining of

their speci4c granules. All %erive rom C0U4/5spleen7 —> C0U4Eo" 48A/- or C0U4NM -+

C0U4N 49 m#elo'las 49 prom#eloc#e >

m#eloc#e -* meam#eloc#e 4,; /a' 49maure cell*

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5osinophils

• 5osinophils re"uire &M/C1F, I%/*, and I%/8 for

their maturaon. 0hey represent ' to (& of

peripheral +lood white cells. 0heir speci4c

granules contain a num+er of factors including

&isaminase" aci% p&osp&aase" an% ma

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>asophils

• >asophils re"uire &M/C1F. I%/*, and I%/3 for

their maturaon. 0hey represent U( of

peripheral +lood white cells. 0heir speci4c

granules contain &isamine" &eparin" an%

c&emoactc acors or eosinop&ils an%neurop&ils*

• 0hey are similar to mas cells in that they

parcipate in IgE4me%iae% imme%iaepersensitvi# responses.

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6eutrophils

• 6eutrophils re"uire &M/C1F, I%/*, and granulocyte colony/

smulang factor !&/C1F# for their maturaon. Hnlieeosinophils and +asophils, the CFH/1 gies rise to a CFH/

6M cell, which, depending on the leel of granulocyte or

macrophage colony/smulang factor in the enironment,

can diJerenate into a CFH/6eut or CFH/M cell. >!? o@!? o all 6&ie cells are neurop&ils*

• T&eir specifc granules conain alaline p&osp&aase"

l#so$#me" lacoerrin" p&agoc#tc an% #pe IB

collagenase* T&e# are &e earlies p&agoc#tc cells oappear in a 'acerial inecton an% are a prominen

constuen o cellular immune response*

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%MP$EPEI51I1

• %ymphopoiesis is the a+ility of CFH/%y to form either CFH/%y> or

CFH/%y0 in the +one marrow.• CFH/%y> cells deelop in the presence of I%/: and I%/* in the

marrow to immunocompetent ) cells with slgM.

• Further maturaon of these cells occurs in germinal ceners of

secondary lymphoid ssue. CFH/%y 0 cells +ecome *re-" cells,which leae the +one marrow and 4nd their way to the

su+capsular area of the mic core= where they proliferate and

mature in the deeper thymic corte2 into either CD* V 3V or CD* V ?V

cells.

• 0hus, the 'one marro6 an% mus are considered primar#l#mp&oi% tssue, and l#mp& no%es" spleen" gu4associae%

l#mp&oi% tssue, etc. are considered secon%ar# l#mp&oi% tssue*


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6A0HA% I%%5 C5%%1

• 6atural iller !6# cells also deelop within the

marrow and then are found in peripheral

+lood, lier sinusoids !pit cells#, and spleen

sinusoids +ut not thoracic lymph. duct.

• 6 cells appear early in +acterial infecons,

can secrete interferon-y, and spontaneously

ill some viral inece% cells an% umor cells.

• 0hey respond to I+4 and deelopindependently of the thymus.


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ME6EC051

• Monoc#es deelop from CFH/M progenitors under the in;uence of &M/C1F,

I%/*, and &/C1F. 0hey represent * to ? of leuocytes in peripheral +lood.

• Monoc#es hae numerous a-urophilic granules !lysosomes# in their

cytoplasm and can readily leae the circulaon to gie rise to macrophages

within almost eery organ. 0hey are thus the source of the mononuclear

phagocytc sysem throughout the +ody.

• 0hey are een more phagocyc than neutrophils or eosinophils in that they

can degrade larger 'aceria within phagosomes ia the formaon of

hydrogen pero2ide, hypochlorous acid, and supero2ide.

• 0hey can also fuse to form foreign body gian cells in response to a large

angenic load. Macrop&ages e=press class II ma

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D56DI0IC C5%%1

• Dendric cells are +one marrow/deried cells speciali-ed

for presenng angens to either CD3 V or CD?V 0 cells inorder to iniate a primary immune response.

• 0hese cells appear to +e generated from CD*3V cells and

re"uire &M/C1F, 06F alpha, and possi+ily 0&F +eta for

full maturaon. Dendric cells are found in all lymphoid

ssues where they hae speci4c names. >ecause of their

highly eGcient funcon in antgen presenaton, they

hae come to +e called natureBs adKuantW.

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0$MH1

• 0he thymus is a primar# l#mp&oi% organ that is re"uired for the

generaon of immunocompetent CD*V

3V

and CD* V

?V

cells necessaryfor an adape immune response .

• 0he stroma of the thymus is composed of epithelial cells that

originate from the third pharyngeal pouch in the em+ryo. 0he

parenchyma is made up of thymocytes that are either posiely and

then negaely selected for maturaon !U(# or deleted !X# +yapoptosis.

• Most of the deleon of cells occurs in the corte2, with the medulla

containing mainly mature cells.

