11 Autoimmune Disease

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Lecture 22Lecture 22AutoimmunityAutoimmunity



Autoimmune DiseaseAutoimmune Disease

Self tolerance is lostSelf tolerance is lost

Specic adaptive immuneSpecic adaptive immune

responses mounted against selfresponses mounted against selfantigensantigens

Inability to eliminate antigen leadsInability to eliminate antigen leads

to chronic inammatory processto chronic inammatory process Ehrlich termed thisEhrlich termed this horrorhorror

autotoxicusautotoxicus



Autoimmune diseases mediated byAutoimmune diseases mediated by

cytotoxic antibodies !ype II"cytotoxic antibodies !ype II"



Autoimmune diseases mediatedAutoimmune diseases mediated

by immune complexes !ype III"by immune complexes !ype III"



Autoimmune diseases mediatedAutoimmune diseases mediated

by !#cells !ype I$"by !#cells !ype I$"



Autoimmune diseaseAutoimmune disease

susceptibilitysusceptibility %enetic predisposition%enetic predisposition

!&in studies Diabetes' 2() !&in studies Diabetes' 2()

mono*ygotic vs+ ,) di*igotic"mono*ygotic vs+ ,) di*igotic" -amily studies-amily studies

Association &ith ./0 genotypeAssociation &ith ./0 genotype /LA genotyping/LA genotyping



%enetic organi*ation of the ./0 in%enetic organi*ation of the ./0 in

humans and the mousehumans and the mouse



Detailed map of the human ./0Detailed map of the human ./0

regionregion



AssociatioAssociatio

n bet&eenn bet&een/LA and/LA and

susceptibilsusceptibil

ity toity to

autoimmuautoimmu

ne diseasene disease



1opulation studies sho& association of1opulation studies sho& association of

susceptibility to insulin#dependent diabetessusceptibility to insulin#dependent diabetes

mellitus IDD." &ith /LA genotypemellitus IDD." &ith /LA genotype



-amily studies sho& strong linage of susceptibility to-amily studies sho& strong linage of susceptibility to

insulin#dependent diabetes mellitus IDD." &ith /LAinsulin#dependent diabetes mellitus IDD." &ith /LA

genotypegenotype



Autoimmunity involves !Autoimmunity involves !

cellscells Ability of a ! cell to respond is determinedAbility of a ! cell to respond is determined

by ./0 genotypeby ./0 genotype

It has been hypothesi*ed that susceptibilityIt has been hypothesi*ed that susceptibility

to an autoimmune disease is determined byto an autoimmune disease is determined bydi3erences in the ability of allelic variants ofdi3erences in the ability of allelic variants of

./0 molecules to present autoantigenic./0 molecules to present autoantigenic

peptidespeptides

Alternatively4 self peptides may drive theAlternatively4 self peptides may drive thepositive selection of developing thymocytespositive selection of developing thymocytes

that are specic for particular autoantigens+that are specic for particular autoantigens+



Levels of autoantigens mayLevels of autoantigens may

drive ! cell selectiondrive ! cell selection If antigens are expressed at tooIf antigens are expressed at too

lo& a level4 they may not drivelo& a level4 they may not drive

negative intrathymic selection4negative intrathymic selection4

but su5cient to drive positivebut su5cient to drive positive

selectionselection

Insulin genes transcribed at highInsulin genes transcribed at highlevel in thymus protect againstlevel in thymus protect against

diabetesdiabetes



1eripheral 6#cell anergy1eripheral 6#cell anergy



Elimination ofElimination of

autoreactive 6autoreactive 6

cells incells ingerminalgerminal

centerscenters



Several &ays in &hichSeveral &ays in &hich

infectious agents could breainfectious agents could brea

self toleranceself tolerance



Association of infectionAssociation of infection

&ith autoimmune disease&ith autoimmune disease



Some body sites areSome body sites are

immunologically priviledgedimmunologically priviledged



Damage to an immunologically privileged siteDamage to an immunologically privileged site

can induce an autoimmune responsecan induce an autoimmune response



S78gren9s SyndromeS78gren9s Syndrome

0hronic autoimmune disorder0hronic autoimmune disorder

.a7or clinical manifestations.a7or clinical manifestations

resulting from changes in exocrineresulting from changes in exocrineglandsglands



-orms of S78gren9s-orms of S78gren9s

SyndromeSyndrome 1rimary S78gren9s is characteri*ed1rimary S78gren9s is characteri*ed

by inammatory cell involvementby inammatory cell involvement

of both the salivary and lacrimalof both the salivary and lacrimal

glandsglands

Secondary S78gren9s includes otherSecondary S78gren9s includes other

dened connective tissue diseasedened connective tissue disease 0auses are unno&n0auses are unno&n



