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Long-Standing Puzzle Of Immune System Is Solved By UCSF Researchers

University of California - San Francisco

Researchers at the University of California San Francisco have solved a decades-long scientific puzzle about how the body's immune system works to combat illness.

In a study also having implications for better understanding cancer, the researchers found that the immune system is able to target virtually any unwanted microscopic invader within the body by subverting the function of an enzyme that normally is used to repair mistakes -- called mutations -- in the genetic material, DNA.

Immunology researchers have long suspected that immune cells take advantage of mutations that arise in genes to generate greater diversity in the genes that encode antibodies, proteins that mark disease agents for destruction. This diversity provides the immune system with a better selection from which to choose the best weapons for fighting disease.

Immunologists previously unearthed evidence indicating that immune cells can even activate mechanisms for producing additional mutations, a process dubbed hypermutation. But until now, none of the key molecular players used by immune cells to generate these mutations had been identified.

The study, co-authored by Mattias Wabl, PhD, professor of microbiology and immunology at UCSF and his laboratory team, is reported in the February 20 issue of Science.

"While mutations are, in general, harmful and unwanted, there is an important exception," Wabl explains. "B cells of the immune system depend on mutations in order to be ready to defend the body against newly arising pathogenic microorganisms.

"Without hypermutation at the immunoglobulin genes, which encode antibodies, we would likely have succumbed to an Andromeda strain long ago," Wabl says, referring to a popular science fiction thriller starring a newly arising microscopic scourge that threatens human life on Earth.

The cellular agent identified by the UCSF researchers as the one used by B cells of the immune system to introduce new mutations into genes encoding antibodies was never suspected to play such an active role, they say.

While some researchers previously had suggested that repair enzymes may be disabled in B cells, none had suggested that repair enzymes might actually be contributing to the generation of mutations in the family of genes affected, called immunoglobulins.

In B cells, which rapidly divide in response to disease threats, mistakes in newly replicated DNA strands are preserved by the repair enzyme Pms2. In other cells of the body these mutations normally would be corrected by Pms2 and other DNA-repair enzymes.

In studies of mice, Marilia Cascalho, a graduate student with Wabl's laboratory, found that the disruption of the gene that encodes Pms2 resulted in a dramatic decrease in hypermutation.

Pms2 also has been discovered to be abnormal in certain forms of human cancer. This finding has led some cancer researchers to suspect that a defect in the gene encoding the repair enzyme resulted in a failure to repair harmful mutations, thereby contributing to the growth of these tumors.

However the UCSF researchers suggest that Pms2 may still be active in these tumors, but that its function may be altered so that, similar to the way it operates in B cells, the enzyme may perpetuate mutations instead of correcting them. Wabl and co-author Charles Steinberg, PhD, point out that cancer researchers conducting experiments on "knockout" mice lacking Pms2 found that rates of tumor formation are similar to normal mice. To contribute to cancer, Pms2 may need to be active but altered, they propose.

"Many human tumors have been reported to exhibit high mutation rates," Wabl says. "We hope that a complete elucidation of hypermutation in B cells will provide clues as to how to better treat such tumors."

Antibodies were discovered a century ago, and since the 1930s many immunologists believed that they targeted disease agents by adapting their shapes to engage the microscopic invaders. But by the 1960s it became clear that, rather than germs, it is the DNA in genes that determines the shapes of proteins, including antibodies, and researchers set out to explain how a large but limited number of genes could nonetheless give rise to a seemingly infinite variety of antibodies.

Researchers discovered that bits and pieces of immunoglobulin genes can rearrange themselves in myriad permutations to potentially generate 4 million different antibody proteins. B cells that produce the antibodies that best target invading pathogens are selected for replication. In a sense, these B cells clone themselves. The generation of mutations results in additional antibody diversity and serves to refine this clonal selection over time, Wabl, Steinberg and most other geneticists who study immunology now believe.

In the mouse study reported in Science, Cascalho, assisted by research associate Jamie Wong, compared mutation rates in immunoglobulin genes in B cells and other cells containing zero, one or two copies of normal Pms2 genes. She determined that immunoglobulin genes were mutated at a much higher rate in mice with B cells containing Pms2 compared to mice lacking the gene, suggesting that Pms2 somehow acts differently to play an active role in hypermutation of these genes in B cells.

Prior to cell division, when a cell duplicates its genetic material, the double-stranded DNA helix unzips and each strand serves as a template for making new DNA. Sometimes the template is misread and the wrong building block is inserted into the new strand. DNA-repair enzymes then step in to repair the damage before it becomes fixed.

When DNA-repair enzymes detect a mismatch, they use several clues to distinguish the old, correct DNA strand from the new, incorrect DNA strand, so that the mismatch is resolved to eliminate the potential mutation.

"The so-called immunoglobulin-mutator system in B cells seems to fool the DNA-repair system into confusing the old, correct DNA strand with the new, incorrect DNA strand, so that the mismatch is resolved by fixing the mutation in place instead of eliminating it," Steinberg says.

The National Institutes of Health and the Arthritis Foundation were the major funders of the study.


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