By David N. Leff

In baseball, if the pitcher throws a curve past the batter and the catcher fumbles it, a runner on base gets the chance he's been waiting for. And in football, a wide receiver had better not miss the forward pass hurtling his way. In both sports, it's not just the ball in motion, but the inter-player signaling that guides its trajectory.

So it is in cell biology. A protein, no matter how potent or specific, is lost without its receptor.

A stark clinical example of what can happen when a receptor goes wrong or missing is the case of a 19-year-old Dutch woman seen at the Leiden University Medical Center. At the ages of four, 13 and 17, she had recurrent systemic infections with Mycobacterium avium intracellulare. This pathogen is a less-virulent cousin of M. tuberculosis, the perpetrator of tuberculosis.

But that's not all. At ages four, seven and 14, this same patient came down with severe bouts of non-typhoid Salmonella infection.

Two other Leiden patients, a 26-year-old woman and a 3-year-old child, had strangely similar immunodeficiency infections. So did four children admitted to hospitals in France and studied by pediatric immunologist Jean-Laurent Casanova at INSERM — the French National Institute of Health and Medical Research — in Paris.

Casanova is senior author of two papers in the current issue of Science, dated May 29, 1998. One bears the title: "Impairment of mycobacterial immunity in human interleukin-12 receptor deficiency."

The second — of which Leiden immunologist Tom Ottenhoff is co-senior author — is titled: "Severe mycobacterial and Salmonella infections in interleukin-12 receptor-deficient patients."

"Based on data from knockout mice," Casanova told BioWorld Today, "we knew that interleukin-12 [IL-12] was essential for optimal production of interferon-gamma [INF-gamma].

"And because the human phenotype of mycobacterial infection, as shown in a number of families we studied, is due to mutations in the INF-gamma receptor, we thought that IL-12 or its receptor could be good candidate genes to incriminate in the etiology of this syndrome."

As reported in Science, Casanova and his co-authors screened the families of children with the rare idiopathic disseminated mycobacterial infection (IDMI), and found mutations in the IL-12 receptor at both the cDNA and gene levels. "Then," he recounted, "we looked at the protein, and the functional and immunological consequences of the mutation."

French, Dutch Met In Middle

In Leiden, Ottenhoff took the opposite approach. His team looked first at the expression and function of the receptor. "Once they had some indication that there could be a defect in IL-12 receptor signaling," Casanova continued, "they collaborated with us. And we did the genetics, and identified mutations, in their patients as well."

The IDMI syndrome is a rare inherited disease, but with broad implications.

Only one country, France, has conducted a thorough epidemiological survey. "We found the incidence to be," Casanova said, "0.6 cases per million births, determined retrospectively from 1974 to 1994."

But he considers that figure a low estimate. "It's our impression," he added, "that the incidence is high in some countries or ethnic groups, around 10 per million; in others, low; 0.1 per million."

The clinical features of the syndrome were described in the 1950s, Casanova continued, "and there have been at least 100 cases reported in the literature from those years until we reported the first gene mutation in 1996. "The two present Science papers report the second gene as a molecular variant of IL-12's receptor. (The first was for the IFN-gamma receptor, which he reported in 1996.)

"There are two modes of entry into the disease," Casanova explained. "One is recurrent or disseminated disease after BCG vaccination against tuberculosis. This is not current practice in the U.S., but BCG is the most widely distributed vaccination in the world. Some 85 to 90 percent of children worldwide are vaccinated with it.

"BCG is a live attenuated vaccine of Mycobacterium bovis," Casanova went on, "and two to four months after vaccination, children with this syndrome develop inflamed lymph nodes. Then, depending on the severity of the genetic defect, they tend to have localized but recurrent BCG infection. But when it's severe — as in the case of complete deficiency of the INF-gamma receptor — then the children have disseminated disease due to BCG, which infects liver, spleen, lungs, bones — basically all organs."

Mutated Receptor Life-Threatening

The second mode of entry that Casanova described "is atypical mycobacteriosis. This is infection with so-called nontypical mycobacteria, which can be either localized but recurrent, such as pneumonia due to M. avium — or whatever.

"The overall prognosis of the syndrome, irrespective of the gene mutation," Casanova pointed out, "is 50 percent mortality after the first episode of infection. Children with complete defect of the INF-gamma receptor have the worst prognosis, and thus far all such children have died.

"We are now in the process of talking about bone marrow transplantation for these patients, because interferon-gamma cannot work in the absence of receptors.

"For IL-12 receptor deficiency, the children have a milder phenotype. Usually anti-mycobacterials help them. And INF-gamma has a very powerful therapeutic effect, so they tend to heal with this medication."

The French pediatric immunologist pointed out, "This is one of the reasons why we have undertaken to work on such a rare disease. It's because we think this is a way to identify mycobacterial susceptibility genes, genes which potentially play a role in vulnerability to very common diseases, such as TB and leprosy.

"Not everybody gets TB," he added. "Only one in ten people infected with M. tuberculosis develops clinical disease. It is most likely due to genetic factors, so our intention now is to understand the inherited susceptibility to TB."

He and his co-authors have not patented their interferon-gamma and IL-12 receptor genes, "because we are basically pediatricians, and we have had very little contact with biotechnlogy.

"But what we know now is that there are at least two genes underlying this syndrome, and we have preliminary evidence that there are other mycobacterial susceptibility genes yet to be identified.

"So we would be very keen," Casanova concluded, "to find a partner in the biotechnology world willing to help us extend our research into TB susceptibility, into patenting mutations in genes, etcetera. We simply need a partner." *