Conf. Dr.

Olivia Ligia Burta

Dr. Bogdana Alexandru
 Totalitatea mecanismelor de aparare impotriva
structurilor non-self:
◦ Sursa exogena: microorganismelor invazive (bacterii, virusuri,
paraziti etc)
◦ Sursa endogena: alterari celulare/tisulare/ organe (glanda
tiroida, glob ocular, corpi cavernosi..)

 Distinctia intre celulele proprii (self) si cele straine

organismului (non-self) in conditii de homeostazie
I. Ereditara (naturala, de specie)
II.Dobandita
1)Activa:
a)Naturala-Postinfectioasa-
b)Artificiala (in urma vaccinarii)
2)Pasiva:
a)Naturala (transplacentara)
b)Artificiala (seruri imune)
Vaccinarea este o metodă
 de imunizare activă, profilactică, împotriva
unor boli, prin inocularea unui vaccin.
 Vaccinurile sunt preparate biologice dotate
cu proprietăți antigenice, care declanșează
apariția răspunsului imun la organismele
supuse vaccinării.
 Protecția imunologică se instalează după un
interval de timp variabil de la inoculare
(săptămâni, luni), în funcție de vaccin, și
este de lungă durată (ani).
 Antigen (greacă: anti=contra și geano=a
naște, a genera) este termenul care definește
orice substanță de origine endogenă sau
exogenă, care, odată ajunsă în organism, nu
este recunoscută ca proprie și determină
apariția unui răspuns imun, ce vizează
neutralizarea și eliminarea ei.
 Odată pătrunse în organism antigenele pot
determina:
 Sinteza de molecule de anticorpi, care le
recunosc specific.
 Instalarea memoriei imunologice ("amintirea"
organismului despre întâlnirile anterioare
avute cu același antigen).
 Apariția eventuală a unor reacții imune
aberante: reacții alergice, autoimune.
1) Exogene:

 bacteriene
 parazitare
 alergene –alimentare (capsuni, ciocolata,
e.t.c.) medicamente.
 substante de origine industriala
autoantigenele - orice organism normal produce
in mod continuu cantitati mari de autoantigene,
limitate sau sechestrate de catre o serie de
bariere morfofunctionale care impiedica
contactul sistemului imunitar cu aceste
autoantigene,-> NU apar raspunsuri fata de
acestea. Patologic, ca urmare a deteriorarii
barierelor morfofunctionale e posibil contactul
autoantigenelor cu diversele elemente ale
sistemului imunitar-> raspunsuri imune
autoreactive -> boli autoimune.
 tumorale– orice organism normal elaboreaza
celule tumorale (cca. 200 – 250 / 24 h). Acestea
sunt insa recunoscute de catre sistemul imunitar
dupa prezenta Ag specifice. Aceasta recunoastere
conduce la distrugerea lor, procesul =
supraveghere imunologica antitumorala.
 virale – marea majoritate a virusurilor isi includ
propriul genom in genomul celulei gazde →
ulterior componentele virale se sintetizeaza ca
niste componente proprii organismului.
 Ag. sunt substante capabile sa activeze
limfocitele Ag-specifice.
 Limfocitele Ag-specifice = limfocite T sau B care
prezinta pe suprafata lor receptori antigenici, in
constitutia carora exista un situs combinativ
pentru Ag, capabil sa interactioneze cu Ag
inductor.
 Interactiunea e posibila datorita faptului ca
situsul are o conformatie complementara celei a
Ag inductor -> activarea limfocitelor Ag-
specifice cu generarea unui raspuns imun.
 1. Umoral: actiunea limfocitelor B->Ac
 2. Celular: actiunea limfocitelor Tc-> citokine
imunogene

-> Ag e o substanta capabila sa activeze

limfocitele Ag-specifice si sa declanseze
raspunsuri imune.
 Patient A is 19 YO and a college student who presented to
her physician's office with mild jaundice. The patient
reports being in good health until a week before, at which
time she began having flu-like symptoms of headache,
low-grade fever, nausea, loss of appetite. She self-treated
the fever with acetaminophen. The symptoms persisted.
Upon awakening this morning, she noticed that her eyes
were yellow. She therefore contacted her physician's office.
 In response to her physician's questions, she indicated
that her urine has been darker than usual and she has
been experiencing joint pain for the last 3 days. She also
acknowledged that her stools have been lighter than usual.
 Her medical history is positive for mild exercise-induced
asthma, for which she uses a prophylactic bronchodilating
inhaler. Her only other routine medication is a daily
vitamin/mineral supplement. She reports no surgeries.
 Other significant history includes that she was
immunized against hepatitis B at 12 years of age
and she recently participated in a 2-week
mission trip to Central America. Although she
was very cautious about the foods she ingested
during the mission trip, the patient indicated that
a primary recreational activity after the day's
work was to swim in the lagoon near the village.
The lagoon was fed both by the stream in which
the natives washed their clothes and the adjacent
bay.
PATIENT A LABORATORY TEST RESULTS

Normal Value or RangeHematocrit (Hct): 40%

Hemoglobin (Hgb)13.3 mg/dL12.0–16.0
mg/dL
White blood cell count 6200
Aspartate aminotransferase (AST) 323 Units/L;
5–40 Units/L
Alanine aminotransferase (ALT)358 Units/L
5–35 Units/L
Total bilirubin3.7 mg/dL 0.2–1.6 mg/dL
HBs Ag Negative-Negative
HBs Ab Positive; Positive indicates previous
disease or immunization; negative indicates
no exposure.
Anti-HAV IgM Positive
Negative Anti-HCV antibody: Negative
Alkaline phosphatase (ALP) 85 Units/mL 30–
115 Units/mL
Prothrombin time (PT)11.6 secondsControl
10.4 seconds (normal is ±2.0 seconds from
control)
Albumin3.8 mg/dL 3.5–5.5 mg/dL
Glucose84 mg/dL 70–110 mg/dL
Sodium142 mEq/L 135–150 mEq/L
Potassium3.8 mEq/L3.6–4.8 mEq/L
 Patient A has presented with classic signs and
symptoms of acute hepatitis. Based on her past
history, travel, and exposure history, the most
likely diagnosis is acute hepatitis A infection. The
hepatic chemistry profile and serologic studies
confirm this diagnosis. Exposure probably
resulted from accidental ingestion of
contaminated water while swimming in the
lagoon.
 Because acute viral hepatitis is usually a self-
limited disease and Patient A is alert with no
evidence of coagulopathy, she can be managed
as an outpatient with close follow-up.
 Liver enzymes and PT should be monitored every
5 to 7 days until liver enzymes return to normal
level.
 Bed rest is not indicated, but the patient should
avoid strenuous activity.
 She should eat a well-balanced diet and abstain
from alcohol for the duration of the illness.
 Because acetaminophen can be toxic to the liver,
ibuprofen would be a better alternative for
controlling fever.
 No other alterations in the patient's medications
are necessary at this point. If nausea precludes
the patient from ingesting food and fluids, IV
replacement of fluids and electrolytes may be
necessary.
Conf.Dr.Olivia Ligia Burta
Dr. Alexandru Bogdana
 1. toate Ag interactioneaza cu receptori Ag
solubili sau membrane – SPECIFICITATE.
 2. unele Ag pot interactiona cu receptorii
antigenici limfocitari, dar ele NU sunt capabile sa
activeze limfocitele Ag specifice ( haptenele)
 3. Ag pot interactiona cu receptorii limfocitari,
pot activa limfocitele Ag specifice, dar NU
declanseaza rapunsuri imune (tolerogene)
 4. exista Ag care interactioneaza cu receptorii
limfocitari, activeaza limfocitele Ag-specifice si
au si proprietati de a declansa raspunsuri imune
(imunogene) – IMUNOGENITATE.
Ag au 2 proprietati importante:
Specificitate= proprietate obligatorie a Ag ce
consta in capacitatea acestuia de a
interactiona specific NUMAI cu situsul
complementar pentru Ag al unui receptor Ag
unic (anticorp sau receptor limfocitar).
 receptorii Ag: membranari

– TCR (T Cell Receptor)

– BCR (B Cell Receptor)
 situsul combinativ din receptori = portiunea
direct raspunzatoare de recunoasterea Ag.
 IMUNOGENICITATEA
 = capacitatea de a declansa RI
 are 3 faze:

 1. Selectia clonala
 - selectia de catre Ag dintr-un repertoriu
preexistent de limfocite doar pe acelea care
sunt Ag specifice
 - limfocitele B au situsuri combinative diferite
 - selectie clonala = recunoasterea Ag de catre
limfocite NU poate fi realizata decat daca
limfocitul Ag specific se afla in stare de
repaus (G0 a ciclului mitotic).
 2. Activarea clonala si transformarea blastica
 = consta in activarea metabolica a limfocitelor Ag
specifice
 - ca urmare a activarii, celula trece din faza G0
(repaus) in interfaza (G1-S/G2)
 - ajunsa in interfaza, ea se transforma morfologic in
limfoblast.

