A Balanced Response
A news release from Brown University entitled Research Reveals Inner Workings of Immune System “Thermostat” cites research indicating how the immune system is regulated so as to enable it to fight pathogens while at the same time ensuring that inflammatory side effects do not injure the host. A related paper was published in the 'Journal of Immunology.' An italicized portion of the news release follows. My comments are in standard print.
PROVIDENCE, R.I. — When bacteria, viruses or parasites attack, immune system cells unleash the soldiers. These “hot” protein compounds kill invaders – but also trigger inflammation, which, if unchecked, can destroy tissue, induce shock and kill the host. So immune system cells let loose another protein compound to cool down the immune response.
Precisely how this immune system “thermostat” operates is unclear. The leading hypothesis is that these compounds – which act as furnace and air conditioner – battle it out over control of the system’s inflammatory response.
But new research, led by George Yap of Brown University, shows that these cytokines don’t operate independently and in opposition. They operate in harmony and are controlled by the same master. In work published in the Journal of Immunology, Yap and his team show that the “cool” anti-inflammatory protein compound known as Interleukin 10 is activated by Interferon-γ, a class of proteins secreted by a class of white blood cells known as T helper 1 cells. The team then traced secretion of Interferon-γ indirectly to tyrosine kinase 2, or tyk2, the same protein that signals “hot” inflammatory cytokines Interleukin 12 and Interferon-α and Interferon-β.
“Under the prevailing paradigm, scientists believe that the pro- and anti-inflammatory arms of the immune system just antagonize each other,” Yap said. “Here we show that they actually induce each other. ‘Hot’ cytokines don’t inhibit ‘cool’ ones – they trigger their production. Wounding, in effect, triggers a healing process.”
In previous research, Yap discovered that mutant mice with a naturally defective tyk2 gene were immune to arthritis, a condition caused by inflammation. But these mutants were much more susceptible to opportunistic infections. Why? Without tyk2, Yap found, mice didn’t make enough of the pro-inflammatory warriors that destroy harmful bugs and cause inflammation. This finding established the notion that tyk2 signaling controlled Interleukin 12, the furnace side of the system. But what controlled Interleukin 10, the air conditioner?
To find out, Yap and his team conducted a series of experiments in mutant mice infected with the parasite Toxoplasma gondii. They found that Interleukin 10 production by T helper 1 cells is triggered by Interferon-γbut not directly. Another cell, an antigen presenting cell or APC, sends a stimulatory signal back to the T helper 1 cell, ordering it to make Interleukin 10.
“What we see is that the ‘hot’ and ‘cool’ arms of the immune system aren’t independently regulated,” Yap said. “They talk to each other and respond in a dynamic and coordinated fashion.”
As expected, signals were found to regulate the functions studied. However researchers discovered that in this biochemical interaction the two distinct, but cooperative, functions are harmoniously regulated. Immunological killer proteins and anti-inflammatory proteins are both triggered by common signaling protein tyrosine kinase 2.
Yap said the findings should send a message to drug companies designing and testing tyk2-inhibiting medicines for arthritis and other autoimmune diseases. Block tyk2 function, Yap said, and patients will be more prone to infection – and their arthritis may not be relieved. “There could be a downside to these drugs,” he said.
Incomplete knowledge, coupled with an erroneous assumption, can be dangerous. If it were only known that tyrosine kinase 2 triggers the attack response it could be tempting to treat inflammation problems by inhibiting the secretion of tyrosine kinase 2. This study shows how self-defeating that approach would have been.
PROVIDENCE, R.I. — When bacteria, viruses or parasites attack, immune system cells unleash the soldiers. These “hot” protein compounds kill invaders – but also trigger inflammation, which, if unchecked, can destroy tissue, induce shock and kill the host. So immune system cells let loose another protein compound to cool down the immune response.
Precisely how this immune system “thermostat” operates is unclear. The leading hypothesis is that these compounds – which act as furnace and air conditioner – battle it out over control of the system’s inflammatory response.
But new research, led by George Yap of Brown University, shows that these cytokines don’t operate independently and in opposition. They operate in harmony and are controlled by the same master. In work published in the Journal of Immunology, Yap and his team show that the “cool” anti-inflammatory protein compound known as Interleukin 10 is activated by Interferon-γ, a class of proteins secreted by a class of white blood cells known as T helper 1 cells. The team then traced secretion of Interferon-γ indirectly to tyrosine kinase 2, or tyk2, the same protein that signals “hot” inflammatory cytokines Interleukin 12 and Interferon-α and Interferon-β.
“Under the prevailing paradigm, scientists believe that the pro- and anti-inflammatory arms of the immune system just antagonize each other,” Yap said. “Here we show that they actually induce each other. ‘Hot’ cytokines don’t inhibit ‘cool’ ones – they trigger their production. Wounding, in effect, triggers a healing process.”
In previous research, Yap discovered that mutant mice with a naturally defective tyk2 gene were immune to arthritis, a condition caused by inflammation. But these mutants were much more susceptible to opportunistic infections. Why? Without tyk2, Yap found, mice didn’t make enough of the pro-inflammatory warriors that destroy harmful bugs and cause inflammation. This finding established the notion that tyk2 signaling controlled Interleukin 12, the furnace side of the system. But what controlled Interleukin 10, the air conditioner?
To find out, Yap and his team conducted a series of experiments in mutant mice infected with the parasite Toxoplasma gondii. They found that Interleukin 10 production by T helper 1 cells is triggered by Interferon-γbut not directly. Another cell, an antigen presenting cell or APC, sends a stimulatory signal back to the T helper 1 cell, ordering it to make Interleukin 10.
“What we see is that the ‘hot’ and ‘cool’ arms of the immune system aren’t independently regulated,” Yap said. “They talk to each other and respond in a dynamic and coordinated fashion.”
As expected, signals were found to regulate the functions studied. However researchers discovered that in this biochemical interaction the two distinct, but cooperative, functions are harmoniously regulated. Immunological killer proteins and anti-inflammatory proteins are both triggered by common signaling protein tyrosine kinase 2.
Yap said the findings should send a message to drug companies designing and testing tyk2-inhibiting medicines for arthritis and other autoimmune diseases. Block tyk2 function, Yap said, and patients will be more prone to infection – and their arthritis may not be relieved. “There could be a downside to these drugs,” he said.
Incomplete knowledge, coupled with an erroneous assumption, can be dangerous. If it were only known that tyrosine kinase 2 triggers the attack response it could be tempting to treat inflammation problems by inhibiting the secretion of tyrosine kinase 2. This study shows how self-defeating that approach would have been.
posted by Paul at 9:16 PM
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