• Aer slgV > cells, pre/0 cells, monocytes, 6 cells, and dendric cellshae deeloped in the marrow and CD*V3V and CD*V ?V cells hae

matured in the thymus, they leae these primary lymphoid organs

and migrate into peripheral secondary lymphoid ssue) lymph

nodes spleen and mucosal associated lymphoid ssue !MA%0#.


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%MP$ 6ED51

• %ymph nodes !%6s# are encapsulated structuresthat are strategically placed throughout the +ody

to receie and 4lter angens and cells from

peripheral intersal ;uid and lymph.

• All %6s eentually drain into the thoracic ductsystem and +ac to the peripheral +lood.

• 0here are appro2imately 88 idney/shaped, (/(

mm in diameter, lymph nodes in the +ody. 0heirindented hilus contains +lood and lymphac

essels.


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Course ') Immunology, Prof. Ileana Constannescu 8(

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8'Course ') Immunology, Prof. Ileana Constannescu

1tructure of a lymph node

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• 0hus, %6s hae two circulaons, l#mp& an% 'loo%, which

permeate a stroma of largely type III and I collagen. 0he

type III collagen is arranged in a chicen wire fashion,forming lymphac sinuses supporng a parenchyma of

immunocompetent 0 and > cells as well as macrophages

and other angen/presenng cells. 0hese cells are

locali-ed into)• /U(E)0ICIA+ C-)TE: containing primary and secondary

follicles with germinal centers containing dar and light

-ones

• DEE( C-)TE: containing high endothelial post/capillary

enules

• MEDU++A: with medullary cords.

8*Course ') Immunology, Prof. Ileana Constannescu

• %ymph enters a %ymph nod !%6# at its surface as numerous aJerent

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• %ymph enters a %ymph nod !%6# at its surface as numerous aJerent

lymphacs pierce its type I collagenous capsule and empty into the

su+capsular sinus. It then percolates through the corte2 into the medullary

sinuses, where it leaes the hilus ia eJerent lymphacs. Any cells that enter

through aJerent lymphacs can also enter the parenchyma of the %6.• 0he hilar artery supplies the medulla and deep corte2 +ut then empes into

a capillary net on either side of the super4cial corcal follicles. 0hese

capillaries then drain into post capillary enules !PCLs# with a ery high

cu+oidal endothelium in the deep corte2. 0hey then decrease their

endothelial height, pass through the medulla, and leae the %6 as hilar eins.It is at the PCLs !post capillary senules# in the deep corte2 where circulang

0 and > cells adhere to PCL endothelium and migrate +etween these cells

!diapedesis# into the node.

• Most > cells migrate super4cially into follicles, with most of the 0 cells

remaining in the deep corte2. 0hey can remain in the %6 for anundetermined period or enter a lymph sinus and e2it ia an eJerent

lymphac. =e will deelop further the structure of the %6 during an immune

response.


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1P%556

• 0he spleen is an encapsulated organ with l#mp&oi%

tssue called whie pulp (!", which can respond to

+lood/+orne angens surrounded +y red pulp (#!".

More lymphocytes circulate through it each day than

any other secondary lymphoid organ.• 1imilar to %6, the spleen has a stroma of type III and

I !capsule and tra+ecular# collagen that supports the

parenchyma of =P and a +lood sinusoidal system

with cords of hemopoiec and lymphoid ssue calledP separated from each other +y a marginal -one.


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1tructure of spleen white pulp with perarteriolar lymphoid sheath !PA%1#

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• 0he part of the =P around a central arteriole is called the periareriolar

lymphoid sheah (!$%&" and contains primarily 0 cells. It is thus analogous

to the deep corte2 of %6. 0he periphery of =P contains > cellrich lymphoid

follicles Kust lie the periphery of %6. >etween the periphery of the =P andthe marginal -one is a +lood 4lled marginal sinus, which receies capillary

+ranches from the central arteriole. 0 and > cells leae the splenic

circulaon here and then migrate to the PA%1 or follicles, respecely.

• 0he marginal -one contains macrophages and some memory > cells. 0he

marginal -one and sinus funcon as a part of > and 0 cell entry points into

the =P similar to high endothelial enules of %6, +ut the marginal sinus

has a low endothelium. > and 0 cells can migrate out of the =P into an P

cord through +ridging channels !>Cs# in the marginal -one.

• 0he P contains +lood sinusoids with associated macrophages that line

cellular cords. 1ome P cords contain granulocytes, +ut others connect

with =P follicles and contain plasma cells. T&e sinusoi%al macrop&ages

%esro# ol% plaeles an% er#&roc#es. 0he central arterioles empty

directly into the P cord or sinuses and then into tra+ecular eins.