-eatures of S78gren9s-eatures of S78gren9s

SyndromeSyndrome Glandular epithelial cells participate in theGlandular epithelial cells participate in the

autoimmune disease processautoimmune disease process

Epithelial cells produce a number ofEpithelial cells produce a number ofimmunologically active mediatorsimmunologically active mediators

May serve as antigen-presenting cellsMay serve as antigen-presenting cells

Epithelial cell responses modulateEpithelial cell responses modulatemechanisms occurring in the salivary glandsmechanisms occurring in the salivary glands



Is S78gren9s Syndrome anIs S78gren9s Syndrome an

Autoimmune Disorder:Autoimmune Disorder:

Described as an autoimmuneDescribed as an autoimmune

exocrinopathyexocrinopathy Strand and !alal4 ;<=("Strand and !alal4 ;<=("

%rouped &ith other connective tissue%rouped &ith other connective tissue

diseasesdiseases >heumatoid arthritis>heumatoid arthritis

Systemic lupus erythematosis SLE"Systemic lupus erythematosis SLE" ?hat is the evidence that it is an?hat is the evidence that it is an

autoimmune disease:autoimmune disease:



Evidence that S78gren9sEvidence that S78gren9s

Syndrome is an AutoimmuneSyndrome is an AutoimmuneDiseaseDisease A specic auto#immunogen andA specic auto#immunogen and

pathogenic antibodies have not beenpathogenic antibodies have not been

identiedidentied Autoantibodies that have been found haveAutoantibodies that have been found have

not been sho&n to have any directnot been sho&n to have any direct

pathogenic e3ects on exocrine tissuespathogenic e3ects on exocrine tissues

!here is substantial circumstantial !here is substantial circumstantial

evidence that tissue damage is the resultevidence that tissue damage is the result

of autoimmunityof autoimmunity



1olyclonal1olyclonal

/ypergammaglobulinemia/ypergammaglobulinemia 6#cell hyper#responsiveness6#cell hyper#responsiveness

.ared elevations of Ig% 1roduction of rheumatoid.ared elevations of Ig% 1roduction of rheumatoid

factorsfactors

1resence of anti#nuclear antibodies1resence of anti#nuclear antibodies Extractable nuclear antigens Anti#SS#A >o" and anti#SS#Extractable nuclear antigens Anti#SS#A >o" and anti#SS#

6 La"6 La"

Antibodies are found directed against salivaryAntibodies are found directed against salivary

duct cells <() of patients"duct cells <() of patients"

1rimarily against extractable nuclear antigens1rimarily against extractable nuclear antigens 0oncentration does not correlate &ith gland destruction0oncentration does not correlate &ith gland destruction



@ther 0haracteristics@ther 0haracteristics

Elevated sedimentation rates andElevated sedimentation rates and

decreased ?60 counts4 as seen in otherdecreased ?60 counts4 as seen in other

autoimmune connective tissue diseasesautoimmune connective tissue diseases

Specic extended ./0 haplotype at aSpecic extended ./0 haplotype at a

higher freuency than controlshigher freuency than controls

./0#encoded proteins./0#encoded proteins

Induction of tolerance to self proteinsInduction of tolerance to self proteins Selection of the !#cell repertoireSelection of the !#cell repertoire

6inding and presentation of antigen to !#cells6inding and presentation of antigen to !#cells



/istopathology/istopathology

.ononuclear inltrate consisting primarily.ononuclear inltrate consisting primarily

of !#cells primarily 0DBof !#cells primarily 0DBCC""

/ost of mediators/ost of mediators

Altered cell adhesion molecules expressionAltered cell adhesion molecules expression

Increased /LA class II antigens expressionIncreased /LA class II antigens expression

Immunosuppressive therapy often e3ectiveImmunosuppressive therapy often e3ective



0lassical /istopathological0lassical /istopathological

LesionLesion

Lympho#epithelial lesion a3ecting the parotidLympho#epithelial lesion a3ecting the parotid

glandgland

1rogressive replacement of the salivary tissue by1rogressive replacement of the salivary tissue by

dense lymphoid inltratesdense lymphoid inltrates -ormation of proliferating islands of ductal-ormation of proliferating islands of ductal

epithelial cellsepithelial cells

0reates &ell#formed lymphoid follicles typical of0reates &ell#formed lymphoid follicles typical of

.AL! and may give rise to lymphomas of the

.AL! and may give rise to lymphomas of the

.AL! type as an expansion of monoclonal 6#cells.AL! type as an expansion of monoclonal 6#cells



SalivarySalivary

%land%land

StructurStructur

ee





0onclusion0onclusion

umerous changes in immune factors inumerous changes in immune factors in

S78gren9s SyndromeS78gren9s Syndrome

Salivary glands appears as a highly active4Salivary glands appears as a highly active4immune#mediated inammatory sitesimmune#mediated inammatory sites

Salivary epithelial cells are immunologically#Salivary epithelial cells are immunologically#

active participants in the disease processactive participants in the disease process

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11 Autoimmune Disease