|Scientists Learn the Origin of Rogue B
Doctors have long wondered why, in some people, the immune system
turns against parts of the body it is designed to protect, leading
to autoimmune disease. Now, researchers at the National Institutes
of Health’s (NIH) National Institute of Arthritis and Musculoskeletal
and Skin Diseases (NIAMS), in collaboration with the Oklahoma Medical
Research Foundation, have provided some new clues into one likely
factor: the early development of immune system cells called B cells.
B cells are formed in the bone marrow and produce antibodies.
Antibodies are generated from the cutting and splicing of immunoglobulin
genes early in B-cell development, and have the potential to develop
strong and highly specific affinity for different pathogens. When
an infectious pathogen (a disease-causing agent) enters the body,
B cells are activated and release antibodies into the bloodstream
to combat the pathogen. When antibodies encounter the pathogen,
they bind to it, rendering it incapable of causing further harm.
Antibody molecules also serve as receptors on the surface of B
The problem occurs when the random cutting and splicing of immunoglobulin
genes results in an antibody that recognizes a component of one’s
own body. While the body has a built-in mechanism to correct these
errant cells, the NIAMS researchers discovered this doesn’t always
work the way it was intended. “What happens is that, if the body
ever produces a cell with a self-reactive antibody molecule, that
cell will get arrested in development at the point where it is
actually combining and creating an antibody receptor,” says Rafael
Casellas, Ph.D., an investigator in NIAMS’s Genomic Integrity and
Immunity Group. Often, rather than killing off the cell, the body
edits — or corrects — the receptor, like one might
edit a paper, he says. In normal circumstances, this new, good
receptor replaces the bad one, but what Casellas and Dr. Patrick
C. Wilson of the Oklahoma Medical Research Foundation found was
that about 10 percent of the body’s B cells retain both receptors:
a good, useful one and the faulty self-reactive one that the good
receptor was designed to replace. This means that the aberrant
B cells have escaped the body’s mechanism to correct them. “Our
research goes against the theory that B cells should only express
a single receptor,” says Casellas.
Using a technique in which they inserted a piece of human gene
into the cells of laboratory mice, the researchers created a model
for visualizing the process in live animals. “Most of what scientists
do is to create systems to visualize complex phenomena, then to
allow nature to give you the answers to your questions,” says Casellas.
Their new findings raise the question of how this knowledge might
eventually help people with autoimmune disease. That question,
says Casellas, is one that will take time to answer. “This is only
one step,” he says. “We all carry these cells around, but not all
of us develop autoimmunity. Our work provides one explanation for
the origin of these self-reactive B cells.”
“If you understood the system extremely well and were able to
delete the editing cells during development, for instance, then
you would only have lymphocytes that don’t express self-receptors
at all,” he says.
For now, the step forward to understand where these self-directed
cells are coming from is a big one. “Our objective is to understand
the ins and outs of this process,” says Casellas.
The research was also funded by the NIH’s National Center for
Research Resources as part of its Institutional Development Award
Program (IDeA). The program fosters health-related research and
improves the competitiveness of investigators in states that historically
have not received significant levels of research funding from NIH.
The mission of the National Institute of Arthritis and Musculoskeletal
and Skin Diseases (NIAMS), a part of the Department of Health
and Human Services’ National Institutes of Health, is to support
research into the causes, treatment and prevention of arthritis
and musculoskeletal and skin diseases; the training of basic
and clinical scientists to carry out this research; and the dissemination
of information on research progress in these diseases. For more
information about NIAMS, call the information clearinghouse at
(301) 495-4484 or (877) 22-NIAMS (free call) or visit the NIAMS
Web site at http://www.niams.nih.gov.
NCRR provides laboratory scientists and clinical researchers
with the environments and tools they need to understand, detect,
treat, and prevent a wide range of diseases. With this support,
scientists make biomedical discoveries, translate these findings
to animal-based studies, and then apply them to patient-oriented
research. Ultimately, these advances result in cures and treatments
for both common and rare diseases. NCRR also connects researchers
with one another, and with patients and communities across the
nation. These connections bring together innovative research
teams and the power of shared resources, multiplying the opportunities
to improve human health. For more information, visit www.ncrr.nih.gov.
The National Institutes of Health (NIH) — The Nation's
Medical Research Agency — includes 27 Institutes and
Centers and is a component of the U.S. Department of Health and
Human Services. It is the primary federal agency for conducting
and supporting basic, clinical and translational medical research,
and it investigates the causes, treatments, and cures for both
common and rare diseases. For more information about NIH and
its programs, visit www.nih.gov.