 3. Expansiunea clonala
 - limfocitele activate incep sa se divida
 - prin diviziuni mitotice successive => cresterea
numarului de limfocite per clona activate, de aceea
etapa se numeste expansiune clonala
 - clonele produc Ac Ag specifici. Ei prezinta situsuri
combinative pentru Ag, capabile sa recunoasca Ag
inductor.
 Sunt produsi de celulele B ca raspuns la Ag
 Sunt alcatuiti din 4 lanturi polipeptidice: 2
lanturi grele identice si 2 lanturi usoare
identice, unite prin legaturi disulfidice pentru
a forma o configuratie in Y.
 Lanturile grele si usoare au o regiune
variabila-V- si una constanta-C-.
 Reg V sunt localizate la capetele
aminoterminale ale bratelor in Y-contin multi
AA diferiti, care determina specificitatea Ig.
 Reg C-secventa relativ constanta de AA.
Fab=fragmentul de legare a Ag;
Fc=fragmentul cristalizabil; contine majoritatea regiunilor C; e
responsabil de activarea complementului;
 Exista 5 tipuri de lanturi grele, care definesc
5 clase de Ig:

 Ig M
 Ig G
 Ig A
 Ig E
 Ig D
 Ig M=primul Ac format dupa expunerea la un
nou Ag. Circula in principal in spatiul
intravascular, se complexeaza cu Ag si-l
aglutineaza si poate activa complementul, in
consecinta facilitand fagocitoza.
 Ig G=cel mai raspandit izotip de Ig din ser;
prezent in spatiile intra- si extravasculare. Ig G
este principalul Ig circulant produs dupa
reimunizare (rasp imun sec). Ig G protejeaza
impotriva bacteriilor, virusurilor si toxinelor si
este singurul izotip care traverseaza placenta.
Exista 4 subclase de Ig G: (1), (2), (3), (4) si difera
in functie de abilitatea de a activa complementul.
 Ig A apare la suprafata mucoaselor, in ser si
in secretii (saliva, lacrimi, secretii din tractul
resp, GI, colostru) in care asigura o aparare
antibacteriana si antivirala precoce.
 Ig D exprimat in principal pe suprafata
celulelor B inocente, influentand maturarea
celulelor B-functia lui Ig D circulant este
necunoscuta.
 Ig E prezent in concentratii mai scazute in ser
si in secretiile mucoase ale tractului
respirator si GI. Ig E se leaga cu o mare
afinitate de receptorii cel mastocitare si pe
bazofile si in concentr mica pe alte cel
hematopoietice inclusiv cel dendritice. Daca
alergenul uneste 2 molecule Ig E de suprafata
legate de supraf cel mastocitare sau bazofile,
celulele degranuleaza, eliberand mediatori
chimici care determina un raspuns alergic.
 Nivele crescute de Ig E in boli atopice(astm
extrinsec, rinita alergica) si inf parazitare.
 Pacienta A.G. în varsta de 13 ani, din BV, fără
antecedente heredo-colaterale şi personale
patologice semnificative, se internează în
data de 12.02.2016 pentru: dureri
retrosternale cu iradiere în umărul drept,
dispnee uşoară. Simptomatologia a apărut
afirmativ cu 4 zile înaintea internării.
 Greutate = 63kg, Înălţime = 160cm, Indice de
Masă Corporală = 24, stare generală
mediocră, subfebrilă (37,5 C), fără adenopatii
decelabile clinic, MV uşor diminuat la baza
hemitoracelui stâng, fără raluri, dispnee
mixtă uşoară, saturaţia de O2=92%, AV =
100 bătăi/min, zgomote cardiace ritmice,
bine bătute, fără sufluri, TA = 110/60mmHg
 Abdomen suplu, depresabil.
 Investigaţii paraclinice la internare (data
12.02.2016):
 Hb = 11,2g/dl, Ht = 33,1%, MCV=85,4fl,
MCH=28,6pg, MCHC=33,5g/dl,
 L=10190/mmc, Ly = 16,7%, N = 68,8%,
 Tr = 151000/mmc, frotiu periferic neutrofile
cu nucleu polilobat,
 VSH = 52 mm/1h, fibrinogen 479 mg,
 CRP = 9,83 mg/dl, ASLO = 511 UI/ml, probe
renale normale.
 Investigaţii imagistice. Radiografia
pulmonară: transparenţă pulmonară în limite
normale, cordul cu diametrul transvers uşor
mărit. Ecografie abdominală: splină mărită cu
diametrul longitudinal de 13,5 cm, fără lichid
în cavitatea peritoneală. Ecografie cardiacă
14.02.2017: FE = 50%, sept interatrial şi
interventricular intacte, lamă fină de lichid în
pericard (5 mm) → pericardită. EKG:
tahicardie sinusală, fără modificări ale
segmentului ST si undei T.
 Diagnostic de etapă: pericardită acută cu
următoarele argumente:

 examenul clinic - dureri precordiale, dispnee,

tahicardie sinusală
 examene paraclinice - sindrom inflamator,
diametrul transvers al cordului uşor mărit pe
radiografia pulmonară, prezenţă de lichid
ecografia cardiacă în cantitate mică – 5 mm.
 Tratament iniţial: oxigenoterapie, monitorizare
(T, TA, AV, Sa O2, FR, diureză), antibiotice:
Cefuroxima-II- (750 mg la 8 ore i.v.),
Gentamicină (AMN) (40mg la 8ore),
simptomatice.

 Diagnosticul diferenţial: a) Boli infecţioase:

