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MAJOR HISTOCOMPATIBILITY

COMPLEX (MHC)

MHC Class I Processing -
http://www.youtube.com/watch?v=vrFMWyJwGxw

MHC class I assembly and presentation -
http://www.youtube.com/watch?v=VPvCekgPwRI

MHC Class II Processing -
http://www.youtube.com/watch?v=_8JMVq7HF2Y&list
=PL558A62E700A8D024

The Class II MHC Pathway of Antigen Presentation -
http://www.youtube.com/watch?v=dw73PzjgGJA&list=
PL558A62E700A8D024

TCR-APC Interaction -
http://www.youtube.com/watch?v=Xt_y7f6KivI&list=PL
558A62E700A8D024


Antigenele de histocompatibilitate se definesc ca
molecule ale suprafeei celulare i care, datorit
diferenelor biochimice individuale sunt recunoscute
de sistemul imunitar al unui organism cu un alotip
diferit (cu o alt combinaie de gene alele la situsul
codificator).
Diversitatea biochimic la nivel individual a acestor
molecule, st la baza unicitii biochimice a fiecrui
individ uman i este determinat de o diversitate
genetic corespunztoare.
Deoarece se comport ca antigene majore n
organismul receptor de gref, antigenele CMH se
numesc i antigene de transplantare.

n funcie de capacitatea lor de a stimula rspunsul
imun de respingere a grefei, antigenele CMH
sunt tari i slabe.
1. Antigenele CMH tari reprezint principala
barier n calea transplantului de esuturi i
organe. La oarece, moleculele CMH tari aparin
sistemului H-2. Grefele de esuturi i organe ntre
organisme care difer prin antigenele complexului
H-2 ale suprafeei celulare sunt invariabil respinse
n 10-14 zile. Antigenele tari aparin claselor I i II.
2. Antigenele slabe (uoare) sunt codificate
de sistemul minor de histo-compatibilitate i
determin respingerea lent a grefei de piele, n
circa 200 de zile.

-Heterodimer
-- 2 lanuri legate necovalent
- lanul greu alfa (a1, a2, a3)(43kDa)
- codificat de gene MHC
-Transmembranar
-- lant usor beta2-microglobulina (12kDa)
- nu este codificat de gene MHC
- nu traverseaz membrana

MHC I nu pot fi exprimate n absena
b2-microglobulinei
MHC clasa I
a1 i a2 formeaz situsul de legare a Ag

a3 are rol structural, nu intervine direct n
legarea peptidului antigenic

CD8 se leag la nivelul domeniului a3
Regiunea citoplasmatic conine situsuri
pentru fosforilare i care se leag de
citoschelet.
Regiunea transmembranar conine
aminoacizi hidrofobi prin intermediul crora
moleculele sunt ancorate n membran.
Situsul de legare antigenic poate fixa peptide a 8-10 AA
MHC clasa I
b2-
microglobulina
antigenul

Rolul HLA I
Moleculele CMH clasa I sunt adevrate certificate de
identitate biochimic i genetic, pentru fiecare
organism, datorit polimorfismului lor biochimic foarte
accentuat. Ele vegheaz la pstrarea homeostaziei
biochimice a organismului i devin inta sistemului
imunitar n urmtoarele situaii:
dup grefarea esuturilor i organelor care poart
molecule incompatibile;
dup ce se asociaz cu antigenele virale, tumorale
sau cu cele induse de agenii chimici;
dup modificarea biochimic printr-un proces
mutaional.
Recunoasterea Atg de catre Lf T citotoxice CD8+
MHC clasa II
- heterodimer

- 2 lanuri legate necovalent

-lant alfa (alfa1, alfa2) (30-34kDa)
-lant beta (beta1, beta2) (26-29kDa)
- ambele codificate in MHC
- ambele transmembranare

- ambele lanuri sunt necesare pentru
exprimarea MHC II


- a1 i b1 formeaz situsul de legare al Ag

- a2 i b2 au rol structural, nu intervin
direct n legarea Ag

- la nivelul domeniului b2 se leag CD4

MHC clasa II
Lanul beta
antigenul
Situsul de legare antigenic poate fixa peptide a 13 -18 AA
Membrana celulara
Peptid
MHC clasa I MHC clasa II
Situs de legare
peptid
ANTIGEN PROCESSING AND
PRESENTATION
Antigen processing and presentation are processes
that occur within a cell that result in fragmentation
(proteolysis) of proteins, association of the fragments
with MHC molecules, and expression of the peptide-
MHC molecules at the cell surface where they can
be recognized by the T cell receptor on a T cell.
However, the path leading to the association of
protein fragments with MHC molecules differs for
class I and class II MHC. MHC class I molecules
present degradation products derived from
intracellular (endogenous) proteins in the cytosol.
MHC class II molecules present fragments derived
from extracellular (exogenous) proteins that are
located in an intracellular compartment.

