Benign recurrent intrahepatic cholestasis (BRIC) is an autosomal recessive liver disease characterized by multiple episodes of cholestasis without progression to chronic liver disease. The gene was previously assigned to chromosome 18q21, using a shared segment analysis in three families from the Netherlands. In the present study we report the linkage analysis of an expanded sample of 14 BRIC families, using 15 microsatellite markers from the 18q21 region. Obligate recombinants in two families place the gene in a 7-cM interval, between markers D18S69 and D18S64. All intervening markers had significant LOD scores in two-point linkage analysis. Moreover, we identified one family in which the BRIC gene seems to be unlinked to the 18q21 region, or that represents incomplete penetrance of the BRIC genotype. IntroductionBenign recurrent intrahepatic cholerstasis (BRIC) is a rare autosomal recessive liver disease (De Koning et al. 1995) characterized by intermittent attacks of cholestasis without extrahepatic bile duct obstruction (Summerskil and Walshe 1959;Brenard et al. 1989). Each cholestatic attack starts with rising serum bile acid levels, usually followed by hyperbilirubinemia and overt cholestasis (Bijleveld et al. 1989;Brenard et al. 1989). The attacks vary in duration (weeks to months) and resolve spontaneously. No biochemical abnormalities are found in patients between attacks. The initial episode can occur at any age from infancy to adulthood, although most patients present before the age of 25 years. The frequency of attacks varies from several times a year to less than once per decade (Brenard et al. 1989). Progression to chronic liver disease has not been observed, but cholestatic episodes result in substantial morbidity, including pronounced weight loss and deficiency of fat-soluble vitamins. No established treatment is available, although cholestyramine may alleviate symptoms in some patients. Development of an effective therapy is hampered because the basic defect in BRIC is unknown.The gene for BRIC was originally mapped to chromosome 18q21 through the identification of a shared chromosomal segment in three distantly related patients from an isolated community in the Netherlands (Houwen et al. 1994). The region shared in these patients extended from D18S363 to D18S55, a genetic distance of more than 20 cM. To facilitate future molecular genetic studies we subsequently started to delimit the region of interest by studying additional BRIC families with a more densly spaced set of markers. We now present an analysis of 14 BRIC families from different ethnic sources with microsatellites selected primarily from the Généthon map, with the addi- Benign recurrent intrahepatic cholestasis (BRIC): evidence of genetic heterogeneity and delimitation of the BRIC locus to a 7-cM interval between D18S69 and D18S64

Chaperonins have classically been thought of as intracellular molecules involved in the correct folding of proteins. Their expression is upregulated during times of stress such as heat (hence their common nomenclature as heat shock proteins [HSP]), anoxia, hypoglycaemia and reactive oxygen species [1]. These are conditions found in infected tissues or in tissues with chronic inflammation such as the rheumatoid synovium. In their intracellular location they protect the cell from apoptotic death due to stress. Increasingly chaperonins have been recognised to subserve extracellular functions for which they have received the name 'chaperokines' since they bind to specific receptors on the cell surface and activate cells of the innate immune system to secrete inflammatory cytokines, chemokines and small molecular weight mediators such as prostaglandins [2]. Indeed, an early event in inflammation is cell stress/necrosis leading to the release of HSP60 and HSP70 that binds via a CD14-mediated mechanism to Toll-like receptors 2 and 4 [2] as part of the 'danger' signal [3]. The secretion of tumour necrosis factor alpha, IL-1, IL-12 and other chemokines prepares the environment for a TH1 adaptive immune response. It is now recognised that some chaperonins, such as BiP and HSP27, may activate the innate immune system to secrete anti-inflammatory cytokines, such as IL-10 [4,5] that may skew the adaptive immune response to TH2. Recent work by our group has shown that BiP can not only prevent but also treat ongoing collagen-induced arthritis in DBA/1 mice [6], suggesting that chaperonins may down modulate ongoing TH1 responses. Thus, it may be possible to suppress rheumatoid inflammation by administration of appropriate chaperonins such as BiP. Finally, chaperonins may be important system regulators determining the outcome between TH1 and Th2 immune responses. References 1. Pockley AG: Heat shock proteins as regulators of the immune response. Lancet 2003, 362:469-476. 2. Asea A: Chaperokine-induced signal transduction pathways. Exerc Immunol Rev 2003, 9:25-33. 3. Matzinger P: The danger model: a renewed sense of self. Science 2002, 296:301-305. 4. De AK, Kodys KM, Yeh BS, Miller-Graziano C: Exaggerated human monocyte IL-10 concomitant to minimal TNF-alpha induction by heatshock protein 27 (Hsp27) suggests Hsp27 is primarily an antiinflammatory stimulus.