8:Course ') Immunology, Prof. Ileana Constannescu

MUC-/A+ A//-CIATED +YM(,-ID TI//UE 5MA+T7

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MUC-/A+ A//-CIATED +YM(,-ID TI//UE 5MA+T7

• 0he epithelial lining, lamina propria, and su+mucosa of the

gastrointesnal, respiratory, and genitourinary tracts contain wandering

cells, diJuse aggregates, solitary primary nodules, or aggregates of

secondary nodules that can +ecome encapsulated. All of these are

collecely called mucosal associated lym*#oid ssue $MA+"%.

• =hile most of the diJuse and aggregated lymphoid ssue of the MA%0 is

responsi+le for producing IgA, most intraepithelial lymphocytes !I5%# are

CD?V OY !9# or Z[!3# 0 cells. It appears that the Z[ cells may react

to +acterial angens. 0he epithelial lining oer PeyerBs patches !PP#

contains speciali-ed angen transporng cells called M cells, which

transport luminal angen to under lying angen reace lymphocytes.

• It should also +e reali-ed that most of the cells acated in the MA%0 stayin or return to the MA%0. 0hus, cells smulated in (( 5(e#pers pac&es7

or tonsils enter mesenteric or cerical lymph nodes for further

maturaon. Aer re/entering the circulaon, they home +ac to the

MA%0.

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CICH%A0IE6 A6D 5CICH%A0IE6

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CICH%A0IE6 A6D 5CICH%A0IE6

>oth 0 and > cells connuously circulate and recirculate, +lood \X lymph \X

+lood. Appro2imately (/' recirculate eery hour. $oweer, 6 cells are onlyfound in +lood, spleen, and lier.


C T& A t

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Course : T&e Antgen

• De4nion

• Immunogenicity

• 1peci4city

• Angen determinants

• 1uperangens

• 1tructure and funcons

• Immuni-aon

• Laccinaon

9(Course * / Immunology / Prof. Ileana Constannescu

D 4 i

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De4nion• Antgen: su'sance &a can elici an immune response an% &a can reac specifcall# 6i& &e

correspon%ing ant'o%ies or T cell recepors* An antgen ma# conain %eerminans*

• Angenic determinant or epitope) poron of an angen that mars contact with a parcular

an+ody or 0 cell receptor.• A protein many hae se"uenal and

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ANTI.EN: Anantgenis a molecule &a 'in%soa specifc proein

srucurecalle% antbody.

• An angen +inds to a speci4c an+ody to proide a mechanism +y which the angen is

recogni-ed and inacated. In this manner, an angen comple2es with a speci4c an+ody

so that the comple2 can a7ach itself to speciali-ed immune cells that either internali-e thecomple2 to destroy it or release +iologic mediators such as histamine to induce an

allergic

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1chemac of the en-yme/lined immunosor+ent assay !5%I1A#.

93Course * / Immunology / Prof. Ileana Constannescu

Defnitons an% commens

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• antgen !anB/Kon# anbody &r. gennan to produce] any su+stance which is capa+le, under appropriate condions,

of inducing a speci4c immune response and of reacng with the products of that response, that is, with speci4c

an+ody or speci4cally sensi-ed 0/lymphocytes, or +oth. Angens may +e solu+le su+stances, such as to2ins and

foreign proteins, or parculate, such as +acteria and ssue cells howeer, only the poron of the protein or

polysaccharide molecule nown as the angenic determinant !"..# com+ines with an+ody or a speci4c receptor on

a lymphocyte. A++reiated Ag.

• allogeneic a*" one occurring in some 'u no all indiiduals of the same species, e.g., histocompa+ility angens and

human +lood group angens isoangen.

• 'loo%4group aFs, erythrocyte surface angens whose angenic diJerences determine +lood groups.

• CD a., any of a num+er of cell surface marers e2pressed +y leuocytes and used to disnguish cell lineages,deelopmental stages, and funconal su+sets such marers can +e iden4ed +y speci4c monoclonal an+odies and

are num+ered CD(, CD', CD*, etc.

• &epatts 8 core a* 5,8cAg7" a core protein angen of the hepas > irus present inside complete irions !Dane

parcles# and in free core parcles in the nuclei of infected cells the angen is not present in the +lood of infected

indiiduals, +ut an/$>c an+odies appear during the acute infecon they do not protect against reinfecon.

• &epatts 8 e a. 5,8eAg7" a core protein angen of hepas > irus present in the +lood in some infected indiiduals.

An/$>e an+odies appear transiently during conalescence they do not protect against reinfecon.

• &epatts 8 surace a* 5,8sAg7" a coat protein angen of the hepas > irus present on complete irions !Dane

parcles# and smaller spherical and 4lamentous parcles circulang in the +lood of indiiduals with ace or chronic

infecons. An/$>s an+odies appear in the +lood in late conalescence and are protece against reinfecon.

Eriginally called Australia $An% angen +ecause it was 4rst found in an Australian a+origine also formerly called

#e*as-associated a. $HAA% and serum-#e*as $H% a.98

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Course * / Immunology / Prof. Ileana Constannescu 99

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Course * / Immunology / Prof. Ileana Constannescu 9:

Defnitons an% commens

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• &eerologous a*" an angen that reacts with an an+ody that is not the one !the homologous angen# that induced its

formaon.