I. Antigen processing and presentation in
cells expressing class I MHC
All nucleated cells express class I MHC.
1. Proteins are fragmented in the cytosol by proteosomes
(a complex of proteins having proteolytic activity) or by
other proteases.
2. The fragments are then transported across the
membrane of the endoplasmic reticulum by transporter
proteins. (The transporter proteins and some
components of the proteosome have their genes in the
MHC complex).
3. Synthesis and assembly of class I heavy chain and
beta
2
microglobulin occurs in the endoplasmic reticulum.
4. Within the endoplasmic reticulum, the MHC class I
heavy chain, beta
2
microglobulin and peptide form a
stable complex that is transported to the cell surface.

MHC clasa I leag peptide Ag
i le prezint limfocitelor T CD8
+

II. Antigen processing and presentation
in cells expressing class II MHC
Only a limited group of cells express class II MHC, which
includes the antigen presenting cells (APC). The principal APC
are macrophages, dendritic cells, and B cells, and the
expression of class II MHC molecules is either constitutive or
inducible, especially by interferon-gamma in the case of
macrophages.
1. Exogenous proteins taken in by endocytosis are fragmented
by proteases in an endosome.
2. The alpha and beta chains of MHC class II, along with an
invariant chain, are synthesized, assembled in the
endoplasmic reticulum,
3. transported through the Golgi and trans-Golgi apparatus to
reach the endosome, where the invariant chain is digested,
and the peptide fragments from the exogenous protein are
able to associate with the class II MHC molecules,
4. which are finally transported to the cell surface.

MHC clasa II leag peptide Ag
i le prezint limfocitelor T CD4
+

III. Important aspects of antigen
processing and presentation
One way of rationalizing the development of two different pathways
is that each ultimately stimulates the population of T cells that is most
effective in eliminating that type of antigen.
Viruses replicate within nucleated cells in the cytosol and produce
endogenous antigens that can associate with class I MHC. By killing
these infected cells, cytolytic T cells help to control the spread of the
virus.
Bacteria mainly reside and replicate extracellularly. By being taken
up and fragmented inside cells as exogenous antigens that can
associate with class II MHC molecules, helper Th2 T cells can be
activated to assist B cells to make antibody against bacteria, which
limits the growth of these organisms.
Some bacteria grow intracellularly inside the vesicles of cells like
macrophages. Inflammatory Th1 T cells help to activate
macrophages to kill the intracellular bacteria.
Fragments of self, as well as non-self, proteins associate with MHC
molecules of both classes and are expressed at the cell surface.

Which protein fragments bind is a function of the chemical nature of
the groove for that specific MHC molecule.

IMPORTANT ASPECTS OF MHC
Although there is a high degree of polymorphism for a species, an individual has
maximum of six different class I MHC products and only slightly more class II MHC
products (considering only the major loci).
Each MHC molecule has only one binding site. The different peptides a given MHC
molecule can bind all bind to the same site, but only one at a time.
Because each MHC molecule can bind many different peptides, binding is termed
degenerate.
MHC polymorphism is determined only in the germline. There are no
recombinational mechanisms for generating diversity.
MHC molecules are membrane-bound; recognition by T cells requires cell-cell
contact.
Alleles for MHC genes are co-dominant. Each MHC gene product is expressed on
the cell surface of an individual nucleated cell.
A peptide must associate with a given MHC of that individual, otherwise no immune
response can occur. That is one level of control.
Mature T cells must have a T cell receptor that recognizes the peptide associated
with MHC. This is the second level of control.
Cytokines (especially interferon-) increase level of expression of MHC.
Peptides from the cytosol associate with class I MHC and are recognized by Tc
cells. Peptides from within vesicles associate with class II MHC and are recognized by
Th cells.
Polymorphism in MHC is important for survival of the species.
Determinismul genetic al
moleculelor CMH
Moleculele CMH sunt codificate de genele complexului
major de histocompatibilitate. Calificativul complex
este justificat de numrul mare de gene componente,
iar cel de major semnific importana deosebit a
moleculelor codificate de aceste gene, n realizarea
unor funcii imunitare importante:

-elaborarea rspunsului imun
-respingerea grefelor de esuturi i organe.

n raport cu tipul de proteine pe care le codific, genele
CMH aparin clasei I i clasei a II-a.
In acest complex se gsesc 3 tipuri de gene descoperite
independent:
-primul grup de gene (descoperit n anii 40) codific
antigenele tari de transplantare, care induc
respingerea rapid a grefelor de tegument i de organe,
ntre indivizi neidentici genetic (aparin unor alotipuri
diferite). Acestea sunt genele CMH clasa I, care codific
moleculele CMH clasa I;

-al II-lea grup, denumite genele rspunsului imun (IR)
codific sinteza unor molecule care
condiioneaz intensitatea rspunsului imun al
organismului, slab sau puternic, fa de un antigen.
Genele IR codific proteinele clasei a II-a de
molecule CMH, denumite i molecule Ia (I
associated);

-al III-lea set de gene ale complexului CMH codific
sinteza unor componente ale complementului.