endocardită infectioasă acută sau subacută
(absenţa suflurilor cardiace), pericardită TBC
(infirmată pe baza IDR negativ şi a radiografiei
pulmonare normale), pericardite virale,
bacteriene, mycoplasme, Ricktettsii, Chlamidii
etc.; b) pericardite prin contiguitate (în boli
pleurale, pneumonii );
 c) boli de colagen: dermatomiozită,
sclerodermie, lupus eritematos sistemic (nu
s-a exclus datorita prezentei a doua criterii:
eritem la nivelul pomeţilor, lamă fină de lichid
în pericard); d) artrita reumatoidă juvenilă
(exclusă pe baza absenţei sindromului febril
prelungit şi artritei); e) vasculite imune,
poliarterita nodoasă; f) pericardita din
reumatismul articular acut;
 S-au recoltat pentru diagnostic diferenţial:
anticorpi antinucleari prezenţi, pattern pătat
fin (in lucru la momentul externării), factor
reumatoid: 11,0 UI/ml, complement C3 193,4
mg/dl (N = 90- 180), anticorpi anti-CCP: 0,5
U/ml (negativ până la 7 U/ml).
 Diagnostic pozitiv iniţial: cardită
reumatismală - formă uşoară. Argumente:
criterii Jones: un criteriu major – cardita cu
pericardită, două criterii minore: reactanţi de
fază acută pozitivi (VSH, CRP, fibrinogen),
dovada infecţiei streptococice (titru ASLO
crescut).
 Tratamentul curativ: 1.eradicarea infecţiei
streptococice: penicilină G (800.000 UI la 6
ore i.v.) – 10 zile, 2. tratamentul carditei:
corticoterapie – Prednison 60 mg/zi (2
mg/Kgc/zi) iniţiat în 14.02.2016 – 3
săptămâni doză de atac, apoi 3 săptămâni cu
scăderea progresivă a dozelor, 3. tratament
adjuvant corticoterapiei (Maalox, Omez,
calciu lactic), 4. profilaxia secundară:
prevenirea recurentelor de cardită obligatorie
la toţi bolnavii cu prim puseu de RAA (cu/fără
cardită) cu Moldamin (1.200.000 UI
/săptămână).
 Evoluţia sub tratament a investigaţiilor
paraclinice: VSH 10 mm/h, CRP 0,38mg/dl, ASLO
457UI/ml, ecografie cardiacă (27.02.2007) fără
lichid in pericard.
 S-a interpretat cazul ca fiind cardită acută
reumatismală formă uşoară (pericardită izolată
fără semne de insuficienţă cardiacă, titru ASLO
crescut, sindrom biologic inflamator). Nu s-a
putut exclude pericardita din cadrul
colagenozelor (AAN pozitivi - pattern pătat, la
momentul externării fiind în lucru). Sub
tratament a evoluat cu remisia simptomatologiei
clinice, a sindromului biologic inflamator şi
dispariţia lichidului pericardic la examinarea
ecografică.
 Recomandări la externare: Regim fără sare;
continuarea tratamentului cortizonic, cu
scăderea progresivă a dozelor, tratament
adjuvant corticoterapiei (Maalox, Ca
+vitamina D3, Aspacardin), profilaxia
endocarditei.
 În perioada 24.06 - 13.07.2016 s-a reinternat
pentru dureri la nivelul hemitoracelui stâng,
fatigabilitate, simptomatologie cu debut de 1 zi.
 Examenul clinic la internare: G = 68 kg., talie =
161 cm., IMC = 26, stare generală mediocră,
afebrilă, facies cushingoid, eritem malar „în
fluture”, fără adenopatii decelabile clinic, murmur
vezicular prezent bilateral, fără raluri, dureri la
nivelul hemitoracelui stâng, AV = 97 bătăi /min.,
zgomote cardiace ritmice, fără sufluri, TA =
110/65 mmHg, abdomen suplu, depresibil, fără
hepato-splenomegalie.
 În evoluţie (a doua zi de la internare): alterarea
stării generală, precordialgii (senzaţie de
presiune toracică cu iradiere în umărul stâng),
dispnee moderată, cianoză discretă, Sa O2 = 90%
fără O2, FR = 30/min, AV = 60/min., TA =
90/40 mmHg, motiv pentru care se transferă în
secţia terapie intensivă. Se efectuează de urgenţă
radiografie pulmonară care decelează
cardiomegalie (cord „în carafă”). Ecografie
cardiacă evidenţiază pericardita (lichid cu
grosimea de 8 mm). Ecografie abdominală
evidenţiază splenomegalie (13,5 cm) şi
pericardită (lichid cu diametrul ~ 10 mm).
 Tratament: S-a iniţiat terapie cu Solumedrol
125 mg la 6 ore i.v. apoi din 03.07: Medrol
32 mg 1+1+0, tratament cu Penicilina G (1 M
ui la 6 ore). În 28.06.2007 a prezentat:
perioade de bradicardie sinusală 38 / min. în
clinostatism, la ridicarea în ortostatism AV =
60/min, zgomote cardiace uşor asurzite,
saturaţie O2 = 90% (fără oxigen), accentuarea
eritemului facial, EKG cu bradicardie sinusală,
QRS normal.
 anticorpi antinucleari: pozitivi, pattern: pătat,
titru anticorpi anti-ADN dublu catenar (N), cel
lupice absente.
 Nu s-a putut exclude lupusul eritematos
sistemic datorita prezentei a 3 criterii: eritem
la nivelul pomeţilor, serozită (pericardită),
anticorpi antinucleari pozitivi . Sub tratament
evoluţia a fost favorabilă cu: remisia
simptomatologiei clinice, remisia sindromului
biologic inflamator, dispariţia lichidului
pericardic la examinarea ecografică.
 Dovada infecţiei streptococice şi a pericarditei
a orientat iniţial diagnosticul către cardită
reumatismală. La debutul bolii nu au existat
cel puţin 4 criterii pentru a defini diagnosticul
de LES.
Conf.Dr.Olivia Ligia Burta
Dr.Bogdana Alexandru
 Sistem limfoid
-vase limfatice, organe limfoide, tesuturi
limfoide si celule izolate, toate avand
potential imunitar.
Organele limfoide= aglomerari specifice de
celule delimitate de o capsula de tesut
conjunctiv, aceste organe reprezinta sediul in
care celulele sistemului imunitar se dezvolta
si se matureaza/isi indeplinesc functiile imune
specifice.
 Tesuturile limfoide=nu sunt delimitate de
capsula de tesut conjunctiv, sunt grupari de
celule dispersate inegal pe mucoasa tractului
respirator, digestiv, urogenital.

 Organele limfoide se clasifica in:

1) Organe limfoide primare
2) Organe limfoide secundare
1. Organele limfoide primare (maduva osoasa
hematogena, timusul, ficatul embrionar-
responsabil de sinteza de limfocite numai in
timpul vietii intrauterine)
2. Organe limfoide secundare=periferice
(ganglioni limfatici, splina, tesutul limfoid
asociat sistemului digestiv, respirator si
aparatului urogenital).Se mai numesc
MALT=Mucosa Associated Lymphoid Tissue.
 Maduva Hematogena
- reprezinta aproape 5% din greutatea totala a
corpului si este responsabila de procesul de
formare al sangelui la adulti (hematopoieza)
- generează toţi progenitorii celulelor sanguine
- toate aceste celule provin din celule stem
hematopoietice pluripotente nediferentiate
(PHSC)
- ofera un micromediu necesar pentru
maturarea limfocitelor B si formarea de celule
pre-T (limfopoieza), nu exista limfocite T
mature in maduva.
 Organ limfoid primr situat in mediastinul
anterior, retrosternal, organizat în lobuli
 Zona Corticala alcatuita din celule limfoide
tinere=timocite
 Zona Medulara=centrala, saraca in limfocite
bogata in celule epiteliale, reprezinta spatiul
in care limfocitele T se matureaza
 Celulele epiteliale secretă factori timici
timozina, timopoietina, etc., implicaţi în
maturarea limfocitelor T
 Corpii Hassal: structuri epiteliale în medulară
 Timusul involueaza la pubertate, odata cu
inceperea secretiei de hormoni sexuali
androgeni si estrogeni si cu cresterea nivelului
de corticosteroizi din SR.
 Involutia nu este completa, raman insule de
celule timice care functioneaza toata viata,
capabile sa genereze noi clone limfocitare.
 =limfonoduli
 structuri localizate de-a lungul vaselor
limfatice
 filtreaza lich limfatic indepartand Ag
continute de acesta
 Incapsulate, cu trei zone:
 corticala
 paracorticala
 medulară
 Corticala: contine limfocite grupate in
foliculi limfoizi
 foliculi primari cu limfocite B-aflate in repaus,
celule dendritice, macrofage
 foliculi secundari centre germinative, sediul
principal al maturării limfocitelor B=aflate in
proliferare
-dupa ce stimulul Ag inceteaza, foliculii limfoizi
sec -> foliculi limfoizi primari

 Paracorticala: Limfocite T şi celule

dendritice

 Medulara:
sediul plasmocitelor,
predomina limfocitele B.
Functiile ggl limfatici:

