Au1ClMMunl1?

Lrwln 1aher
AuLolmmune dlseases resulL from Lhe
breakdown of lmmune Lolerance Lo self
anLlgens 1he loss of selfLolerance may
resulL from one or more of several
mechanlsms lncludlng Lhe lack of
ellmlnaLlon of selfreacLlve clones Lhe
acLlvaLlon of anerglc selfreacLlve cells and
Lhe release of sequesLered selfanLlgens
LhaL are normally lnaccesslble Lo Lhe
lmmune sysLem lncludlng Lhe geneLlc
consLlLuLlon of Lhe hosL and lnfecLlon wlLh
cerLaln mlcroorganlsms
DLIINISI
ASlllASl
W AuLolmmune dlseases are classlfled elLher as
organ speclflc or as sysLemlc (le nonorgan
speclflc) on Lhe basls of Lhe prlmary locaLlon
of Lhe ln[ury
uiseose 1orqet of 4ntibody
WM|xed connect|ve t|ssue
D|sease
W9olymyoslLls
W8heumaLlc fever
W8heumaLold arLhrlLls
WSc|eroderma
WSystem|c |upus
Lrythematosus
WGoodpasture's syndrome
WJegener's granulomaLosls
WS[gren's syndrome
WNuc|ear r|bonuc|eoprote|ns
Wnuclel !o1 97 hlsLadylL8nA
synLheLase LhreonylL8nA
synLheLase 9M1 Ml2
WMyocardlum hearL valves
Chorold plexus
WgClobulln LpsLeln8arr
vlrusrelaLed anLlgens Lypes
ll and lll collagen
WNuc|e| Sc|70 SSA (ko) SS8
(La) centromere
WDNA r|bonuc|eoprote|ns
h|stones nuc|ear ant|gens
W8asement membranes
WneuLrophlls
WgClobulln SSA (8o) SS8 (a)
@argets of Ant|bod|es |n Se|ected Auto|mmune D|seases
uiseose 1orqet of 4ntibody
WAddlson's dlsease
WCraves' dlsease
WPashlmoLo's LhyroldlLls
W9remaLure ovarlan fallure
WSponLaneous lnferLlllLy
WAllerglc rhlnlLls asLhma and
auLolmmune abnormallLles
W8u||ous pemph|go|d
Wemph|gus
WAuLolmmune hemolyLlc
Anemla
WldlopaLhlc LhrombocyLopenlc
purpura
WAdrenal cells
W1hyroldsLlmulaLlng hormone
(1SP) recepLor
W1hyroglobulln 1SP recepLor
WlnLersLlLlal cells corpus luLeum
Cells
WSperm cells
Wb2adrenerglc recepLors
W8asement membrane zone of
sk|n and mucosa
WInterce||u|ar substance of sk|n
and mucosa
WLryLhrocyLes
W9laLeleLs
A@GLNLSIS I @ISSUL INIUk
1 clrculaLlng auLoanLlbodles reacL wlLh modlfled
or unmodlfled anLlgens on cell surfaces 1he
bound anLlbodles Lhen sLlmulaLe Lhe release of
medlaLors of lnflammaLlon Lrlgger Lhe
complemenL paLhway or acLlvaLe cyLoLoxlc
cells of Lhe lmmune sysLem LhaL have recepLors
for Lhe lc porLlon of lgC such as macrophages
and a subpopulaLlon of large granular
lymphocyLes known as cells 1he lasL Lwo
processes menLloned lead Lo cell lysls
2 complexes beLween auLoanLlbodles and
anLlgens form ln Lhe clrculaLlon or ln
lnLercellular flulds 1hese lmmune complexes
Lhen deposlL ln varlous Llssues lncludlng
glomerull [olnLs and blood vessels Lhey
subsequenLly flx compl emenL and cause
lnflammaLlon and Llssue ln[ury 1he slLe of
deposlLlon ls deLermlned by Lhe physlcal
properLles of Lhe lmmune complex such as
lLs slze and charge
senslLlzed 1 cells elLher ln[ure cells dlrecLly or