• &eerop&il a*" &eerop&ile a*" any of a group of cross/reacng angens occurring in seeral species and haing a species

distri+uon that does not correspond to phylogenec relaonships, e.g., Forssman angen. Called also #eterogenec a.

• &isocompat'ili# aFs" systems of allelic alloangens that can smulate an immune response that leads to transplant reKecon

when the donor and recipient are mismatched. Called also trans*lantaon angens.

• &isocompat'ili# aFs" ma

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• nuclear aFs" the components of cell nuclei with which annuclear an+odies !see under anbody% react.

• - a. o#ne Hauc#, "..],the lipopolysaccharide/protein somac ant gens of gram/negae +acteria, important in the serological

classifcaon of enteric +acilli. 1ee li*o*olysacc#aride. Cf. Ha.

• oncoeal a*" an angenic gene product that is e2pressed durin fetal deelopment, parally or completely repressed in adult sssues,

and derepressed in some ssues that hae undergone neoplasc transformaon oncofetal angens, e.g., alpha/fetoproten

carcinoem+ryonic angen, and pancreac oncofetal angen, are thus useful tumor marers.

• 5CEA7" a glycoprotein, mol. wt. '!#!#,!#, secreted into the glycocaly2 coang the luminal surface of gastrointesnal epithelia.

Eriginally thought to +e a speci4c angen of the fetal digese tract and adenocarcinoma of the colon, C5A is now nown to occur

normally in feces and pancreaco+iliary secreons and to appear in the plasma in a dierse group of neoplasc and non/neoplasc

condions including cancers of the colon, pancreas, stomach, lung, and +reast, alcoholic cirrhosis and pancreas, in;ammatory

+owel disease, rectal polyps, and cigare7e smoing. 0he primary use of C5A is in monitoring response to treatment of colorectalcancer.

• (rosae4specifc a* 5(/A7" a serine endopepdase secreted +y epithelial cells of the prostate gland serum leels are eleate +enign

prostac hyperplasia and prostate cancer. Measurement of P1A serum leels is somemes used as a screening test for prostate

cancer.

• pancreatc oncoeal a* 5(-A7" a glycoprotein, mol. wt. ?, found in fetal and neoplasc pancreac ssue +ut not in that normal

adults it also occurs at lower leels in the serum of paents with cancer at other sites and some normal adults.

• organ4specifc a., any angen that occurs e2clusiely in a parcul organ and seres to disnguish it from other organs. 0wo types

organ speci4city hae +een proposed) !(# 4rst/order or ssue spei4city is a7ri+uted to the presence of an angen characterisc of

parcular organ in a single species !'# second/order organ speci4city is a7ri+uted to an angen characterisc of the same organ

many, een unrelated species.

9Course * / Immunology / Prof. Ileana Constannescu

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Epiopes* Inasie micro+es e2press many angenic molecules that can +e indiidually

iden4ed +y diJerent angen receptors !immunoglo+ulins#.

0herefore, the an+ody response against a micro+e can consist of many diJerent

immunoglo+ulins recogni-ing diJerent speci4c sites on the micro+e. An indiidual

molecule can een consist of smaller parts that are speci4cally recogni-ed +y diJerentimmunoglo+ulins.

0he smallest indiidual enty that can +e detected +y a receptor is termed an epiope.

:Course * / Immunology / Prof. Ileana Constannescu

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Immunogenici#* Angens that are more comple2 in structure tend to hae more +inding sites

and e=press a greaer varie# o %iGeren epiopes.

Angens that can +e recogni-ed +y the greatest range of aaila+le 0 and > cell receptors, and

an+odies will generally smulate the strongest oerall immune responses !they hae greater

immunogenicity#.

Antgenici#) a+ility of an angen to) 1* in%uce an immune response

* com'ine 6i& specifc ant'o%ies an%Hor cell

recepors* :(Course * / Immunology / Prof. Ileana Constannescu

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• A'ili# o ant'o%ies or l#mp&oc#es o %iscriminae among %iGerenligan%s*

- Angenemia ^ the presence of angen in the +lood.

- Angenemic ^ e2hi+ing angenemia.

- Angenic ^ haing the properes of an angen

- Angenicity ^ the property of +eing a+le to induce a speci4c immune

response or the degree to which a su+stance is a+le to smulate animmune response. Called also immunogenicity.

:'Course * / Immunology / Prof. Ileana Constannescu

/pecifci#

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>inding aGnity of an+ody

:*Course * / Immunology / Prof. Ileana Constannescu

Immunogens &apens an% olerogens

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Immunogens" &apens" an% olerogens

• 0here are three types of angens) immunogens, haptens, and

tolerogens.