-stocheaza celule limfoide, reprezentand si

locul in care acestea prolifereaza
-contin numeroase macrofage care distrug Ag,
fara a distruge si epitopii care sunt prezentati
limfocitelor Ag-specifice
-se modifica structural in momentul in care
densitatea de Ag depaseste nivelul de
prelucrare al macrofagelor->adenopatii
-dupa eliminarea inf, limfonodulii revin la
dimensiunile initiale
 Organul limfoid care filtreaza Ag din sistemul
sanguin, asa cum ggl limfatici filtreaza Ag din
sistemul limfatic.
 Organ încapsulat cu pulpă albă şi pulpă roşie
 Pulpa roşie: cea mai imp parte, alcatuita din
sinusuri venoase si cordoane de celule splenice=
Bilroth->arie B dependenta-> eritrocite şi
macrofage.
 Pulpa albă: foliculi limfoizi sub forma de manson
in jurul unei arteriole centrale
 O zona interna: celule T
 zona manta: zona marginală a celulelor B, limfocite B
dispuse sub forma de conglomerate= foliculii splenici/
corpusculii Malpighi.
 responsabil de blocarea Ag exogene, care
incearca sa patrunda in mediul intern
 Acest sistem limfoid nu trebuie sa lezeze flora
microbiana saprofita, care colonizeaza aceste
mucoase
 Astfel, se formeaza arii T/B dependente, ce
constituie aglomerari de limfocite T/B,
capabile sa distruga Ag
 In functie de localizare:
 Mucoasa digestivă, respioratorie, urogenitală

 Ţesut limfoid asociat mucoasei intestinale =

GALT Gut Associated Lymphoid Tissue
(Plăcile Peyer  mai ales celule B)
 Ţesut limfoid asociat mucoasei nazale =
NALTNasal Associated Lymphoid Tissue
(inel Waldeyer, tonsile  celule B)
 Ţesut limfoid asociat mucoasei respiratorii =
BALTBronchus Associated Lymphoid Tissue-
foliculi limfoizi aglomerati mai ales pe
traiectul bronhiilor mari.
Ţesutul limfoid asociat mucoaselor
(MALT)
 LP IV.

Conf.Dr.Olivia Ligia Burta

Dr.Bogdana Alexandru
 Labaza RIU declanşat faţă de Ag
timodependente stă o cooperare celulară la
care participă 3 tipuri de celule:

1) APC-cel prezentatoare de Ag-macrofage,

cel.dendritice, Limf B.
2) L cu rol imunoreglator ( LTH – amplifică RI,
LTS – diminuă RI)
3) L cu rol efector (LB)
 Ag timodependente sunt preluate de APC,
internalizate şi scindate cu generarea unui
număr de epitopi
 Epitopii sunt prezenţi pe membrana APC în
complex cu diverse molecule de MHC
orientate către TH, care amplifică RI
 Alţii sunt prezentaţi către TS, care diminuă
RI
 TH ulterior cooperează cu LB care se
activează şi se transformă in plasmocite
(produc Ac).
 Condiţia fundamentală a cooperării: e
întotdeauna bidirecţională (se realizează 2 tipuri
de secvenţe de cooperare)
1) secvenţa de activare (efectorie)
 corespunde RIU propriu-zis
 cuprinde toate influenţele activatoare exercitate
dinspre APC către LB => activarea LB
 presupun participarea doar a 3 categorii de
celule din cele 4 (APC, TH, LB)
 Funcţiile de principiu:
 Selecţia clonală a LB/LT (selecţia TH se realizează de
către epitopii prezenţi pe membrana APC, selecţia LB e
realizată de Ag timodependent nativ)
 Activarea clonală
 Expansiunea clonală
 E generată o cantitate adecvată de Ac pentru
neutralizarea/îndepărtarea/distrugerea Ag declanşator
 RIU e declanşat ca urmare a pătrunderii
intratisulare a diverselor Ag intratisulare (Ag
complete)
 Ag sunt captate de APC. NU toate APC
captează, ci doar APC non-β (orice APC,
excepţie LB => doar Mcf sau celulele
dedritice)
 APC se activează şi apoi încep migreze,
trecând din ţesuturi în ariile timodependente
ale organelor limfoide, transportând Ag,
urmând să-l prezinte către TH
 Prezentarea se face prin intermediul MHC II,
Ag fiind prezentat către TH, orientat către
TH prin partea carrier (TH e capabil să
recunoască doar partea carrier a Ag).
 2) secvenţa de retrocontrol
 Funcţia de principiu:
 Limitarea intensităţii RIU la un minim necesar unei
apărări imune eficiente
 Arevaloarea unui mecanism de protecţie
prin care sunt evitate 2 efecte defavorabile
care ar putea rezulta din orice RIU:
 Evită expansiunea necontrolată/exagerată a clonelor
TH/LB Ag specifice
 Este evitată generarea unor cantităţi exagerate de APC
 acest control e activat de celule TS. Ele
produc şi elaborează factori inhibitori de
natură proteică (TSF – factor T supresor). Ei
inhibă în primul rând LB, ulterior TH şi în
cele din urmă APC participante
 între 1 şi 2 e un echilibru funcţional foarte
fin care asigură homeostazia RIU.
 Recunoaşterea se face prin TCR => celulele
încep să coopereze (cooperare cognitivă). Ea
e ocazionată de recunoaşterea şi prezentarea
Ag.
 Această cooperare e completată întotdeauna
de o a doua cooperare, NON-cognitivă. Ea se
realizează ca urmare a eliberării de către
APC a unor IL, cea mai importantă fiind IL-1.
Ea stimulează suplimentar TH (NON-cognitivă
pentru că se realizează prin aceeaşi IL-1
indiferent de ce tip de Ag e prezentat.
 La finele acestei duble cooperări => activarea TH,
care e parţială
 Activate, TH, după un interval de timp, încep să se
desprindă de la contactul cu APC şi migrează din aria
timodependentă în aria bursodependentă învecinată.
Pe măsura migrării se transformă morfologic,
devenind limfoblast TH.
 În aria bursodependentă aşteaptă LB.
 LB sunt activate într-o etapă ulterioară direct de
către Ag nativ care e antrenat în circulaţia
limfatică/sangvină şi el ajunge ca substanţă solubilă
în ariile bursodependente. Aici e recunoscut de către
LB prezente obişnuit în ariile bursodependente. LB de
regulă recunosc NUMAI partea haptenică => activarea
parţială a LB. După un interval de timp LB se
îdepărtează de contactul Ag şi încep să migreze,
rămânând în aria bursodependentă respectivă
 Pe măsură ce migrează, ea se transformă în
limfoblast B.
 Cele 2 categorii de limfoblaşti vin în contact
 Cooperarea e ocazionată iniţial de prezenţa
şi recunoaşterea Ag
 Celula care prezintă Ag e doar limfoblastul B,
care capătă funcţie de APC (expune pe
membranele sale MHC II). El prezintă Ag
către TH (limfoblast), orientând Ag cu partea
carrier către limfoblastul TH. Ea e
recunoscută de TCR => cooperare cognitivă
 Sensul de cooperare e limfoblast B 
limfoblast TH => activarea totală a
limfoblastului TH
 Deveniţi total activaţi, limfoblaştii TH produc
cantităţi mari de IL (IL-4, IL-5, etc) => o
cooperare NON-cognitivă. Sensul ei e de la
limfoblastul TH către limfoblastul B.
Rezultatul constă în activarea totală a
limfoblastului B
 Rezultatul activării totale: limfoblastul B se
transformă în plasmocite, care după urma
formării încep să migreze şi la distanţă pun
în libertate Ac specifici, capabili să
recunoască Ag (după partea haptenică).
 Precizări:
 dintre cele 2 categorii de limfocite, primele
care participă în RIU sunt doar LT pentru că
ele sunt celule intens recirculante
 LB participă târziu pentru că sunt celule
puţin recirculante
 în cadrul RIU, de-a lungul său, sunt implicate
toate categoriile de APC (iniţial NON-B, apoi
B).
 Pacient in varsta de 55 ani, sex M, mediu
urban, se interneaza pentru acuzele: durere
de tip colicativ in etajul abd superior,
subfebrilitate (37,8 C), transpiratii, greata si
varsaturi cu debut acut in urma cu ~ 48 h.
 Ex obiectiv: pacient obez, zg cardiace
ritmice, tahicardice (105 bpm), MV normal
bil, sensibilitate la palpare la nivelul
epigastrului si hipocondrului drept, TI-
normal, mictiuni spontane nedureroase.
?
 Ex de lab: val patologice:

