Anatomically and functionally, the difference betweenmales and females has been common knowledge since thedawn of humankind. But at the molecular level, whatseparates the sexes became known only recently, and tothis day only partially.

We know that all the 6 billion or so descendants of Adamand Eve carry in their genome 46 chromosomes, 44 ofthem paired, the last two sex-linked. Females have two Xchromosomes, only one of which is functional. Maleshave one X and _ the distinguishing genomic mark ofmasculinity _ one Y chromosome.

Among the many phenomena immunologists haven'tbeen able to explain is why a female mouse will reject askin graft from an immunologically identical male mouse,but not vice versa. That simple transplant experimenttook place in 1955, and has remained a scientificconundrum ever since.

Now, two teams of molecular immunologists, one British,one American, have simultaneously solved the riddle _from its opposite ends. The British used a genetic, DNA-based transfection technique; the Americans, aspectroscopy-assisted peptide elution technique.

Science, in its Sept. 15, 1995, issue, carries a paper byimmunologist Victor Engelhard from the University ofVirginia, Charlottesville, titled: "Human H-Y: A male-specific histocompatability antigen derived from theSMCY protein."

Nature, in its Aug. 24, 1995, issue beat Science to thisparticular punch by three weeks. The senior author of itsarticle, "Identification of a mouse male-specifictransplantation antigen, H-Y," is immunogeneticistElizabeth Simpson, who directs transplantation biology atthe U.K. Medical Research Council's Clinical SciencesCenter in London.

Simpson and Engelhard are friendly competitors of longstanding. Originally, the editors of Science and Naturehad agreed to publish both manuscripts simultaneously."But it was not to be," observed an editorial in Science.

One of Engelhard's co-authors, molecular biologistAlexander Agulnik, had sequenced a relevant gene on thehuman Y chromosome while employed by PromegaCorp., of Madison, Wisc. "Promega," the editorialreported, "complained, and demanded time to file apatent on the gene, thus delaying publication of theScience paper."

Still, three weeks' delay is but a blip on the 40-year-oldscreen of mystification as to female rejection of maletissue.

What both groups found is a stubby peptide encoded by ashort segment of the SMCY gene, which resides on the Ychromosome. As females lack this males-onlychromosome, their immune systems "see" its antigenicgene products as alien. But this clear-sightedness is not assimple as, say, an antibody zeroing in on an invadingbacterial epitope [immunogenic target].

The H-Y histocompatability antigen beckons T cells, notantibodies.

Except for identical twins, most human immune systemsexpress peptides as antigenically diverse as theirfingerprints, or their DNA forensic patterns. This explainswhy organs transplanted from mismatched donors riskrejection.

`Minor' Antigen May Make Major Difference

These transplantation antigens are of two sorts, major andminor, Engelhard explained to BioWorld Today. "Themajor histocompatability [MHC] antigens present _ thatis, display _ most peptides out on the surface of cells forrecognition by the immune system. A tissue transplantacross a `major' barrier _ that is, between people whodiffer in one or more of their MHC antigens _ elicits astrong transplant rejection response."

Organ grafts between a donor and recipient withmatching major antigens, but divergent minor ones, leadsto a much weaker rejection response.

"A special case of one of these minor MHC antigens,"Engelhard pointed out, "is the H-Y antigen, which is sex-linked, rather than disseminated throughout the genome."

He added that this H-Y "was the first minorhistocompatibility antigen ever described." What he andhis co-authors have now accomplished is to pin down onevariant of this long-elusive peptide. "We've identified theH-Y antigen that's presented by one particular MHCmolecule called human leukocyte antigen B7, whichoccurs in about 12 percent of the human population.

"So one of the questions we want to pursue," Engelhardcontinued, "is whether the SMCY protein is the source ofH-Y antigens that are presented by other MHC molecules.One of them may come from an entirely different geneand protein."

Besides what he calls "this basic science issue," theVirginia scientist perceives "the clinical relevance oropportunity to begin to do something of medicalimportance with the SMCY sequence. The mostobvious," he pointed out, "is in the transplantation area."

But not in "solid" donor organs, such as heart, lung andkidney. "There," Engelhard observed, "the use ofimmunosuppressive agents is so routine, that minorantigen differences don't seem to be a major concern.

"In bone-marrow transplants," he added, "nowincreasingly used to treat leukemia and breast cancer,these minor antigens continue to be a major problem,because we don't practice immunosuppression, butmaintain a low-level immune response to help the graftestablish itself."

He continued: "One can certainly conceive of trying tomake a female bone-marrow donor tolerant of the H-Yantigen, as a pre-transplant conditioning regimen. Then,when her marrow is transplanted into a male recipient, itdoesn't initiate the sometimes fatal graft-vs.-host diseasethat is the major problem in bone-marrowtransplantation."

On which score, Elizabeth Simpson, senior author of theNature paper, told BioWorld Today, "Where you're doingbone-marrow transplants between HLA-identical siblings,the only targets for these rejection responses are in factthese minor histocompatability antigens, of which H-Y isbut one of many dozens. So you're not going to solvethese problems at a glance, just by cloning one H-Yepitope."

A quite different use for the now-identified H-Y antigen,Engelhard suggests, is to prevent X-linked geneticdeficiencies, such as hemophilia, which only malesinherit. "If one were to kill off male or female sperm priorto artifical insemination," he said, "or in vitrofertilization, then you're doing something people mightfind less ethically reprehensible than elective abortion _although it has some Orwellian implications." n

-- David N. Leff Science Editor

(c) 1997 American Health Consultants. All rights reserved.