Discovering new molecular switches to control autoinflammatory disease

Photo of Thirumala-Devi Kanneganti, PhD, in her lab

Recent work from the lab of Thirumala-Devi Kanneganti, PhD, involves identifying and understanding the body’s immune system.

The immune system is a marvelous biological machine that protects us against bacteria, viruses and other invaders. It is constantly vigilant, able to exquisitely sense infection and marshal multiple weapons to battle microbes.

But sometimes the innate immune system loses its control, triggering an inflammatory response that can be dangerous — even lethal. In such “autoinflammatory” disorders, the immune system attacks the body’s own tissues.

The sad reality is that we have no drugs that can precisely switch off a particular malfunctioning immune circuit responsible for a specific autoinflammatory disease. The only recourse clinicians have is drugs that shut down the entire immune system, leaving patients vulnerable to infection.

For more than a decade, my research team has done pioneering explorations of the function of a master immune switch called IL-1 alpha. It is produced by different immune and non-immune cells, and it is a key inflammatory promoter, as well as a trigger of fever and sepsis, a potentially lethal overreaction to infection.

In our latest work, published in the journal Immunity, we probed the unknown “black box” of immune machinery that links IL-1 alpha with a controlling gene called Ptpn6. It was known that abnormalities in Ptpn6 were responsible for the inflammation in such diseases as pyoderma gangrenosum, multiple sclerosis, leukemia and psoriatic arthritis.

Photo of Thirumala-Devi Kanneganti

Thirumala-Devi Kanneganti, PhD, Vice-Chair of the Immunology Department, investigating the role of Ptpn6 in the immune system.

Our challenge was incredibly difficult because we couldn’t just shut down the Ptpn6 gene to trace the effect on the immune circuitry. Mice lacking a functioning Ptpn6 gene do not survive. Fortunately, we could use a strain of mice in which the gene was “dialed down.” Mice with such a gene appear normal when born, but later develop an inflammatory skin disorder similar to neutrophilic dermatosis in humans. In humans, the various forms of this disorder include Sweet’s syndrome, pyoderma gangrenosum and subcorneal pustular dermatosis. The inflammation may also accompany cancers such as leukemia, as well as infections and inflammatory bowel disease.

We had a great many molecular candidates for biological switches in the immune machinery linking IL-1 alpha and Ptpn6. So our strategy was to cross our “dialed-down” mice with other animals genetically deficient in one of these switches. If the resulting cross-bred mice did not develop the disease, we knew that particular switch was part of the biological control circuitry.

It was a prodigious effort. We created some 50 combination mice with deficiencies in different candidate genes. But it paid off because we identified myriad switches and mapped how they all connected to form the control machinery by which Ptpn6 regulated IL-1 alpha. These switches have an alphabet of names: RIPK1, TNF, TAK1 and SYK.

In our studies, we also discovered new information about the “geography” of this immune machinery—that is, where in the body the components operate. While the abnormal Ptpn6 gene operates in the bone marrow, where many disease-instigating immune cells are produced, the IL-1 alpha master switch functions in the skin. This means that cross-talk between the different cell compartments is critical to the disease. This finding gives us not only insights into autoinflammatory diseases, but also into the basic structure of the immune system itself.

Particularly important, now that we have identified these switches that can be shut down to prevent these autoinflammatory disorders, we can begin searching for drugs that precisely target them. These drugs would leave the rest of the immune system fully operational to battle disease.

So this black box has now turned out to be a treasure chest.

About the author

Thirumala-Devi Kanneganti, PhD, is a faculty member and vice-chair of the Immunology Department, and a Rose Marie Thomas Endowed Chair at St. Jude Children’s Research Hospital. View bio.

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