LEU: 17000 /µL

Neu: 70 %
Bil T: 6 mg/dL
Gli: 115 mg/dl
PCR: 150 mg/dL
VSH: 90 mm/h
 EKG- NORMAL
 RELATII ECO-NORMALE
 Consult Chirurgical- Suspiciune de Apendicita
acuta. (semn Blumberg-negativ), fara lichid
liber in fundul de sac Douglas.
Efectueaza CT Abdomen-COLECISTITA ACUTA
CU REACTIE PANCREATICA.

Se instituie repaus alimentar, se monteaza

sonda nasogastrica, se adm: PEV, solutie
pentru alimentatie exclusiv parenterala
(Aminoplasmal), Antibiotice (Cefort +
Ciprofloxacin).
 Dupa 12 h, durerea se remite, pacient
afebril, TI prezent.

 Analize de lab:
 LEU: 8000/ µL
 Bil T: 1,1 mg/dl
 PCR: 17 mg/dl

Dupa 48 h se adm Glucoza tamponata cu

Insulina, continua tratamentul, dupa inca 48
h, pacientul incepe sa se alimenteze.
Evolutia favorabila.
 Particularitatile cazului:

-Amilaza (s), (u)- in limite fiziologice;

-Ecografia- fara modificari;
-Etiologia: Colecistita acuta alitiazica (10% din
cazuri).
Conf.Dr. Olivia Ligia Burta
Dr. Bogdana Alexandru
• The adrenal produces various classes of
hormones, each of which aid in dealing with
the stress faced by animals and people
almost daily
• At least two of these groups –
Glucocorticoids and Mineralocorticoids
are necessary for life
• Corticosteroids or corticoids refer to
natural
gluco- and mineralo-corticoids and their
synthetic analogues
 1855 – Addison`s disease
 1856 – Adrenal glands essential for life
 1930 – Cortex > medulla
 1932 – Cushing’s syndrome
 1952 – Aldosterone
 An inner medulla, is a
source of catecholamine –
adrenaline and nor-
adrenaline
 Chromaffin cell is the
principal cell type
 Medulla is richly innervated
by sympathetic fibres and is
considered as extension of
sympathetic nervous
system
 Medulla develops from
ectoderm (neural crest)
 An outer cortex, which
secretes several classes of
steroid hormones including
Glucocorticoids and
Mineralocorticoids
 Three different concentric
zones of cells that differ in
major steroid hormones
they secrete
 Cortex develops from
mesoderm
  The adrenal cortex is a factory of steroid hormones
 10 – 30 different steroids are synthesized from this
tissue, but two classes are of importance

Steroid Class Prototype Physiological effect

Mineralocorticoid Aldosterone (z. glomerulosa) Na, K and water

homeostasis
Glucocorticoid Hydrocortisone or cortisol (z. fasciculata) Glucose and many
Corticosterone other homeostasis

Adrenal cortex also produces sex steroids – Androgens,

Dehydroepiandrosterone (DHEA) – z. reticularis
 Synthesized from
cholesterol through a series
of enzyme-mediated
transformations
 ACTH stimulates adrenal
steroid synthesis
 Aldosterone synthesis is
not stimulated by ACTH but
by angiotensin II, although
ACTH does stimulate
synthesis of aldosterone
precursors
 Circulating Potassium
exerts a permissive effect
on angiotensin II
stimulation; high potassium
enhances and low
potassium diminishes
 Group Hormone Daily
Glucocorticoids Cortisol 5 – 30 mg
Corticosterone 2 – 5 mg
Mineralocorticoids Aldosterone 5 – 150 mcg
11- deoxycorticosterone Trace
Sex Hormones
Androgen DHEA 15 – 30 mg
Progestogen Progesterone 0.4 – 0.8 mg
Oestrogen Oestradiol Trace
• Synthesized and
released under
influence of ACTH - Ant.
Pituitary (HPA axis)

• Regulated by CRH
from hypothalamus
and by feedback
levels of blood
concentrations
1. Control by
circadian rhythm
(Diurnal rhythm) –
morning rise
2. Stress:
hypoglycaemia,
physical stress etc.
 Not stored:
◦ rate of synthesis = rate of release
 Synthesize rhythmically and controlled by
irregular pulses of ACTH, influenced by
light and major pulses occur early in the
morning and after meals
 Glucocorticoids act via their receptors
located in nucleus (GR)
 GRs are widely distributed and located
almost in all cells of the body
 They are made up of almost 800 amino
acids
 Aldosterone is the prototype of mineralocorticoid
effects
 Acts on the distal tubule to enhance absorption of
Na+
 Increase excretion of K+ and H
 Similar effects occur in colon, sweat gland and
salivary gland
 Deficiency of mineralocorticoid action leads to –
dilutional hyponatraemia, hyperkalamia, acidosis,
massive loss of Na+ and decreased EFC volume
(essential for survival)

 Hyperaldosterinism: Positive Na+ balance,

expansion of ECF, increased plasma Na,
hypokalaemia, alkalosis and progressive rise in BP –
hypertension, myocardial fibrosis etc.
 Profound effect on carbohydrate and protein
metabolism – aimed at protecting glucose dependent
tissues (brain and heart)
 Promotes glycogen deposition in liver and stimulate it
to form glucose from amino acids – gluconeogenesis
 In peripheral tissues decreases utilization of glucose,
increase protein breakdown and activate lipolysis – form
amino acids and glycerol for gluconeogenesis
 All these results in -
◦ Diabetes like stat resistant to insulin – increased glucose
release from liver + decreased peripheral glucose utilization
◦ Negative Nitrogen balance (catabolic effect) – amino acid used
up in gluconeogenesis – increased urea production
◦ Mobilization of amino acids – muscles, thinning of bone and
skin
 Negative nitrogen balance & hyperglycaemia
 Gluconeogenesis
◦ Peripheral actions (mobilize AA & glucose and glycogen)
◦ Hepatic actions

 Peripheral utilization of glucose

 Glycogen deposition in liver

(activation of hepatic glycogen synthase)
 Redistribution of fats in different areas of
the body
 Due to permissive facilitation of effects of
other agents – GH, glucagons, Adr,
thyroxine and insulin
◦ Deposition of fats in face, neck and shoulder –
moon face/buffalo hump
◦ Glucocorticoids facilitated hormone sensitive
lipolysis action of GH and Adr. + Glucocorticoids
mediated increased insulin = net result is insulin
mediated lipogenesis and fat deposition
◦ Peripheral adipocytes are less sensitive to insulin,
but in face and neck predominant action – fat
deposition
 Water excretion:
◦ Glucocorticoids play important role in maintaining normal GFR -
in adrenal insufficiency capacity to excrete water is lost – water
intoxication
 Calcium Balance:
◦ Decrease absorption of Ca++ in GIT and increased excretion –
calcium depletion - osteoporosis
 Skeletal muscle:
◦ Normal muscular activity needs Glucocorticoids at its optimum
level
◦ Excess level leads to muscular weakness and wasting
◦ Muscular weakness occurs in both Hypocorticism (due to
hypodynamic circulation) and hypercorticism – due to
hypokalaemia
 CNS:
◦ Euphoria – in pharmacological doses
◦ Addison's disease – apathy, depression and psychosis
◦ High doses – induce seizure
 CVS: Permissive role on pressor effect with Adr and angiotensin
◦ Maintain tone of arterioles and myocardial contractility
◦ Adrenal insufficiency leads to low cardiac output and arteriolar
dilatation and poor response to adrenaline
◦ Cardiovascular collapse – along with mineralocorticoids
 Blood and lymphoid tissues:
◦ Destruction of lymphoid tissue – modest in normal persons

