Investigating defects arising from a single gene alteration in real patients can give surprising insights into the resilience of the immune system. This is what happened when researchers in Australia studied people with a rare disease and found the reality was quite different to what they had been led to expect from animal studies.
Elissa Deenick and Stuart Tangye, from the Garvan Institute of Medical Research in Sydney, and colleagues, write about their immune system study involving patients with Autosomal Dominant Hyper IgE Syndrome in a paper published in the July 8th online issue of Journal of Allergy and Clinical Immunology.
Some cases of Autosomal Dominant Hyper IgE Syndrome (Hyper IgE), once known as Job syndrome, arise from just one change in the STAT3 gene. The mutation affects several systems of the body, including the immune system where it causes abnormally high levels of a protein called immunoglobulin E (IgE) in the blood.
People with Hyper IgE are slightly more susceptible to blood cancers known as "lymphomas", and they may also suffer recurrent infections such as skin infections and pneumonia, plus eczema, and occasionally bone and tooth abnormalities.
But while many of the symptoms of Hyper IgE can be very distressing and problematic, there are much fewer of them than lab models and studies on animals predict. These suggest that the immune system of such patients should be far more vulnerable to viruses and cancer than is actually the case.
When scientists examine how alterations in genes lead to disease, one of the things they look at is the effect of that gene change on the biochemical signals that control how cells behave.
In the case of the STAT3 gene, this affects signals in the immune system's "killer T cells" that destroy invading microbes and cancer cells.
When they tested immune cells from patients with Hyper IgE, the team was expecting to see what studies using mouse models suggested: that their immune systems would be considerably impaired.
Surprisingly good immune systems in people with Hyper IgE condition
But to their surprise they found immune systems of patients with Hyper IgE performed remarkably better than anticipated: it was as though something was compensating, in part at least, for lack of signals essential for killer T cells to do their job in killing viruses and cancer cells.
Is there a sort of backup pathway through which some of the signals can reroute?
"Under normal circumstances, the STAT3 molecule passes biochemical signals in T cells which instruct them to turn on their killing machinery. In Hyper IgE patients, who lack the gene, the signal just appears to take a diversion most of the time, and that seems to work," Deenick says in a statement.
"There are certain molecules that killer T cells need in order to become effective - and possibly in the case of a very few viruses and lymphomas - Hyper IgE patients are unable to generate the signals necessary to make these molecules. However they do make effective responses against most viruses and cancers," she explains.
The researchers conclude that while the "STAT3 pathway is required for many aspects" of killer T cell activity, in some cases it "can be compensated by other signals", and this helps explains the "relatively mild susceptibility to viral disease" in Hyper IgE patients.
Tangye points out that in research it is "just as useful to find an explanation for a prediction that didn't happen as it is to have a prediction confirmed".
He says the findings are important because they show that sometimes working with mouse models produces quite different results to what happens in real human diseases.
This study helps us understand why people with Hyper IgE are not as "super unwell" as one might expect, says Tangye. Such insights are valuable because they help address the actual clinical symptoms, he adds.
This is not the first study involving patients with Hyper IgE to show how mouse models can underestimate the role of signals in the human immune system. In 2006, a team in Japan showed how cells from patients showed severe defects in cytokine pathways that were in stark contrast to earlier studies using mouse models.