release lymphoklnes LhaL ampllfy Lhe
lnflammaLory response (eg by augmenLlng
Lhe lnflux of oLher lnflammaLory cells)
AlLhough Llssue ln[ury caused by cellmedlaLed
mechanlsms may be lmporLanL ln
auLolmmune dlsease lLs role ls currenLly
unclear
Mechan|sms of Auto|mmun|ty
W AuLolmmune dlseases resulL from abnormallLles
ln lymphocyLe funcLlon
W AbnormallLles ln 1 cell funcLlon can be
responslble for dlsease Lhrough cellmedlaLed
lmmunlLy and Lhrough Lhe acLlvlLy of helper 1
cells Lo sLlmulaLe auLoanLlbody formaLlon
W 1here are several posslble mechanlsms for
auLolmmunlLy sLemmlng from fallure of one or
more sLeps ln Lhe malnLenance of Lolerance
@o|erance
W 1olerance ls deflned as a sLaLe of lmmunologlc
unresponslveness Lo anLlgens
W 8ecognlLlon of anLlgens Lakes place on speclflc
recepLors on 1 and 8 cells of Lhe lmmune
sysLem
W 1hese encounLers resulL ln elLher lnhlblLlon or
acLlvaLlon of lymphocyLes dependlng on
several condlLlons aL Lhe Llme of encounLer
W 1olerance may be acqulred Lo forelgn
anLlgens selfLolerance ls a speclal form LhaL
applles Lo selfanLlgens
MLCPAnlSMS Cl 1CL8AnCL
W 1olerance ls a consequence of one of Lwo
effecLs on 1 and 8 cells
(1) clonal deleLlon ln whlch encounLers wlLh
anLlgens resulL ln Lhe ellmlnaLlon or
programmed cell deaLh (apopLosls) of speclflc
lymphocyLes or
(2) clonal anergy ln whlch Lhe lymphocyLes
are noL kllled buL are rendered unresponslve
Lo a speclflc anLlgen
lAlu8L Cl CLn18A 1CL8AnCL
W 1he ellmlnaLlon of selfreacLlve 1 cells ln Lhe
Lhymus ls a ma[or mechanlsm for selfLolerance
and fallure of Lhls negaLlve selecLlon may allow
selfreacLlve 1 cells Lo survlve
lAlu8L Cl 9L8l9PL8A 1CL8AnCL
AcLlvaLlon of SelfAnLlgenSpeclflc 1 Cells
W Cne mechanlsm for perlpheral Lolerance ls Lhe
presenLaLlon of selfanLlgen by A9Cs lacklng
cosLlmulaLors such as 87 under some
condlLlons (eg lnflammaLlon) A9Cs may
become acLlvaLed Lo express cosLlmulaLors
Lhereby provldlng Lhe condlLlons necessary for
acLlvaLlon of selfanLlgenspeclflc 1 cells
AnLlgenlc LplLopes
Complex anLlgens may presenL Lwo or more anLlgenlc eplLopes Lo Lhe
lmmune sysLem ln an example of selfLolerance
(a) a selfanLlgen presenLs lLs Lwo selfeplLopes Lo a speclflc 8 cell 1he 8
cell ls poLenLlally reacLlve and recognlzes one of Lhe eplLopes buL
Lolerance ls malnLalned because Lhe processed anLlgen falls Lo ellclL 1
cell help (1 cells recognlzlng Lhe selfanLlgen have been elLher deleLed or
rendered anerglc) ln an example of molecular mlmlcry a hypoLheLlcal
mechanlsm for auLolmmunlLy
(b) one of Lwo eplLopes presenLed by a forelgn anLlgen Lo a 8 cell
mlmlcs a selfeplLope because of an am|no ac|d sequence |dent|ca| to
an am|no ac|d sequence of the spec|f|c se|fant|gen 1he second
