Discovery Could Open Doors to Treatments for Lupus, Arthritis, Even HIV
Nov 16, 2004
Researchers at Weill Cornell Medical College believe they've uncovered a molecular switch that naturally suppresses the body's immune response in situations where it's not needed.
Drugs that mimic or oppose this mechanism might someday fight autoimmune disorders like lupus or rheumatoid arthritis, or protect immune cells from enemies like HIV.
"It has real implications for infectious diseases, where you want improved immunity, and also autoimmune diseases, where you don't want such a strong immune response. It works both ways," said lead researcher Dr. Xiaojing Ma, an Associate Professor in the Department of Microbiology and Immunology at Weill Cornell Medical College in New York City.
His team's findings are published in the Nov. 17 issue of Immunity.
When bacteria, viruses or other invaders threaten cells, compounds called pro-inflammatory cytokines produced by the infected cells send out chemical signals that alert immune T-cells to ready themselves for battle. T-cells are primed to recognize "the enemy" by the presence of specific molecules, called antigens.
However, scientists have long puzzled over the fact that, in some cases, T cells can remain dormant, even in the presence of these antigens.
"That's definitely what happens when the body's own cells die a natural death, through apoptosis – programmed cell death," Dr. Ma said.
When cells reach the end of their natural lifespan, immune white blood cells called macrophages act as the main disposal units, "eating up" dead or dying cells.
However, even though the macrophage releases antigens during this cleanup, T-cells keep quiet.
"That's a good thing, because you wouldn't want a big immune response in this case, triggering inflammatory symptoms such as aches and fever," Dr. Ma said.
In fact, runaway immune systems are the very heart of painful chronic conditions such as lupus, rheumatoid arthritis, and inflammatory bowel diseases like Crohn's. Scientists have been looking for decades for a way to short-circuit the immune response, as a means of easing these conditions.
In their investigation, Dr. Ma and his team looked closely at the activity of human and mouse macrophages using a variety of cellular and molecular tools.
They discovered that "even though the activated macrophage presents the proper antigens as it eats up dead or dying cells, one particular pro-inflammatory cytokine, called interleukin 12 (IL-12) is not produced," according to Dr. Ma.
IL-12 is a major factor that activates lymphocytes such as Natural Killer (NK) and T cells to fight off infection and eliminate cancerous cells. Without IL-12, the normal immune response is suppressed.
Digging deeper, the Weill Cornell team discovered that cell-to-cell contact between the macrophage and the dying cell activates a novel protein called GC-binding protein (GC-BP), "possibly through a specific receptor on the macrophage's surface," Dr. Ma said. GC-BP then undergoes a chemical change that allows it to enter into the nucleus of the macrophage.
Once there, the protein targets and switches off the gene responsible for IL-12 production.
The result: macrophage activity with suppressed immune response.
"We studied this in mouse and human cells, and it works the same way," Dr. Ma said. "We were the first to identify GC-BP, which appears to be a key player in this natural immune-suppression system."
The discovery opens intriguing new pathways to understanding and fighting immune disorders.
"In some cases of autoimmune disease, maybe this process breaks down," Dr. Ma speculated. "For instance, deficiencies in the 'clean-up' of dying cells have been linked to lupus for a long time. And IL-12 is so key to so many of these common immune disorders – if we could find out how to suppress or induce its expression, maybe we could find new treatments to fight diseases like lupus or rheumatoid arthritis."
The finding might even lead to treatments against diseases characterized by a severe weakening of the immune system, as happens during infection with HIV.
"One of the earliest events that take place when HIV enters the body by infecting macrophages is that IL-12 production is severely impaired. This has significant impact on the host's immune capacity. HIV subsequently infects T-cells and ultimately destroys them through a process similar to programmed cell death," Dr. Ma explained. "In that case, then, we'd look for a way to spark immune system activation, not suppression, perhaps by blocking GC-BP."
All of this is a long way off, he stressed, "but understanding the process is the first step."
"We believe that by understanding how the body controls the immune response, we can someday harness or mimic that process via drug therapy, to prevent or control disease."
Dr. Ma's co-researchers on this study include former Weill Cornell graduate student Dr. Sunjung Kim, now a postdoc at Columbia University; and Dr. Keith B. Elkon, Professor of Medicine and Immunology at the University of Washington, Seattle.