Thursday, February 26, 2009

More B cell news

B cells as targets for asthma as well as autoimmune? Turning off select B cell clones and turning off allergy? or autoimmune disease? All is becoming possible. Rituxan is good first step in B cell depletion, but much better is coming. Read below.

Contact: Tom Rickey
University of Rochester Medical Center
A worm-and-mouse tale: B cells deserve more respect

By studying how mice fight off infection by intestinal worms – a condition that affects more than 1 billion people worldwide – scientists have discovered that the immune system is more versatile than has long been thought. The work with worms is opening a new avenue of exploration in the search for treatments against autoimmune diseases like diabetes and asthma, where the body mistakenly attacks its own tissues.

The findings, reported by scientists who performed the work at the Trudeau Institute in Saranac Lake, N.Y., and who are now at the University of Rochester Medical Center, appear in the March issue of the journal Immunity. The article was published online Feb. 26.

The research focuses mainly on B cells, one of many types of immune cells that the body maintains to fight off invaders like bacteria, viruses, and parasites. Besides B cells, there are T cells, macrophages, neutrophils, monocytes, mast cells and others, all working in concert to keep an organism healthy. The cells cruise our bodies, looking to eliminate infectious threats before they become a serious risk to our health.

For many years, scientists believed that the major job of B cells was to identify foreign invaders and tag them with antibodies, marking the microbe for destruction by the immune system. But scientists are discovering that B cells do much more, resulting in new information about our immune system that could be useful for developing more effective vaccines and better treatments for many types of disease.

In the past few years, Frances Lund, Ph.D., professor of Medicine in the Division of Allergy/Immunology and Rheumatology at the University of Rochester Medical Center, has found an array of unexpected functions for B cells. In the laboratory, she has found that B cells produce chemical signaling molecules known as cytokines that spur other immune cells in the body to action. Her team has also shown that B cells are crucial for presenting to T cells snippets of proteins from invaders, so that the T cells can recognize the invader, a crucial step that allows T cells to mature into useful cells which can then fight an infection efficiently.

In the new paper, Lund's team tested how the findings actually translate by watching closely as an organism – in this case, a mouse – actually fights off infection by a parasite. They chose to study the intestinal parasite Heligmosomoides polygyrus, a bright red worm about one-third of an inch long that infects mice.

It's a cousin of the scores of worms that infect more than 1 billion people worldwide. Roundworms, hookworms, pinworms, and others – these and other worms cause fatigue, diarrhea, nausea, and death.

"Nematodes – worms – sicken a lot of people, they can cause severe malnutrition, and they play havoc with the immune system, making many people more vulnerable to other threats, such as malaria," said Lund, whose project was funded by the National Institute of Allergy and Infectious Diseases.

The team not only verified the additional actions of B cells that they've discovered in the laboratory, but, importantly, they showed that these functions are crucial for the organism to fight off infection.

Lund's team showed that the chemical messengers produced by B cells, such as interleukin-2 and tumor necrosis factor, are necessary for the immune system to protect mice against Heligmosomoides polygyrus. The team also showed that B cells must be present in order for T cells to mature and operate properly.

"It's long been dogma that B cells need the help of T cells to make antibody. That's in all the textbooks," said Lund. "Now work from our laboratory and others shows that it's a two-way street, that T cells need the help of B cells also."

B cells' effects on T cells may open a new window on such diseases as lupus, asthma, multiple sclerosis, and diabetes, where doctors know that T cells are active. Maybe manipulating B cells offers a new way to affect the activity and survival of the T cells that cause disease.

The work also brings up the possibility of more targeted treatments than current treatments, which generally affect all B cells. Lund has found that different B cells produce different collections of chemical signaling molecules. Someday, instead of having a drug that simply targets all B cells, it may be possible to target a specific type of cell, cutting down side effects and making a treatment more effective.

"It may be that only certain B cells play a role in damaging immune responses. If we can narrow down the group of cells at the root of the problem, we may be able to find important new targets for improving treatment," said Lund.

