Relación entre PCI e Indicadores de Calidad de Mezcla

In occ upying the MHC II binding groove, li prevents endog eno us material bi n d i n g class II molecules prior to the MH C II comple x re aching endocytic co m p ar tm e n ts conta inin g exogenous antigens (Cresswell, 1994; Rom agn ali & Ger main, 1994). As discussed in section s 1.7.1 and 1.7.2, on arrival in the antigen proc ess ing comp ar tmen t, the pr oteolytic removal of li from the class II complex is a req uiremen t for the bi nding of antigenic peptides. Such deg radation occurs in a disti nct series of steps, rem ov al of the te r m in al portions of li occurring first ( N ew com be & Cres swe ll , 1993(a); N e w c o m b e & Cresswell, 1993(b)). The region of the li that actually occup ies the MHC II binding groove is that which is re sp on si b le for the p re v en ti o n of pr emature peptide b in di n g of endoge no us peptides th ro u g h o u t the jou rne y of the class II com pl ex from the ER to the en do s om a l pathway. This is the final po rti on of li to be re m ov ed prior to the bin di ng of antigen in the pr ocessing co m p ar tm e n t (Riberdy et al, 1994). Te rm ed class II associated li peptide (CLIP), this re gulatory p o r tio n is that

which is also re spo ns ib le for the co rrect assembly of the CX/p/Ii no n om er ic

co m p le x in the ER, namely the region of the lumenal domain of li sp anning re sid ue s 85 to 105 (Riberdy et al, 1994; R om agn ali & Germain 1994).

MHC II o /p dimer

Invariant chain

nascent MHC II present in ER or in golgi en route to processing compartments

V

initial proteolytic degradation of

N and C terminal conponents o f li by cathepsins B, S, L ect. in ag

processing compartments

CLIP

Antigenic p ^ tid e

HLA-DM

removal and degradation of CLIP facilitated by cathepsin S and

catalysed by HLA-DM binding o f antigenic peptide to produce mature class II complexes F i g u r e 1.2

Proposed pattern of step-wise degradation of invariant chain from MHC II

The re moval of CLIP from the class II comp lex is therefore a critical event in the mo du la ti o n of MHC Il-pep ti de binding. This event has been shown to be cataly sed by a member of the MHC glycoprotein family, HLA -DM (Denzin & Cresswell, 1995). H LA -DM is a non po ly mo rp hi c class H-like m olecule, shown to accumulate in the antigen proc ess ing co mp ar tm e n ts of APC (Sand ers on et al, 1994; Sand er son et al, 1996). DM com pr ise s the

prod uct s of the DM OC and (Î genes (Kelly et al, 1991; Cho et al, 1991).

Antigen pr oc es si ng has been shown to be defective in B cell lines lacking

either the OC or P chain of HLA -DM (Mellins et al, 1990; M ellins et al,

1991; Green et al 1995). Such DM deficiencies result in im pai red class II m edi ate d antigen pre sen tatio n and also the altered co nf orm at io n of surface MHC II mole cul es in such cells (Ceman et al, 1992). The class II m olecules of APC lacking functional HLA -DM contain a nested set of li peptides, rather than the expec ted range of exogenous products (Riberdy & Cresswell, 1992; Riberdy et al, 1992).

The bo und li der ived fragments have been id entified as those sp ann ing the CLIP region of li. As such, it appears that HLA-DM is a r e q ui re m en t for the rem ova l of CLIP, thus faci lit ati ng class H-loading of antigenic peptides (Sa nderson et al, 1996). The DM mole cule ther efore catalyses the exchan ge of CLIP peptide for exogenous material and interacts with the cysteine pr o te in a se s r es pon si ble for the initial deg radation of the li. The precise me ch an is m by which DM fun ctions as such, reg ulating the final step in li removal from class II remains unc lear as yet. In vitro, Reise et al have

de m on st r at ed that the removal of CLIP from a / p / C L I P com pl exe s

gener ated from the cathepsin S degradation of a / p / I i , and s ub seq uen t

bin di ng of antigenic peptide, is catalysed by the incl usio n of HLA-DM. This may be evidence for cathe ps in S being re spo ns ib le for the terminal pro ce ss in g of in variant chain, re sulting in a 13Kd CLIP frag men t which is

then replac ed by immu no gen ic deter min an ts by a process cata ly se d by HL A-D M (Reise et al, 1996).

A recent finding hi ghlighting APC specific differ enc es in class II pr oce ss in g and pr ese ntation, is that HLA-DM is not r eq ui red for antibody- de pe nd ent antigen pr ocessing by B cells. Thus, while r eq uir ed for other m ec h an is m s of class II associated antigen p r es ent ati on, H L A -D M does not play a role in the loading of Ig-captured antigen to B cell class II molec ule s (K ors rud et al, 1997).

endosomal, class II containing processing compartmoits recycling presentation of processed antigenic æitopes proteolysis exogenous endoplasmic reticulum

»

nascent o/p/Ii trimers proteolytic and HLA-DM mediated Ii removal to form mature MHC II newly synthesised a, p and li chains lysosomes F i g u r e 1.3

Life cycle o f the MHC II complex and the interaction with exogenous antigen.

In document Evaluación post construcción de la calidad de mezcla asfáltica, como indicador de la serviciabilidad en la carretera desvío Yocará – Cabana, Puno (página 126-143)