• Immunogens are molecules that can, +y themseles, +oth smulate an

immune response and, in turn, +e a target of an immune response

1u+se"uent e2posures to the same immunogen generally lead to

heightened secondary responses +y the adape immune system.

• $aptens are small molecules that, +y themseles can +oth smulate

immune responses and sere as targets of those responses.

• Hnlie immunogens, su+se"uent e2posure of the immunline system tothe same tolerogen leads to diminished responsieness against it.

:3Course * / Immunology / Prof. Ileana Constannescu

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Immunogens" &apens an% olerogens* Immunogens and tolerogens, +y themseles,

can +oth smulate and sere as targets of immune responses. $aptens cannot smulate

responses on their own, +ut can sere as targets of responses generated if the hapten is

a7ached to an immunogen. ee2posure to immunogens and haptens usually generate

heightened responses. ee2posures to tolerogens usually result in diminished

responses.


/U(E)ANTI.EN/

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/U(E)ANTI.EN/

• 1uperangens are certain +acterial and iral glycoproteins that +ind TC) and

M,C class II angens ousi%e o &e conventonal groove or antgenicpept%e 'in%ing, leading to nonspecifc actvaton o multple T cell clones*

• =hile a single pepde angen may +e recogni-ed +y or is immunogenic for a

small num+er of 0 cell clones, a special category of angens, nown as

superantgens, hae the capacity to smulate mulple 0 cell clones.

1uperangens, which hae +een iden4ed thus far as +acterial and iral

glycoproteins, are su*er-smulators of 0 cells +ecause they are capa+le of

+inding to a large num+er of 0 cell receptor LY se"uences, as well as to M$C

class II molecules outside of the pepde presentaon grooe.

• 0he +inding of superangens to relaely nonpolymorphic regions of M$C and

0C molecules promoes a%&erence o T cells o antgen4presentng cells,

irrespece of 0C speci4city. 1uch cross/lining of 0C with M$C molecules

leads to the acaon of multple clones o T cells" especiall# CD23 cells*


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::Course * / Immunology / Prof. Ileana Constannescu

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An immunogen is an angen that acates immune cells to generate an immune response against

itself.

T&us" an immunogen is an antgen" 'u an antgen is no necessaril# an immunogen*

• )y itsel8, penicillin is an anti!en that can bind to a speci8ic

antibody, but it is not immuno!enic it cannot actiate immune cells

to elicit an immune response to produce those speci8ic antibodies.

• In order to be immuno!enic, penicillin must 8irst become achemically reactie molecule, such as penicilloic aci, that is able

to coalently attach itsel8 to an endo!enous carrier protein, such as

serum albumin or other cell sur8ace membrane proteins. In this

manner. the penicilloic aci-protein molecule becomes animmunogen that is capable of acti/ating both 0 an B

lymphocytes to elicit the prouction of antiboies by B cells that

are able to specifically bin to penicillin. the antigen"

:?Course * / Immunology / Prof. Ileana Constannescu

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(enicilloic aci%4proein con

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. ,A(TEN) A hapten is a small organic molecule that is not immunogenic +y itself.

• In order to study the specificity of antigen binding by antibody molecules, researchers have

synthesized small organic molecules whose structures can be specifically modified at

specific sites.

• For example, benzene rings with either nitroso or arsonate groups at different positions in

the ring possess only one site for the binding of an antibody and are referred to as

haptens. Using a specific hapten coupled to an immunogenic protein carrier, a specific

antibody can be produced that either binds strongly to that specific hapten alone, and notto related haptens, or binds strongly to that specific hapten, and wealy to related haptens.

• !he latter finding provides a mechanistic basis for the ability of an antibody to bind other

molecules that closely resemble a particular antigenic structure "a cross-reacting

antibody#.

• $ther examples of haptens include nucleic acids, phospholipids, and small molecular

weight molecules such as penicillin. ?Course * / Immunology / Prof. Ileana Constannescu

C%''C$% $!!%'C$)' $!) C/0$)'Coupling of haptens to a protein carrier improes the immunogenicity of the hapten. 0his

approach is used successfully to prepare accine against Haemo*#ilus in0uenae type +.

As a result, meningis due to Haemo*#ilus b, which was the most common cause of

meningis in children, has +een irtually eliminated.

C-MMENT/

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• #utside o8 the laboratory, haptens pose a serious health ris1 to humans.

&his ris3 has increased dramatically in recent years, since humans areeposed to a eer increasin! number o8 haptens in their enironment.

• (hen these haptens !ain entry into the host, they may comple 2ith host

proteins to create immuno!emic haptenprotein molecules. In this manner,

an enironmental hapten, such as nic3el, may initially comple 2ith host

proteins and elicit the initial production o8 antibodies a!ainst the hapten.Ho2eer, upon reeposure to nic3el, t2o separate reactions can occur.

