A young woman who sees in the mirror a butterfly-shaped rashacross her nose and cheeks is likely looking at the onset of systemiclupus erythematosus _ SLE for short.Lupus (Latin for "wolf") is grimly and aptly named. As far back as1590, a medical book described it: "Lupus is a malignant vlcer...andit is very hungry, like vnto a woolfe."Immunologist Argyrios Filotheopoulos, of the Scripps ResearchInstitute in La Jolla, Calif., updates that description: "SLE is adisease," he told BioWorld Today, "where the immune system,largely in disarray, raises autoantibodies against almost everycomponent in our body." Its primary prey, he added, "is DNA in thecell's nucleus, but it also devours other cellular molecules, such asplatelets and red blood cells."As a result," he continued, "complexes form between antibodiesand antigens. These settle on a variety of organs, causinginflammation and tissue damage, especially in kidney, spleen, heart,skin, blood vessels, liver and the brain. Such complications in thebrain," he added, "can be fatal."In earlier days," he observed, "SLE patients used to have amiserable time, and many died. Now, a combination of anti-inflammatories and corticosteroids, and cytostatic drugs hasreduced mortality considerably, but morbidity and severedisabilities remain.Filotheopoulos leads a group at Scripps dedicated to discovering thegenetic basis of SLE. "Like most human diseases," he said, "lupusis considered to be polygenic. It is not inherited in a simpleMendelian manner."In other words, instead of searching for a single needle in ahaystack, this means seeking an unknown number of genes in 23haystacks of varying sizes _ the chromosomes of the humangenome.Mice Mimic TraitIn this pursuit, the bloodhounds are mice.Crossing two strains of New Zealand mice, one black, one white,produces progeny that mimic the cellular and organic ravages oflupus in virtually every fiber of their being."In that first [F1] generation," Filotheopoulos explained, "all themice will be alike, so we would not be able to correlate anyparticular chromosomal or gene association with disease. But in theF2 generation, we have random distribution of the various genescontributed by the parental strains, so we are able to identifylinkages."He spells out the group's latest findings of "Lupus susceptibilityloci in New Zealand mice" in the current Proceedings of theNational Academy of Sciences (PNAS), dated Oct. 11. His group'slinkage analysis covered more than 90 percent of the hybrid murinegenome, and identified eight SLE susceptibility loci on as manychromosomes.These related to chromatin autoantibody production (againstnuclear DNA), glomerulonephritis (against kidney), splenomegaly(against spleen) and death, as an SLE characteristic. A constellationof linkages on chromosome 4 in particular "suggested a single locuswith pleiotropic effects," and led to the paper's conclusion that "theimmunopathological features of lupus are affected by distinct, butadditive, genetic contributions."The Scripps SLE task force is now trying to narrow down that hotspot on chromosome 4. "At present," Filotheopoulos said, "weknow its position to within seven centiMorgans. We'd like to bringit down to perhaps 0.1 to 0.5 cMs, because that would allow us touse more advanced molecular technologies, such as yeast artificialchromosomes." That in turn would permit "sequencing thecomplete segment there, and perhaps identifying the gene thatcauses this phenotypic characteristic."Large Pedigree DescribedFilotheopoulos is collaborating with immunologist John Harley andendocrinologist Hal Schofield of the Oklahoma Medical ResearchFoundation in Oklahoma City. They are collecting SLE familieswith more than one affected member. Next Tuesday, at theAmerican College of Rheumatology meeting in Minneapolis,Harley will report on one pedigree multiplex with eight lupusmembers. This, Schofield told BioWorld Today, "is the largestnumber ever described." He added that "We followFilotheopoulos's work very intensely."Harley's paper will conclude that the Oklahoma data supports "thehypothesis that some aspect of the environment found in multiplexlupus pedigrees influences the prevalence of the autoimmunephenotype."Filotheopoulos told BioWorld, "What we find in the mice we cansupply, by known homologies between mouse and humanchromosomes, to the Oklahomans, who have put together theselupus families. We can then tell them, `Look, this particular markeron that and that chromosome seems to be associated with thisdisease.'" He added, "So we give them a head start in trying tolook in corresponding human areas, to see whether there is indeed acorresponding genetic contribution."Nine times as many women as men contract SLE, and theprevalence is estimated at perhaps 10 in a million of the U.S.population.Those New Zealand mouse models also confer their diseaseexclusively on females. In a quite different murine hybrid, knownas BXSB, it's the male that develops severe lupus. "You know,"Filotheopoulos remarked wryly, "mice have a peculiarnomenclature."He plans to cross the BXSB and New Zealand models "to determinewhat might be the influence of the Y chromosome versus femalesex hormones."The Scripps scientist expressed the hope that "if we are able toidentify two or three of these SLE genes that contribute to thepathological characteristics of the disease, then we may designdrugs to interfere with their activity." He cites as a hypotheticalexample, "Let's say one of these genes hyper-produces a cytokine.Then one might consider creating blockers to prevent this cytokinefrom binding to its receptor. Or utilize antibodies against thatmolecule."Such specific treatments, he pointed out, would not act broadly, asdo corticosteroids, for example, that frequently lead to side effects."They would be targeted to these desired genetic effects, eithersingly or in combination." n
-- David N. Leff Science Editor
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