La om, moleculele CMH clasa I sunt codificate
de genele HLA, iar moleculele CMH II, de regiunea
cromosomal D, localizate pe cromosomul 6.
Moleculele CMH I sunt codificate de trei gene: HLA-A,
HLA-B, HLA-C. S-au descris genele HLA-E, -F, -G, -H
i -J, dar acestea sunt considerate gene neclasice
pentru c produsele lor de sintez se deosebesc
structural i funcional de ale genelor HLA-A, -B i C.
Moleculele CMH II sunt codificate de regiunea
cromosomal HLA-D, ce aparine genelor clasei a II-a.
Genele clasei a III-a codific sinteza acelorai
proteine plasmatice (C4, C2, Bf).

Genele HLA clasa I i II au cel mai nalt grad de
polimorfism genetic dintre toi determinanii genici
cunoscui ai organismului uman:
HLA-A are 83 de alele
HLA-B, 185 de alele
HLA-C, 42 de alele.
ntr-o populaie uman, moleculele CMH I i CMH II
sunt foarte diferite din punct de vedere biochimic, ca
o expresie a polimorfismului genic al indivizilor umani

Distribuia tisular a moleculelor
CMH I i II
Moleculele CMH I se gsesc pe suprafaa majoritii
esuturilor, pe celulele endoteliale ale capilarelor, iar
leucocitele exprim cea mai nalt densitate a
moleculelor CMH I: 1% din moleculele de suprafa
ale membranei leucocitare sunt molecule HLA.
Moleculele CMH I au o densitate mai mic pe
suprafaa celulelor hepatice, din plmn, rinichi i
sunt foarte diluate pe suprafaa celulelor musculare
i a celor mai multe glande endocrine (cu excepia
suprarenalelor).

Distribuia tisular a moleculelor
CMH I i II
Moleculele CMH lipsesc pe eritrocite, pe celulele
endoteliului corneean, pe componenta exocrin a
pancreasului, pe celulele acinare ale glandelor parotide,
pe neuronii SNC, pe celulele endoteliale ale capilarelor
SNC, pe esutul placentar.
n condiii normale, o form solubil de molecule HLA
se gsete n plasm. Nivelul ei crete marcat n timpul
infeciei virale, - datorit creterii sintezei moleculelor
HLA, stimulat de interferon i de alte citochine.

Distribuia tisular a moleculelor
CMH I i II
Intensitatea exprimrii noleculelor CMH II este
variabil, fiind controlat de diferii factori:
interferonul i IL-2, sintetizai de limfocitele T,
amplific nivelul de exprimare a moleculelor CMH II,
iar PGE
2
, glucocorticoizii, -fetoproteina, LPS din
bacteriile Gram negative, diminu densitatea
acestor molecule, avnd astfel rol imunosupresor.
Limfocitele B i celulele tumorale secret molecule
CMH II.

Privit n perspectiva evoluiei, existena moleculelor
CMH nu semnific respingerea grefelor de esuturi i
organe, deoarece acestea nu se realizeaz n mod
natural, ci au fost introduse n practica medical a
ultimelor decenii. In sens evolutiv, existena
moleculelor CMH ar putea fi atribuit necesitii
organismelor de a semnaliza rapid, celulele care
prezint molecule antigenice pe suprafaa lor:
celulele infectate cu virusuri sau cele transformate
malign. In acest context, moleculele CMH au o
semnificaie deosebit: pentru supravieuirea
organismului, liza celulelor purttoare de molecule
nonself trebuie s fie rapid, nainte ca virusul s se
multiplice i respectiv, nainte ca celula malign s
se divid i s formeze o microtumor.
Pentru ca intervenia limfocitelor Tc s fie eficient,
este necesar ca moleculele CMH s fie prezente pe
oricare celul ce poate fi infectat de un virus sau
poate s fie transformat malign. Pe de alt parte,
moleculele CMH, al cror rol esenial este acela de a
prezenta epitopii nonself, trebuie s permit aciunea
eficient i rapid a limfocitelor Tc.
Moleculele CMH ndeplinesc i funcii neimune.
Moleculele CMH I sunt componente ale receptorilor
de hormoni. De exemplu, linia celular stabilizat
Daudi nu exprim moleculele CMH I i nu are nici
receptor pentru insulin, deoarece nu sintetizeaz
2-microglobulina.

Transplant = nlocuirea unui esut
defect cu un alt esut, funcional
Autotransplant de la/la acelai individ
Isotransplant ntre doi indivizi identici
genetic (gemeni)
Allotransplant ntre doi indivizi genetic
diferii, dar din aceeai specie
Xenotransplant ntre dou specii diferite

Progrese in transplantul de organe