• 2ne reaction is protecti/e and inoles the production o8 antibodies that

bind to the hapten and clear it 8rom the circulation. 0he other reaction is

pathological an in/ol/es the bining of antigen to specific IgE

antiboy that is attache to mast cells. precipitating histamine releasean an allergic response"

• &hus, haptens are small nonimmuno!enic anti!ens that can be made into

immuno!ens that can elicit either clinical or patholo!ical immune

reactions.

?(Course * / Immunology / Prof. Ileana Constannescu

C-MMENT/

C-MMENT/

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• #ther factors that determine the egree of immunogenicity o8 anti!en include the route of antigen

administration, antigen dose, freuency of antigen aministration. an use of a4u/ant" or eample,

particulate anti!ens, such as bacteria and iruses, are more immuno!enic 2hen they are administered

intraenously. In contrast, soluble anti!ens, such as proteins, nucleic acids and carbohydrates, are more

immuno!enic 2hen administered subcutaneously.• 5lso. antigens gi/en orally (parenterally) may elicit immune responses in the gut that allo6 for the

prouction of antiboies that protect us from the antigen crossing the gut lining an entering the internal

compartments of the boy"

• 7o6e/er. parenterally aministere antigens may also inuce a state of tolerance to the antigen if it shoul

gain entry to the internal en/ironment a secon time /ia another route in an appropriate ose" 0his latter

phenomenon may be relate to the fining that /ery lo6 or /ery high oses of antigen are not able to elicit

a strong immune response an may actually inuce a state of immune nonresponsi/eness8tolerance in the

host"

• In contrast, intermediate doses o8 anti!en elicit stron! immune responses that proide protection to the H#&

a!ainst the anti!en.

• &he frequency of antigen administration also determines the ma!nitude o8 the immune response that is !enerated

a!ainst an anti!en. ost antigens reuire se/eral aministrations to achie/e optimal immunogenicity"

• or e. a primary administration o8 anti!en elicits a primary immune response o8 a !ien ma!nitude. A second

administration o8 the anti!en elicits a seconary response that is o8 a hi!her ma!nitude as compared 2ith the

primary response. A third administration o8 the anti!en elicits an een !reater immune and 8inally, theimmuno!enicity o8 soluble anti!ens can be au!mented 2hen they are administered in con;unction 2ith compounds

3no2n as a4u/ants"

• 54u/ants. such as 3illed mycrobacteria or Bordetella pertussis, help to augment the immune response that is

generate against a particular antigen"

• &he mechanisms responsible 8or the action o8 ad;uants are not 2ell understood at present, but they probably

inole the actiation o8 antigen-presenting cells, such as macrophages, 8or e88icient anti!en upta3e and

processin! 8or the presentation o8 de!raded immuno!enic peptides to & cells.

?'Course * / Immunology / Prof. Ileana Constannescu

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1ummary

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1ummary• 0he immune system must +e a+le to disnguish self\that which +elongs within

the +ody\from nonself. 6onself may enter the +ody from the outside or

represent an unaccepta+le change within the +ody !e.g., a normal cell +ecomingcancerous#.

• T&e &uman immune s#sem is comple=" compose% o multple organs" cell #pes"

an% molecules &a mus 6or oge&er*

• Inial protecon against infecon is proided +y mechanical +arriers !such as the

sin and mucous mem+ranes# and +y chemical +arriers !such as micro+ial

molecules secreted +y some sin cells# that can "uite eJecely +ar the entry of

micro+es in the +ody.

• =e use two immune systems to com+at inasion +y infecous organisms. Ene is

an ancient system of self/defense\the innate immune system !somemes called

the nonspeci4c immune system#. 0he other is the angen/speci4c adape

immune system !somemes called the speci4c immune system#.• Hsing a ariety of surface receptors, cells can sample not only the general

characteriscs of their enironment, +ut also the nature of the cells and molecules

with which they come into contact.

Course * / Immunology / Prof. Ileana Constannescu ?3

• An antgen is a srucure &a can 'e recogni$e% an% 'oun% '# &e specifc recepors o T

an% 8 l#mp&oc#es Antgens ma# 'e proeins car'o%raes lipi%s or com'inatons suc&

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an% 8 l#mp&oc#es* Antgens ma# 'e proeins" car'o%raes" lipi%s" or com'inatons suc&

as gl#coproeins or gl#colipi%s*

• A given antgen ma# provoe %iGeren responses in %iGeren in%ivi%uals*

• 0he smallest iden4a+le part of an angenic molecule that can +e recogni-ed +y a 0 or > cell

receptor is calle% an epiope or %eerminan*• Immunogens are angenic molecules that can, +y themseles, +oth smulate an immune

response and, in turn, +e a target of an immune response. 1u+se"uent e2posures usually

elicit heightened responses against that speci4c immunogen.

• ,apens are small molecules that, +y themseles, cannot smulate an immune response, +ut

can +e recogni-ed +y the immune system if +ound to an immunogenic molecule.

