A newly identified gene, implicated in a rare, hereditaryimmune deficiency already inhibits autoimmune diseases inanimal models. Until this discovery, reported in whole or partby at least four research teams, immunologists assumed theimmunodeficiency represented a disorder of T or B cells, ratherthan a breakdown in communication between the two, as thenew findings show.

Tomorrow's Science will describe the discovery in a reportentitled: "CD40 Ligand Gene Defects Responsible for X-LinkedHyper-IgM Syndrome."

Its lead author, molecular biologist Melanie K. Spriggs ofImmunex R&D Corp., Seattle, emphasized to BioWorld, "Ouridentification of this gene defect at the molecular level is notjust a correlation. This is itHthe actual single-gene deficiencyresponsible for the syndrome."

The syndrome first becomes apparent in the first few monthsof an infant's life, when severe recurrent infections, such asPneumocystis carinii pneumonia, leads to diagnosis of Hyper-IgM, and maintenance immunoglobulin therapy. P. carinii is aleading cause of death in AIDS.

Spriggs said an estimated five individuals per 1 million areborn with this life-threatening failure of B cells to makeinfection-fighting IgA , IgE and Ig G antibodies. Instead, forlack of a signal from helper T cells, the B's churn out less usefulIgM antibodies. This accounts for the Hyper-IgM name of thedisease.

Located on the long arm of chromosome X, the gene istransmitted through carrier mothers to affect only boys.

Helper T cells get their message across to the CD40 receptor onthe B-cell surface via a linking molecule, the CD40 ligand.Mutations of the gene encoding this ligand, researchers nowrealize, prevent the crippled ligand from triggering a B cell'sswitch from IgM production to the other three pathogen-killingantibody isotypes.

"In addition to identifying the CD40 ligand as non-functional,"Spriggs said, "We went one step further and took antibody-producing B cells from Hyper-IgM patients and cultured themin vitro with functional, recombinant CD40 ligand. Those B cellsdid just fine, perfectly normal."

"In other words," she added, "everything in those patients isready to go, except that they have no ligand."

The Bristol-Myers Squibb Pharmaceutical Research Institute inSeattle has also cloned the human CD40 ligand gene. Dartmouthimmunologist Randolph Noelle told BioWorld that the institute,for which he produced the antibodies, is in effect pursuing theflip side of the CD40 ligand: If curing the defect can restorehumoral (B-cell) antibody production, then exploiting theantibody to CD40 ligand might curb loose-cannon B-cells, whichover-produce IgM and presumably contribute to autoimmunediseases.

In mouse models of rheumatoid arthritis, multiple sclerosis andgraft-vs.-host disease, Noelle said, "the CD40 ligand antibodyinhibited disease progression."

Today's issue of Nature carries two other reports on thedefective CD40 ligand in Hyper-IgM disease patients; one fromGermany, the other from France.

A third, by Harvard Medical School pediatrics professor RaifGeha, director of immunology at Boston Childrens Hospital, willappear in the Proceedings of the National Academy of Sciences(PNAS) next month. Geha's report details other cases in whichHyper-IgM has been firmly attributed to mutationsHwhetherpoint, sequence deletion or frameshiftHthat disrupt the CD40ligand.

Geha told BioWorld that the next stage in dealing with thesyndrome at the molecular level should be to construct knock-out mice as a Hyper-IgM model of possible gene-therapies,"rather than going into humans right away."

Microbiologist Owen Witte, of UCLA's Howard Hughes MedicalInstitute, urges "cellular engineering to transfer genes intohematopoietic stem cells, and ligand-receptor pairs for treatingautoimmune diseases, if B-cell response is out of control."

Spriggs deems CD40 ligand "a good candidate for gene therapy,aiming to insert the gene into CD4+ helper T cells. She alsosuggests that with the use of flow cytometry, a simple prenatalor neonatal blood test to pinpoint mutated ligand moleculescould have the effect as well, of swelling the incidence statisticsupward from five-in-a-million (a figure Geha regards as"generous.") Moreover, she urges that female carriers be testedto determine their CD40 ligand expression.

She concludes: "Any molecule as potent as the CD40 ligandclearly is, is something whose commercial potential has yet tobe realized. It will certainly be worth watching for the nextyear or two."

-- David N. Leff Science Editor

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