Estructuración de Informe y tablas de cifras de Reservas y Recursos

B cell growth and differ ent iatio n are con tr oll ed by a m ul ti tu d e of cytokines and growth factors, of which, in the latter stages of di ffe re nt iat io n , IL-6 is perhaps the most imp orta nt (van Snick, 1990; Faris et al, 1997; Morse et al, 1997). IL-6 is pro du ced by a wide variety of cell types inc lu di ng B cells t he m sel ves , CD4+ Th2 T cells, f ibr ob las ts, mast cells, end o th eli al cells and epi th eli al cells. IL-6 is a typical i nt erl euk in in that in addition to its many sources, its actions are m ul ti -p ot en t and pleiotropic. The maj or biolo gic al roles of IL-6 are summ ar ise d in figure 4.1. IL-6 is a p ot ent pr o m o t er of growth, differ ent ia ti on and pr oli fe ra ti o n in lymphocytes, p ar tic ul a ry for B cells (van Snick, 1990; Tanner & Tosato, 1992; Faris et al, 1997; Mors e et al, 1997). Little is known of the effects of IL-6 on the antigen pr o ces si n g and p r es en ta ti on capacity of APC and, in particular, its effects on the APC f u nct ion of B cells remain undefined.

IL-6 is pr esent in the milieu of p r o -i m f la m m at o r y medi ato rs at sites of infe cti on or infl amm ati on (Finkelman, 1995; Lucey et al, 1996). In the c on t ex t of disease path og enesis, IL-6 has also been shown to be pr es en t in high levels at sights of chronic i nf la m m at io n such as the sy no viu m of rh e u m a t o id arthiritis patients, and the lam ina p r o pr ia of pa ti en ts with i n fla m m at or y bowel disease (Suzuki et al, 1990; M ah ida et al, 1991; F i nk le m an , 1995, Peters et al, 1996). From the limited stud ies of the effects of IL-6 on antigen pr ese nta ti on, IL-6 appears to u p re g ul at e the ca pac it y of immu ne cells to pre sen t exogen ous antigen. In a To xop las m a G on di i in fected human fibrob las t line, the addition of ex o ge no us IL-6 was shown to induce the exp ression of HL A- D R (Yang et al, 1996). In gingival f ib r ob la s ts however, another study d em on str at ed that while IFN-y tre at me nt

in vitro induce d HLA-DR, IL-6 had no such effect (Takahashi et al, 1994). In a study conce rnin g antigen p r es ent at io n at mucosal sites, pr e- t r e a t m e n t

of a m ix ed in vitro culture of murine vaginal ep i t h e l i u m / st r o m a l cells and also con trol spleen cell cultures with ex oge nou s IL-6 resu lted in a marked incre ase in the capacity of all cells to stimu lat e a pop ul at io n of allogeneic T cells (P rab h ala & Wira, 1995). In a study of h a e m o ph il ia c boys infected with HIV and HCV, Pasi et al foun d a def inite co rre la ti on with the de cr eas ed serum IL-6 levels in such pati ents and an i m p ai re d antigen pr es en t at i o n function of their m on ocytes in vitro (Pasi et at, 1995). U nf o rt u n at el y the immu ne cells studied in each case cited above are not the ‘maj or p l a y e r s ’ in terms of antigen p r es en ta ti on in the phy sio lo g ica l context. No similar studies co nc er ni ng dendritic cells, B cells or even ma cr o ph ag es exist as yet.

Of r el eva nce to the model used t h ro ug h ou t this study is the role that IL-6 and the IL-6 rec ept or (IL-6R) play in the growth and d iff er en ti at io n of EBV B cells co m pa re d to ‘m o r t a l ’ B cells. The E ps te in -B ar r virus is a potent in du cer of polyclonal B ly m ph o b la st oi d pro lif er at io n. The m e c h a n i s m by which the virus achieves this is through up re gu la tin g the ex p r e ss i o n of the IL-6R in B cells fo llowin g in f e ct io n/ tr an sf o r m at io n . As such, the growth and p r oli f er at iv e resp ons e to ex oge no us IL-6 is po te n ti at ed ( Sc ala et al,

1990 ; Ifver son et al, 1993; Du randy et al, 1994; T o m e c z k o w s k i et al,

1997). The impo rta nce of IL-6 in the growth and d iff er en ti at io n of EBV cells was high ligh ted in studies by Scal a et al in which the rates of p ro li f er at io n and d iff er en ti at io n of an EBV line could be mark edly in cr ea se d on tran sfe cti on of the line with the IL-6 gene, thus p r o v id in g stable and cons tan t high levels of auto crine IL-6 (Scala et al, 1990). N u m er o us studies have shown that exo g en o us IL-6 is able to pro mote di ff er en t ia t i on and growth of EBV B cells in vitro (Ifversen et al, 1993; D u r an d y et al, 1994; Faris et al, 1997). High levels of e x og en ou s IL-6 can even drive EBV ly m pho bla sts to terminal dif fe re n ti at io n , as de t e r m in e d by cell cycle arrest and eventu al apoptosis (Morse et al, 1997).

differentiation of plasma cells and promotion of Ig production, growth and proliferation of B cells + TGF-3 L-2R

class switching and

induction of post-switch Ig secretion

T cell differentiation and proliferation induction of IL-2 and IL-2R macrophages endothelium epitheliu keratinocyte growth and proliferation

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o o

release of soluble mediators of the acute phase response

from hepatocytes

differentiation of myeloid cells from bone marrow stem cell precursors

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F ig u r e 4.1

Schematic summary of the major biological functions of interleukin-6,