• Tolerogens are molecules that, lie immunogens, can +oth smulate immune responses andsere as targets of those responses, +ut su+se"uent e2posures result in diminished response

to that speci4c tolerogen.

• T&e process in 6&ic& a surace recepor ransers inormaton ino &e c#oplasm an% oen

o &e nucleus is no6n as signal rans%ucton* 0his process inoles a series of steps that

acate se"uenal sets of en-ymes that can modify their su+strate molecules to +ecome

+iologically ace.

• 0he adape immune response is inially random and results in 0 and > cell receptors that !(#

appropriately idenfy nonself, !'# are potenally reace against self, or !*# that will !in the

case of 0 lymphocytes# +e una+le to funcon in the +ody.

Course * / Immunology / Prof. Ileana Constannescu ?8

()EBENTI-N -0 IN0ECTI-N: BACCINATI-N

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• $umans hae nown of accinaon, if not its

mechanisms, for thousands of years.• Baccinaton is an inoculaton of non4virulen or

inactvae% micro'es as a means o in%ucing specifc

immuni#* 0hose who suried diseases such as plague,

smallpo2, and other epidemic diseases were generallysale from the same diseases deeloping again, een as

many others around them might +e dying.

• 6ot only was their surial a +lessing to the suriors +ut

also proided society with a set of indiiduals a+le to aidothers and perform crical acies in the face of

su+se"uent epidemics.

Course * / Immunology / Prof. Dr. Ileana Constannescu ?9

,isor# o vaccinaton

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#•0he ancient 5gypans and Chinese performed forms of accinaon to a7empt to protect

themseles against diseases such as smallpo2 +y e2posing indiiduals to powders formed from

the crusts and scales of pocmars on infected indiiduals. 1omemes mild forms of the disease

deeloped in indiiduals so treated, or somemes no isi+le disease deeloped at all, +ut thoseindiiduals found themseles protected.

•In (:3, 5dward Nenner demonstrated that intenonal inoculaon with cowpo2 !a mild disease

in humans caused +y a form of accinia, a irus that normally infects ca7le# conferred protecon

against smallpo2, a potenally fatal human disease caused +y a related +ut more irulent form of

accinia. At the me, of course, there was no nowledge of the role of micro+es in causing such

diseases. Nenner called his procedure accinaon, and the word was later adapted to name the

iral organism found lo +e the causae agent. %ater, the discoery +y o+ert och of the role of

speci4c micro+es in speci4c diseases smulated acity in the 4eld. %ouis Pasteur adanced the

science of accinaon +y deeloping eJece accines against epidemic diseases of agricultural

animals and eentually performed a dramac demonstraon of a ra+ies accine that saed the

life of a young +oy +i7en +y a ra+id dog. 1ince that me, accinaon has reoluoni-ed human

and animal health. oune childhood accinaons hae eliminated much of the misery and

occasional permanent crippling or fatal conse"uences of once commonplace diseases such asmeasles, diphtheria, and polio.

•1mallpo2, a disease that once illed humans +y the thousands, has in turn +een praccally

eliminated and the smallpo2 irus now e2ists only in a few protected la+oratories.

Course * / Immunology / Prof. Dr. Ileana Constannescu ?:

C+INICA+ A((+ICATI-N /MA++(-

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• 1mallpo2 is a highly contagious disease spreading from person to person, oen +y

salia droplets from the aJected personBs mouth. 5arly symptoms are similar to

those of in;uen-a and include high feer, headache, fague, muscle aches, andoming. Appro2imately ' to * days aer the onset of the symptoms, a rash

appears. 0he rash is inially seen on the face and oropharyn2 it then spreads to

the upper arms, legs, and trun.

• 0he mortality rate is appro2imately *, with death usually occurring during the

second wee of illness. 0reatment for smallpo2 is mainly suppore, +ecause

there is no nown eJece treatment. Laccinaon within 3 days of e2posure to

smallpo2 can preent a fatal outcome and can reduce the seerity of the illness.

• 0homas NeJerson, in an (?9 le7er to 5dward Nenner, wrote that, Future naons

3ill 4no3 by #istory only t#at t#e loat#some small*o5 #as e5isted and by you #asbeen e5r*ated. >ecause of a successful worldwide accinaon program, no case

of small po2 has +een reported since (::. In the Hnited 1tates, roune

childhood accinaon for small po2 ended in (:'. 0here is, howeer, current

concern a+out the potenal use of smallpo2 as a weapon of +ioterrorism.

Course * / Immunology / Prof. Dr. Ileana Constannescu ??

• 0he standard accinaon schedule in H1A

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0he standard accinaon schedule in H1A

Course * / Immunology / Prof. Dr. Ileana Constannescu ?

