Nobelists Showed How Immune Defenses Work And Go Awry

Oct 3, 2011

Working with grasshoppers, fruit flies, mice and human cells, the three scientists who won this year's Nobel Prize in Physiology or Medicine opened important windows on how all these creatures defend themselves against microbial invaders and refrain from attacking their own cells – except when they don't.

It's intricate and complicated stuff, but the two main concepts you need to know are: innate immunity and adaptive immunity.

American Bruce Beutler and Frenchman Jules Hoffman made landmark discoveries in innate immunity — the fast, first-line defense against an invading bacterium or virus.

Canadian Ralph Steinman made his mark by discovering some of the key mechanisms in adaptive immunity. It's how organisms process invading microbes and kick off a cascade of immune responses that not only targets the bad guys but also retain an immunologic memory that can get activated when they try again. The immune cell he discovered and elucidated, called a dendritic cell, is also involved in silencing the immune system so it doesn't turn on the organism it's supposed to defend.

The three followed very different paths to today's convergence in their shared Nobel. (The three will split the $1.5 million prize money.)

Bruce Beutler is now at the Scripps Research Institute in California but will soon take a position at the University of Texas Southwestern Medical Center in Dallas. His father was a distinguished physician-scientist who fled Nazi Germany. His mother was born in America to Ukrainian immigrants; she was a technical writer and homemaker.

The Beutler household had high academic standard. Two of Bruce Beutler's siblings also became physicians while a fourth sibling is a successful software designer.

"From the age of 7 or so, I wanted to be a biologist, and nothing else," Beutler writes in an autobiography last month for his acceptance of the Shaw Prize, a 9-year-old award established by a Hong Kong businessman.

He graduated from the University of California, San Diego at the age of 18.

Beutler's most important discoveries were made between 1984 and 1998 when he was at the Rockefeller University in New York City and UT Southwestern. Working with mice, he discovered a molecule called tumor necrosis factor, or TNF. It's important in initiating an inflammatory response, and also devised molecules that inhibits it – advances that have relevance for a wide spectrum of infections and auto-immune diseases.

Beutler also discovered a receptor on mammals' cells that recognizes a molecule on many microbial cells called LPS (lipopolysaccharide). When mammalian cells detect LPS, they mount a strenuous defense – one of the first steps in so-called innate immunity. The LPS receptor is also involved in inflammatory diseases.

Jules Hoffman, a scientist in Strasbourg, France, made his contributions to innate immunity by studying grasshoppers and fruit flies. His father was a high school biology teacher and an ardent insect collector. When Hoffman began his career, almost nothing was known about how insects defended themselves against infection.

His work established that the immune systems of insects and mammals — including humans — share many common mechanisms, especially in the way they respond initially to microbial attack.

Canadian Ralph Steinman received his undergraduate degree at McGill University in Montreal but took his medical training at Harvard and has done most of his important work at Rockefeller.

Steinman's focus on the dendritic cell has shown how these immune sentries capture invading bacteria and viruses and disarm them. Then these dendritic cells display pieces of these captured invaders on their own surface – as if to say "Attack this!"

That touches off a complicated immune response exquisitely adapted to those particular invaders – thus the term "adaptive immunity."

Steinman has also shown that dendritic cells, while they're not dealing with infections, capture "self" cells and environmental proteins as part of a lifelong process of discriminating between dangerous and harmless. Understanding why this system goes awry is key to understanding autoimmune disorders such as diabetes, arthritis, lupus and multiple sclerosis.

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