◦ In presence of malignancy of lymphatic cells – lytic actions are

significant (apoptosis) – used in lymphomas (Basis of Use)

◦ Minor effects on haemoglobin and RBCs – protect against

haemolysis of RBCs – Increase in number of RBCs

◦ Decreases the numbers of circulating lymphocytes, monocytes,

eosinophils and basophils but increases Polymorphs
 Suppress inflammatory response to all noxious
stimuli: Pathogens, chemical,physical and immune
mediated stimuli, hypersensitivity
 Underlying cause of disease is not corrected
 Reduction in cardinal signs of inflammation
 Anti-inflammatory effects are non—specific and
covers all components of inflammation:
◦ Effects on concentration, distribution and functions of
peripheral leukocytes – increased neutrophils & their
activity
◦ In macrophages: reduction of arachidonic acid metabolites
(mediators) like PG, LT and PAF synthesis that results from
activation of phospholipase A2

Basis of exogenous use of most clinical uses

 Recruitment of WBC & monocyte - macrophage
into affected area & elaboration of chemotactic
substances
 Lipocortin: decreased production of PG, LT and
PAF
 Negative regulation of COX 2: inducible PG
production
 Negative regulation of genes in cytokines of
macrophages, endothelial cells and lymphocytes:
production of IL (1, 2, 3, 6), TNFα, GM-CSF
etc. – fibroblast proliferation and T-lymphocyte
function – interference with chemotaxis
 In endothelial cells-Endothelial leucocyte adhesion
molecule (ELAM) and other CAM are inhibited –
adhesion and localization of leucocytes interfered
 Release of histamine from basophils is inhibited
 Decreased production of collagenase – prevention
of tissue destruction
 Decreased functioning of osteoblasts and increased
activity of osteoclastic activity - osteoporosis
 Decreased IgG production
 Decreased generation of induced nitric oxide
 Suppresses all types of hypersensitivity &
allergic phenomenon
 At High dose: Interfere with all steps of
immunological response
 Causes greater suppression of CMI (graft
rejection & delayed hypersensitivity)
 Transplant rejection: antigen expression
from grafted tissues, delay
revascularization, sensitisation of T
lymphocytes etc.
 A number of diverse disease states respond
to GCs
 Physiologic doses of Corticosteroids are
used for replacement therapy in primary
and secondary adrenal insufficiency such as
Addison`s disease
 Supraphysiologic doses are used for their
anti-inflammatory effects in arthritis,
asthma and inflammatory bowel disease
 In organ transplant patients and those with
autoimmune disorders corticosteroids are
used for their immunosuppressive effects
 Two types:
◦ From abrupt withdrawal
◦ Chronic therapeutic use of high dose
 Withdrawal
◦ Flare up of underlying disease
◦ Suppression of HPA axis and acute adrenal
insufficiency
◦ Increased ICT and papilloedema
Cushing`s habitus
 Fluid and Electrolyte Disturbance – Na and water
retention
 Precipitation of Diabetes mellitus – hyperglycemia
 Increased susceptibility to infections – immune
response suppression
 Peptic ulceration – bleeding & perforation
 Osteoporosis – flat spongy bones
 Osteonecrosis – avascular necrosis of head of
femur, humorous etc.
 Myopathy – weakness of muscles
 Cataract – posterior sub capsular
 Glaucoma – prolonged topical therapy
 Growth retardation – in children
 Say no to any drug formulation combined
with steroids
 Remember that STEROIDS are life saving
drugs
 Note the following conditions where u have
to be extremely cautious:
◦ Peptic ulcer
◦ Hypertension and Diabetes mellitus
◦ Viral and fungal infections
◦ Tuberculosis and other diseases
◦ Osteoporosis
◦ Epilepsy and psychosis
◦ CHF and renal failure
 Benefit/risk ratio is a major consideration
 Drugs with primary glucocorticoid activity are
used
 Minimal dose to achieve the desired effects is
chosen
 Topical or local therapy is preferred whenever
possible
Autoimmunity

-VII+VIII-

Conf.Dr.Olivia Ligia Burta

Dr.Bogdana Alexandru
Disorders of the Immune System:

 Immunodeficiency: “too little”

 Hypersensitivity: “too much”

 Autoimmunity: “misdirected”
Autoimmunity Origins
 Horror autotoxicus= literally, the horror of self-toxicity.

 A term coined by the German immunologist Paul Ehrlich

(1854-1915) to describe the body’s innate aversion to
immunological self-destruction.
Autoimmunity is:
 The failure of an organism in recognizing its own constituent
parts as non self, which allows an immune response against its
own cells and tissues. Any disease that results from such an
aberrant immune response is termed an autoimmune disease.

 Autoimmunity is often caused by a lack of germ development

of a target body and as such the immune response acts
against its own cells and tissues.
Autoimmunity
 This is thought to be caused by the loss or breakdown of
mechanisms normally responsible for maintaining self-
tolerance in B cells, T cells, or both.
 The major factors that contribute to the development of
autoimmunity are genetic susceptibility and environmental
triggers, such as infections.
 Autoimmune diseases may be either systemic or organ
specific.
 Various effector mechanisms are responsible for tissue injury
in different autoimmune diseases.
 Epitope spreading: autoimmune reactions initiated against
one self antigen that injure tissues may result in the release
and alterations of other tissue antigens, activation of
lymphocytes specific for these other antigens, and
exacerbation of the disease.
Autoimmune diseases
 A group of 60 to 80 chronic inflammatory diseases with
genetic predisposition and environmental modulation
 Prevalence is greater for females than males
 75 % of cases
 4th largest disease class in women
 Basically means immunity to self

 A condition that occurs when the immune system mistakenly

attacks and destroys healthy body tissue

 Once started, autoimmune diseases are hard to stop

 Severity ranges from minor to lethal

Mechanisms hypothesized to be
involved in the breakdown of tolerance:
-Failure to delete auto reactive lymphocytes:
Central tolerance failure
Peripheral tolerance failure
-Molecular mimicry:
Abnormal presentation of self Ag
Aberrant expression of MHC class II molecules
Coupling of self and nonself Ag
Overproduction of self Ag
Disclosure of cryptic T cell epitopes
Release of sequestered self Ag
Epitope spreading
Polyclonal lymphocyte activation
Autoimmunity
 In the secondary lymphoid organs, peripheral tolerance
is maintained by a delicate balance between the T helper
cell type 1 (Th1) and T helper cell type 2 (Th2)
populations.
 Recent findings indicate that regulatory T cells (Tregs)
play a central role in maintaining this balance and
eliminating harmful autoimmune responses.
Autoimmunity
 Major histocompatibility complex (MHC) products also
seem to influence antigen recognition or nonrecognition by
determining the type of peptides that can be presented to the
T cells.
 The expression of class II molecules on cells where they are
not normally found may result in the presentation of self-
antigens for which no tolerance has been established.
Autoimmunity
 The strongest link found to date between certain HLA
molecules and specific diseases is between HLA-B27 and
ankylosing spondylitis.
 Several other mechanisms are thought be contribute to
autoimmunity: release of sequestered antigens, molecular
mimicry, and polyclonal B-cell activation due to abnormal
expression or function of cytokines and/or receptors.
Autoimmunity
 Systemic lupus erythematosus (SLE) is a chronic
systemic inflammatory disease marked by alternating
exacerbations and remissions.
 The immune response is directed against a broad range of
target antigens, as the typical patient has an average of three
circulating autoantibodies.
Autoimmunity – SLE
 Abnormalities of Fc γ receptors on B cells, macrophages,
dendritic cells, and neutrophils that bind IgG and
prevent excessive immune reactions have also been
found.
 Environmental factors include exposure to ultraviolet
light, certain medications, and infectious agents.
 Hormones, especially estrogen. These disorders occur 10
times more often in women; onset in the 30-40s.
Autoimmunity – SLE
 The clinical signs of SLE are extremely diverse, and
nonspecific symptoms such as fatigue, weight loss, malaise,
fever, and anorexia are often the first to appear.
 Joint involvement seems to be the most frequently reported
manifestation, presenting as a symmetric arthritis that
involves the small joints of the hands, wrists, and knees.
 Autoimmunity – SLE