The paper is dedicated in memory of author Frank Sprague, who was a technical associate at Trudeau and performed many of the experiments.

The first authors of the paper, who share equal credit, are post-doctoral associate Wojciech Wojciechowski, now at Rochester, and former post-doctoral associate David P. Harris, now with Lexicon Genetics. Other authors in addition to Sprague include technicians Betty Mousseau and Kim Kusser, now at Rochester; former technician Melissa Makris; Markus Mohrs and Katja Mohrs of Trudeau; Tasuko Honjo of Kyoto University; and Troy Randall, Ph.D., professor of Medicine at the University of Rochester Medical Center.

Most of the research described in the paper was done by Lund's group at the Trudeau Institute, before the group moved to Rochester last summer.

Contact: Cathleen Genova
Cell Press
Busy Bs: Lymphocyte uses multiple mechanisms to shape immune response

New research expands our understanding of how a type of immune cell called a B lymphocyte enables the immune system to mount a successful defense against an intestinal parasite. The study, published by Cell Press online in the journal Immunity on 26 February, provides some intriguing insight into the variety of mechanisms implemented by B cells to protect the host from infection.

B cells are critical cells of the immune system that produce antibodies (Abs) to help rid the body of harmful pathogens. This type of immunity, called "humoral immunity", is complemented by "cellular immunity" which is mediated by T lymphocytes. Research has shown that B cells do not just produce Abs but can regulate the immune response in many other ways as well. B cells produce critical regulatory chemicals called cytokines and there is some evidence that B cells may amplify T cell dependent immune responses.

An earlier study by Dr. Frances E. Lund from the Department of Medicine at the University of Rochester indicated that specific types of B cells may promote the maturation of T cells. To gain insight into the mechanisms used by B cells, Dr. Lund and colleagues performed a series of experiments to examine whether cytokine-producing B cells are required for protection against the intestinal parasite, Heligmosomoides polygyrus (Hp).

The researchers found that B cells were required for protection against Hp and that B cells mediate protection, in part, by producing Abs. In addition, B cells promoted the production and long-term maintenance of an essential type of T cell, called T helper 2 cells (Th2), which are known to be critical for protection from Hp. Importantly, the influence of B cells on the Th2 cells was independent of antibody production.

The researchers went on to show that B cell-derived cytokines interleukin-2 and tumor necrosis factor ? were required both for effective Ab and for Th2 cell responses to Hp. Therefore, in addition to Ab production, B cells also make a critical contribution to the immune response to this pathogen by regulating T cells.

"Our findings fill an important gap as they show for the first time that multiple cytokines made by B cells regulate both humoral and cellular protective immune responses to infectious organisms," says Dr. Lund. "In addition to protective effects, we also suggest that cytokine-producing B cells may play a role in damaging immune responses, such as reactions to allergens and autoantigens. Therefore, B cell subsets may represent future targets for many types of therapeutics to treat allergy, asthma and autoimmunity."

The researchers include Wojciech Wojciechowski, Trudeau Institute Inc., Saranac Lake, NY, University of Rochester, Rochester NY; David P. Harris, Trudeau Institute Inc., Saranac Lake, NY, Lexicon Genetics, The Woodlands, TX; Frank Sprague, Trudeau Institute Inc., Saranac Lake, NY, Betty Mousseau, Trudeau Institute Inc., Saranac Lake, NY, University of Rochester, Rochester NY, Melissa Makris, Trudeau Institute Inc., Saranac Lake, NY, Kim Kusser, Trudeau Institute Inc., Saranac Lake, NY, University of Rochester, Rochester NY, Tasuko Honjo, Kyoto University, Yoshida-Konoe, Sakyo-Ku, Kyoto, Japan, Katja Mohrs, Trudeau Institute Inc., Saranac Lake, NY, Markus Mohrs, Trudeau Institute Inc., Saranac Lake, NY, Troy Randall, University of Rochester, Rochester NY, and Frances E. Lund, Trudeau Institute Inc., Saranac Lake, NY, University of Rochester, Rochester NY.

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