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Why do some people never get the flu?

For nearly 20 years, Tatyana Golovkina has asked "Why are some people - and animals - able to fend off viruses, while others cannot?"

Golovkina a PhD, professor of microbiology, a geneticist and immunologist at the University of Chicago, has been working on that particularly thorny problem with mice from a strain who are especially good at this. They can control infection with retroviruses from very different viral families, producing antibodies to coat a specific virus and render it harmless.

Golovkina was interested in what makes these mice so good at this, so she began searching for genes responsible for their remarkable immune response. In a new study published this week in the journal Immunity, she and her colleagues identify the gene. They also began to uncover more clues on how it might work to control anti-virus immune responses in humans too.

Using a process called positional cloning, researchers narrowed down the location of the exact gene on a mouse chromosome finding it within the major histocompatibility complex (MHC) locus essential cell surface proteins the immune system uses to recognize foreign molecules. The MHC is well-known as the immunity region of the genome, so it makes sense that the gene was there. But it was a disconcerting discovery.
"It was a bummer at first because there are tons of genes within the MHC locus all controlling immune response, not only against viruses, but also against many other microbial pathogens and non-microbial disorders. Most of the time when people map a gene to the MHC they give up and stop, assuming the gene encodes for one of its two major molecules, MHC class I or and MHC class II."

Tatyana Golovkina PhD, Professor, Department of Microbiology, The University of Chicago, Chicago, Illinois, USA.

With the help of biochemist, Lisa Denzin from Rutgers University, and a computational biologist, Aly Khan from the Toyota Technological Institute at Chicago, Golovkina and her team were able to identify a gene called H2-Ob which enabled viral resistance. Together with another gene called H2-Oa, they make a molecule called H2-O in mice and HLA-DO in humans.

H2-O has been known for years as a negative regulator of MHC class II it shuts down immune responses. Most researchers thought it existed to prevent autoimmune responses from attacking a body's own tissues. However, none of the I/LnJ mice showed any signs of autoimmunity, so H2-O must have another purpose.

Golovkina and her team discovered that when they crossed I/LnJ mice resistant to infections with others more susceptible, the resulting F1 mice are susceptible to infection. This indicates the I/LnJ H2-Ob gene is recessive, so both parents had to have a copy of the mutated gene to be able to pass it on their offspring, and making the I/LnJ H2-Ob gene produce a non-functioning protein.

"That was really surprising," Golovkina adds. "Almost all pathogen-resistant mechanisms discovered so far are dominant, not recessive."
The immune system response to a virus in susceptible mice lasts three to four weeks then the H2-O molecule tells it to stop. But I/LnJ mice, which respond vigorously to infections, have a mutation on H2-Ob making it inactive. After they launch an immune response, that response never shuts off. This keeps persistent retroviruses in check.

Golovkina hypothesizes that letting the immune response continuously run may keep chronic infections in check, like retroviruses, or hepatitis B and C. Other pathogens like tuberculosis can take advantage of a persistent immune response, as they can access certain cells even when coated with antibodies. I/LnJ mice happen to be susceptible to TB and produce anti-TB antibodies.

At some point during the evolution of these genes, it was more advantageous to be able to switch off an immune response to some infections (such as intracellular bacterial pathogens), but that comes at the cost of not being able to fight other long-term infections.

Now that her team has identified the gene underlying anti-retrovirus and potentially anti-hepatitis B and C responses, Golovkina hopes to create genetic therapies that manipulate the function of the gene, or develop molecules that could interfere with the function of H2-O and allow for virus-specific responses in chronically infected people.

Until then, she'll continue working on this problem, just as she has for the past 20 years.

"I have a very persistent nature in the way I do research," she said. "If I sincerely believe there is a very interesting biological question, nothing will prevent me from uncovering it."


I/LnJ mice are resistant to retroviruses by producing virus-neutralizing antibodies

Resistance is conferred by mutant non-classical MHC class II molecule H2-O

Mutations in several alleles of human HLA-DOB affected antigen presentation

Wild-type H2-O and HLA-DO serve as negative regulators of anti-viral immunity

Select humans and animals control persistent viral infections via adaptive immune responses that include production of neutralizing antibodies. The precise genetic basis for the control remains enigmatic. Here, we report positional cloning of the gene responsible for production of retrovirus-neutralizing antibodies in mice of the I/LnJ strain. It encodes the beta subunit of the non-classical major histocompatibility complex class II (MHC-II)-like molecule H2-O, a negative regulator of antigen presentation. The recessive and functionally null I/LnJ H2-Ob allele supported the production of virus-neutralizing antibodies independently of the classical MHC haplotype. Subsequent bioinformatics and functional analyses of the human H2-Ob homolog, HLA-DOB, revealed both loss- and gain-of-function alleles, which could affect the ability of their carriers to control infections with human hepatitis B (HBV) and C (HCV) viruses. Thus, understanding of the previously unappreciated role of H2-O (HLA-DO) in immunity to infections may suggest new approaches in achieving neutralizing immunity to viruses.

Keywords: viral infections, neutralizing antibodies, MHC locus, HLA-DO, antigen presentation, positional cloning

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