 After joint involvement, the next most common signs are skin
manifestations.
 A classic butterfly rash across the nose and cheeks may develop.
Autoimmunity – SLE
 One-half to two-thirds of all patients exhibit evidence of
renal involvement, with diffuse proliferative
glomerulonephritis (DPGN), deposition of immune
complexes in the subendothelial tissues and thickening of the
basement membranes.
 All of these can lead to renal failure, the most frequent cause
of death in patients with SLE.
Autoimmunity – SLE
 For a clinical diagnosis of lupus to be made, 4 of 11 specific
criteria must be present: malar rash, discoid rash,
photosensitivity, oral ulcers, arthritis, serositis, renal
disorder, neurological disorder, hematologic disorder,
immunologic disorder, and presence of antinuclear
antibodies.
Autoimmunity – SLE
 SLE is associated with more than 25 autoantibodies.

 The large number of possible autoantibodies reflects a

generalized dysregulation of the immune system in SLE.
Autoimmunity – SLE
 The constant presence of antigenic material triggers
polyclonal activation of B cells.
 There is an accompanying alteration in the function of both
Th1 and Th2 helper cells, resulting in enhanced production of
certain cytokines that contribute to up-regulation of antibody
production by B cells (eg. IL-4 and IL-6).
Autoimmunity – SLE
 Drug-induced lupus differs from the more chronic form
of the disease in that symptoms usually disappear once the
drug is discontinued.
 Typically, this is a milder form of the disease, usually
manifested as fever, arthritis, or rashes; the kidneys are rarely
involved.
Autoimmunity – SLE
 When SLE is suspected, the first test typically done is a
screening test for antinuclear antibodies (ANA).
 Fluorescent antinuclear antibody (FANA) testing is
the most widely used and accepted test, because it detects a
wide range of antibodies and is positive in about 95 percent
of patients with SLE.
Autoimmunity – SLE
 Double-stranded DNA (ds-DNA) antibodies are the
most specific for SLE, because they are mainly seen only
in patients with lupus, and levels correlate with disease
activity.
 The presence of these antibodies is considered diagnostic for
SLE, especially when they are found in combination with low
levels of complement C3.
Autoimmunity – SLE
 A second major antibody found in lupus patients is
antihistone antibody.
 Histone is a nucleoprotein that is a major constituent of
chromatin.
 Presence of antihistone antibody alone or combined with
antibody to ss-DNA supports the diagnosis of drug-
induced lupus.
Autoimmunity – SLE
 Antibody to a preparation of extractable nuclear antigen
(small nuclear proteins that associated with uridine-rich
RNA) was first described in a patient named Smith, hence
the name anti-Sm antibody.
 The anti-Sm antibody is specific for SLE, because it is not
found in other autoimmune diseases.
Autoimmunity
 Antiphospholipid antibodies are a heterogeneous group
of antibodies that bind to phospholipid alone or lipoprotein.
 They can affect every organ in the body, but they are
especially associated with deep-vein and arterial thrombosis
and with morbidity in pregnancy.
Autoimmunity
 Rheumatoid arthritis (RA) is another example of a
systemic autoimmune disorder.
 RA can be characterized as a chronic, symmetric, and erosive
arthritis of the peripheral joints that can also affect multiple
organs such as the heart and the lungs.
Autoimmunity – RA
 Key symptoms: morning stiffness around the joints lasting
at least 1 hour; swelling of the soft tissue around three or
more joints; swelling of the proximal interphalangeal,
metacarpophalangeal, or wrist joints; symmetric arthritis;
subcutaneous nodules; a positive test for rheumatoid factor
(RF); and radiographic evidence of erosions in the joints of
the hands, the wrists, or both.
Autoimmunity – RA
 Other systemic symptoms of RA may include anemia,
pericarditis, lymphadenopathy, splenomegaly, interstitial lung
disease, or vasculitis.
 For many years, there has been a search for an infectious
agent or agents that may be involved in the cause of RA, but a
causal relationship has not been established.
Autoimmunity – RA
 Anti-CCP is now the lead marker for detection of
RA, because it is much more specific than RF. EIA shows
74% sensitivity and specificity of 96%; precedes symptoms
by several years
 In addition, low titers of antinuclear antibodies are present in
about 40 percent of patients.
 The pattern most identified is the speckled pattern directed
against ribonucleoprotein.
Autoimmunity
 Autoimmune thyroid diseases (AITDs), including
Hashimoto’s thyroiditis and Graves’ disease, are examples of
organ-specific autoimmune diseases.
 Although these conditions have distinctly different
symptoms, they do share some antibodies in common, and
both interfere with thyroid function.
Autoimmunity – AITD
 Follicles within the thyroid are filled with material called
colloid.
 The primary constituent of colloid is thyroglobulin, a large
iodinated glycoprotein, which is the storage form of the
thyroid hormones triiodothyronine (T3) and thyroxine (T4).
Autoimmunity – AITD
 Under normal conditions, thyrotropin-releasing hormone
(TRH) is secreted by the hypothalamus to initiate the process
that eventually causes release of hormones from the thyroid.
 TRH acts on the pituitary to induce release of thyroid-
stimulating hormone (TSH).
Autoimmunity – AITD
 TSH, in turn, binds to receptors on the cell membrane of the
thyroid gland, causing thyroglobulin to be broken down into
secretable T3 and T4.
 Production of autoantibodies interferes with this process and
causes under- or overactivity of the thyroid.
Autoimmunity – AITD
 Hashimoto’s thyroiditis, also known as chronic
autoimmune thyroiditis, is most often seen in middle-
aged women, although it may occur anywhere from
childhood up to about 70 years of age.
 Patients develop a combination of goiter (or enlarged
thyroid), hypothyroidism, and thyroid autoantibodies.
Autoimmunity – AITD
 Symptoms of hypothyroidism include dry skin,
decreased sweating, puffy face with edematous eyelids,
weight gain, and dry and brittle hair.
 The thyroid shows hyperplasia with an increased number of
lymphocytes, altering the cellular architecture of the thyroid.
 Antibodies to thyroglobulin predominate, progressively
destroying thyroglobulin.
Autoimmunity – AITD
 Graves’ disease is characterized by
hyperthyroidism and is the most prevalent
autoimmune disease in the US.
 The disease is manifested as thyrotoxicosis, with an
enlarged goiter, accompanied by nervousness, insomnia,
depression, weight loss, heat intolerance, sweating, rapid
heartbeat, palpitations, breathlessness, fatigue, cardiac
dysrhythmias, and restlessness.
Autoimmunityn – AITD