• 0he +ene4cial impact of accinaon has +een so widespread dial we

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now face the situaon in which many people no longer recogni-e the

dangers that hae +een oercome. A growing num+er of parents fail to

recogni-e the need to accinate children, and some indiiduals

adocate the eliminaon of accinaons +ecause they +eliee them to+e responsi+le for seeral, although rare, side eJects. As a result, the

danger e2ists that a pool of unprotected indiiduals may +e created that

could once again +e su+Kect lo main of the infecous diseases dial once

terrori-ed human populaons.

• It is pro+a+ly not necessary dial eery indiidual in a populaon +e

accinated. 1o long as a suGciently large populaon is accinated, the

chances of an infecous agent 4nding an unprotected indiidual

+ecome ery small, and the populaon as a whole remains essenally

resistant. 0his concept is called herd immunity. 0he inherent ris is dial

if an infecous organism infects a signi4cant num+er of unprotected

indiiduals, the infecon could spread rapidly among them, and ensuing

mutaons unancipated +y the accine could endanger accinated

indiiduals its well.Course * / Immunology / Prof. Dr. Ileana Constannescu

Essental c&araceristcs o vaccines

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For accinaons to +e eJece in protecon of intended populaons,

seeral characteriscs must +e present)

• 0he accine must proide eJece protecon against the pathogen

from which it is deried without signi4cant danger of actually

causing the disease or seere side eJects.

• 0he protecon proided +y the accine must +e eJece oer a longperiod of me.

• 0he accine must smulate deelopment of those immune

responses that are most eJece against the pathogen in "ueson

5proectve T4cell responses7*

• I mus stmulae &e pro%ucton o neurali$ing ant'o%ies o

minimi$e reinecton.

• I mus 'e suJcienl# sa'le or sorage" ranspor" an% use*

• T&e vaccine mus 'e economicall# easi'le or 6i%esprea% use*Course * / Immunology / Prof. Dr. Ileana Constannescu (

T#pes o vaccines• /accines may be prepared 8rom patho!enic or!anisms in a ariety o8 2ays.

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y p p p ! ! y y

• Li/e /accines are those that include or!anisms capable o8 normal in8ection and replication. &hese accines are not used

a!ainst patho!ens causin! seere diseases.

• Attenuated accines are those in 2hich the or!anisms included are lie, but their ability to replicate and cause disease has

been dama!ed by treatment 2ith heat, chemicals, or other means. &hese accines cause only subclinical or mild 8orms o8

the disease at 2orst.• 9ille /accines include or!anisms that hae been 3illed by treatment 2ith physical or chemical a!ents and may include

inactiated toins

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• A%

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• 0he deelopment of eJece accines is not necessarily a straigh_orward one. Although

main dangerous infecous diseases are now preented or minimi-ed +y roune accinaon,

many others such as malaria, histosomiasis, and AID1 sll lac eJece accines. Een the

diGculty in deeloping a accine is related to characteriscs of the infecous organism. Asmenoned earlier, the a+ility o7 cells to se"uester themseles within certain types of host

cells shelters them from the eJects of an+odies. If the host is not generang suGciently

eJece cellular responses, clearance o7 the pathogen is diGcult. And, as descri+ed earlier,

some pathogens such as 8lasmodium enter erythrocytes that do not e2press M$C class ( or

' molecules and are essenally inisi+le to 0 cells.

• In many cases, howeer, the diGculty lies with the a+ility of the pathogen to change itsangens so that immune responses generated to that point are ineJece. Perhaps the

most dramac e2ample of this is $IL. 0he immune system can generate strong an+ody

responses against certain structures on the iral surface, +ut +ecause the irus mutates so

rapidly during replicaon, large num+ers of new surface structures are constantly +eing

generated that are new to the immune system.

• 0hese escape muans are free to connue replicang as the immune system tries to catchup. Hnfortunately, if and when it does, ne6 generatons o ne6 escape muans &ave

alrea%# 'een generae%" an% &e immune response oen pla#s a &opeless game of cac&4

up*

Course * / Immunology / Prof. Dr. Ileana Constannescu 3

1 ggested readings

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1uggested readings

• A++as A, %ichtman A$. &eneral properes of immune responses. In Cellularand molecular immunology, 8th ed. Philadephia) => 1aunders Co., '*.

• >er-ofsy NA, >erower IN. Immunogenicity and angen structure. In Paul =5,

ed. Fundamental immunology, 8th ed. Philadelphia) %ippinco7 =illiams Q

=ilins, '*.

• Chaplin DD. Eeriew of the immune response. J Allergy Clin mmunol '*((( )133'.

• Naneway CA, Nr. 5oluon of the immune system. In Naneway CA Nr, 0raers P,

=alport M, 1hlomchi P, eds. mmunobiology! "#e immune system in #ealt#

and disease, 9th ed. Philadephia) &arland Pu+lishing, '3)998/9?'.

• Paul =5. 0he immune system) An introducon. In Paul =5, ed. Fundamentalimmunology, 8th ed. Philadelphia) %ippinco7 =illiams Q =ilins, '*.

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Course_1_2_3_2015_2016_ENG.pdf