forelgn eplLope ls processed by Lhe 8 cell and presenLed Lo a helper 1
cell LhaL recognlzes Lhe processed forelgn anLlgen 1he acLlvaLed 1 cell
Lhen sLlmulaLes Lhe 8 cell Lo produce anLlbodles Lo Lhe selfeplLope
1PL 8CL Cl Au1CAn1l8CulLS
AlLhough auLoanLlbodles are frequenLly
presenL ln auLolmmune dlseases lL may be
dlfflculL Lo esLabllsh LhaL Lhese anLlbodles
conLrlbuLe slgnlflcanLly Lo Lhe paLhogenesls of
auLolmmune dlseases
Autoant|bod|es to Ce|| Surface Mo|ecu|es
9emphlgus ls a bullous skln dlsease relaLed Lo
acanLholysls or loss of epldermal cell adheslon
assoclaLed wlLh anLlbodles Lo desmosomes
(epldermal cell surface molecules lnvolved ln
lnLercellular adheslon)
paLlenLs wlLh myasLhenla gravls have
auLoanLlbodles Lo aceLylchollne recepLors (AC8s) on
skeleLal muscle
AuLolmmune dlsease of Lhe Lhyrold ls assoclaLed wlLh
anLlbodles dlrecLed Loward Lhree anLlgens mlcrosomal
Lhyrold peroxldase Lhyroglobulln and Lhe Lhyrold
recepLor for LhyroldsLlmulaLlng hormone (1SP)
AL a normal neuromuscular [uncLlon synapLlc veslcles release aceLylchollne when Lhe nerve
cell ls sLlmulaLed AceLylchollne crosses Lhe synapLlc clefL and blnds Lo Lhe aceLylchollne
recepLor (AC8) whlch leads Lo conLracLlon of Lhe muscle 9aLlenLs wlLh myasLhenla gravls
produce auLoanLlbodles agalnsL Lhe AC8 whlch reduces Lhe number of recepLors presenL on
Lhe muscle cell membrane and leads Lo muscle weakness and someLlmes deaLh
Neuromuscu|ar Iunct|on
Autoant|bod|es to Lxtrace||u|ar Mo|ecu|es
1he anLlphosphollpld syndrome (A9S) conslsLs of
recurrenL Lhrombosls feLal loss LhrombocyLopenla
ln assoclaLlon wlLh anLlbodles Lo cardlollpln or
oLher negaLlvely charged phosphollplds and
abnormallLles of cerLaln cloLLlng LesLs referred Lo
as Lhe lupus anLlcoagulanL
A9S ls elLher prlmary ln Lhe absence of assoclaLed
dlsease or secondary usually wlLh SL or lLs varlanLs
Autoant|bod|es to Intrace||u|ar Mo|ecu|es
AuLoanLlbodles may reacL wlLh lnLracellular proLelns
LhaL also appear on cell surfaces or ln exLracellular
locaLlons AnLlbodles Lo rlbosomal 9 proLelns occur ln
SL and are commonly seen ln paLlenLs wlLh
depresslon or psychosls
lL ls lnLrlgulng LhaL Lh ese anLlbodles also reacL wlLh a
proLeln on cell surfaces LhaL ls slmllar ln slze Lo lLs
rlbosomal proLeln anLlgen lL ls unclear yeL wheLher
Lhe cell surface proLeln ls Lhe rlbosomal proLeln LhaL
has been LransporLed Lo Lhe cell surface or ls anoLher
slmllar proLeln
neverLheless Lhe presence of Lhe anLlgen
on Lhe cell surface suggesLs LhaL anLlbodles
Lo rlbosomal 9 proLelns may conLrlbuLe Lo
Lhe neurologlc manlfesLaLlons of SL
AnLlbodles Lo Lhe small nucleoproLeln
anLlgen SSA whlch ls also called 8o and
Lo SS8 or a are found ln paLlenLs wlLh
SL and S[ogrens syndrome as well as ln
neonaLal lupus and congenlLal hearL block