 The major antibodies found in Graves’ disease

include thyroid-stimulating hormone receptor antibody
(TSHRab) and antibodies to thyroid peroxidase.
 Strong association with DR3
Autoimmunity – AITD
 When antigen–antibody combination occurs, it mimics the
normal action of TSH and results in receptor stimulation,
with the release of thyroid hormones to produce the
symptoms of hyperthyroidism.
Autoimmunity – AITD
 The three major thyroid autoantibodies present are
antibodies to thyroglobulin, thyroid peroxidase,
and TSH receptors.
 Antibodies to thyroglobulin can be detected in 90% of
patients with Hashimoto’s thyroiditis.
 Healthy individuals may have a low titer of antithyroglobulin
antibody, but in patients with Hashimoto’s thyroiditis, the
titer is considerably higher.
Autoimmunity – AITD
 Antibodies to thyroglobulin can be demonstrated by
indirect immunofluorescent assays (IIF), passive
agglutination, and EIA.
 Since antithyroglobulin antibodies are not found in
all patients, a negative test result does not
necessarily rule out Hashimoto’s disease.
Autoimmunity – AITD
 Antibodies to peroxidase are most commonly measured by
EIA, although IIF and particle agglutination assays are also
used.
 These antibodies can be found in approximately 90 percent
of patients with Hashimoto’s disease and 80 percent of
patients with Graves’ disease, so the two cannot be
distinguished on the basis of this test.
Autoimmunity – AITD
 The third major autoantibody, anti-TSHR antibody,
is typically associated with Graves’ disease.
 Elevation of the thyroid hormones and free triiodothyronine
(T3) and thyroxine (T4) is checked first if this disease is
suspected.
 TSH levels are low because of antibody stimulation of the
thyroid.
Autoimmunity
 Autoimmune diabetes mellitus, now termed type IA
diabetes, is a chronic autoimmune disease that occurs in
genetically susceptible individuals as a result of
environmental factors.
 Approximately 10 percent of patients with diabetes mellitus
have the immune-mediated form of the disease.
Autoimmunity – DM
 This form of diabetes mellitus is characterized by insufficient
insulin production caused by selective destruction of the beta
cells of the pancreas, located in clusters called the islets of
Langerhans.
 Family studies indicate that there is an inherited genetic
susceptibility to the disease, probably attributable to multiple
genes within the HLA system.
Autoimmunity – DM
 Environmental influences include the possibility of viral
infections and early exposure to cow’s milk.
 Antibody production could possibly be initiated as a result of
molecular mimicry, with a virus as the stimulating antigen
triggering antibody production against a self-antigen.
Autoimmunity – DM
 Progressive inflammation of the islets of Langerhans
in the pancreas leads to fibrosis and destruction of most beta
cells.
 The subclinical period may last for years, and only when 80
percent or more of the beta cells are destroyed does
hyperglycemia become evident.
Autoimmunity – DM
 The generalized inflammation that results is responsible for
the destruction of beta cells.
 It is apparent that autoantibody production precedes the
development of type IA diabetes mellitus by up to several
years.
Autoimmunity – DM
 Among the antibodies found are antibodies to two
tyrosine phosphatase-like transmembrane proteins called
insulinoma antigen 2 (IA-2 or ICA 512) and IA-2βA
(phogrin); anti-insulin antibodies; antibodies to the enzyme
GAD; and antibodies to various other islet cell proteins,
called islet cell antibodies (ICAs).
Autoimmunity
 Multiple sclerosis (MS) is an inflammatory autoimmune
disorder of the central nervous system.
 It is characterized by the formation of lesions called plaques
in the white matter of the brain and spinal cord, resulting in
the progressive destruction of the myelin sheath of axons.
Autoimmunity – MS
 As is the case for most other autoimmune diseases, a
combination of genetic and environmental factors is
responsible for development of MS.
 Once initiated, the immune response becomes directed
against self-antigens that are indistinguishable from the
original foreign antigen.
Autoimmunity – MS
 Within the plaques, T cells and macrophages predominate,
and they are believed to orchestrate demyelination.
 Antibody binds to the myelin membrane and may initiate the
immune response, stimulating macrophages and specialized
phagocytes called microglial cells.
Autoimmunity – MS
 The cascade of immunologic events results in acute
inflammation, injury to axons and glia, structural repair with
recovery of some function, and then postinflammatory
neurodegeneration. (relapse, remission pattern)
 Activated T cells must penetrate into the central nervous
system to begin the response.
Autoimmunity – MS
 The two most common tests for diagnosis of MS are
oligoclonal banding and the CSF IgG index.
 Oligoclonal bands are increased in the spinal fluid in 75–90
percent of patients with MS, producing several distinct bands
on protein electrophoresis that are not seen in the serum.
Autoimmunity
 Myasthenia gravis (MG) is an autoimmune disease that
affects the neuromuscular junction. It is characterized by
weakness and fatigability of skeletal muscles.
 Antibody-mediated damage to the acetylcholine (ACH)
receptors in skeletal muscle leads to this progressive muscle
weakness.
Autoimmunity – MG
 Early signs are drooping of the eyelids and the inability to
retract the corners of the mouth, often resulting in a snarling
appearance.
 Other symptoms may include difficulty in speaking, chewing,
and swallowing and inability to maintain support of the
trunk, the neck, or the head.
 If respiratory muscle weakness occurs, it can be life
threatening.
Autoimmunity – MG
 MG is often associated with the presence of other
autoimmune diseases, such as SLE, RA, pernicious anemia,
and thyroiditis.
 MG is also associated several HLA antigen abnormalities.
 Approximately 80–85 percent of patients have antibody to
ACH receptors; this appears to be the main contributor to
the pathogenesis of the disease.
Autoimmunity – MG
 Normally, ACH is released from nerve endings to generate an
action potential that causes the muscle fiber to contract.
 When the antibody combines with the receptor site, binding
of ACH is blocked, and the receptors are destroyed because
of the action of antibody and complement (see Fig. 14-5).
Autoimmunity
 Goodpasture’s syndrome is characterized by the presence
of autoantibody to glomerular, renal tubular, and alveolar
basement membranes.
 Signs of renal involvement include gross or microscopic
hematuria, proteinuria, decreased creatinine clearance, and
increased BUN and creatinine levels.
Autoimmunity – GS
 Pulmonary symptoms include hemorrhage, dyspnea,
weakness, fatigue, and cough.
 Severe necrosis of the glomerulus is triggered by an antibody
that has specificity for a specific region of collagen.
 Immune deposits accumulate, and complement fixation
causes injury because of the release of oxygen species and
proteolytic enzymes.
 Autoimmunity – GS

 This syndrome differs from glomerulonephritis as a result of the

nonspecific accumulation of circulating immune complexes found
in other autoimmune diseases.
 In Goodpasture’s syndrome, specific antibasement antibodies can
be demonstrated by the formation of a smooth, linear ribbonlike
pattern on direct immunofluorescent assay of patient glomerular
basement membrane.
Autoimmunity – Crohn’s disease
 An inflammatory GI disease appearing anywhere
between the mouth and the anus, mostly in the large
intestine; may present with bloody stools; may be
triggered by an undefined microbe
 Leads to malabsorption and malnutrition
 Therapy includes corticosteroids and antiTNF
 Should be distinguished from celiac disease (due to
gluten) and irritable bowel syndrome (due to gas
production in the bowel; often linked to stress and
anxiety)
Autoimmunity – Sjorgren’s syndrome
 Clinically presents as dry eyes , dry mouth, dry nasal
passages, and vaginal dryness
 50% of patients have other systemic autoimmune disorders
(SLE,RA, scleroderma)
 Autoantibodies, including anti-RNP, and T cells are involved
in destruction of exocrine glands; 75% have RF.
 Usually have leucopenia and elevated ESR
Autoimmunity - Scleroderma
 Primarily in the skin but may involve multiple organs
 Breakdown of parenchymal tissue with replacement by
rapidly dividing fibroblasts.
 Leads to excess collagen production and stiffening or
hardening of the tissue
 Trigger for initial damage is unknown but ANA (anti-
centromere pattern) may be detected
Autoimmmunity – Addison’s disease
 Autoimmune destruction of the parenchyma of the adrenal
cortex, resulting in reduced production of glucocorticoids
and mineralocorticoids
 Often syptom-free until majority of organ is destroyed