B Cells Gone Bad
Researchers Uncover How HIV Causes Abnormalities in Antibody-Producing Cells
HIV wreaks much of its damage by targeting the “orchestra
conductor” of the immune system, a key class of T cells —
CD4+ T cells — whose destructive relationship with HIV has
been well-studied by AIDS researchers. More poorly understood has
been the effect of HIV on another key class of immune cells, antibody-producing
B cells. The malfunction of B cells in HIV-infected patients was
first described more than 20 years ago by H. Clifford Lane, M.D.,
Anthony S. Fauci, M.D., and colleagues at the National Institute
of Allergy and Infectious Diseases (NIAID) of the National Institutes
of Health (NIH). Now, writing in the Sept. 7 online edition of The
Journal of Experimental Medicine, Dr. Fauci, Susan Moir, Ph.D.,
Angela Malaspina, Ph.D., and their colleagues identify a number
of pathways that HIV activates to damage or destroy B cells.
“Our findings further illuminate the insidious nature of HIV,”
notes Dr. Moir, head of the B Cell HIV Unit in the Immunopathogenesis
Section of the NIAID Laboratory of Immunoregulation (LIR). “The
virus has numerous ways of paralyzing or destroying the very cells
of the immune system that are supposed to eliminate it.”
One of the most paradoxical properties of HIV is the fact that it
activates the immune system, which is necessary for an appropriate
immune response, at the same time that the activation itself leads
to deleterious effects. “During the course of HIV infection,
the B cells of people whose virus is not kept under control with
antiretroviral drugs become progressively dysfunctional through
virus-driven, aberrant activation,” explains Dr. Fauci, who
is NIAID director and LIR chief.
These abnormal B cells exhibit visible changes in their structure
and surface. They also overproduce nonessential antibodies, fail
to respond properly to normal immune system signals, and have an
increased chance of dying through apoptosis, a process also called
“programmed cell death.”
In their experiments, Drs. Fauci and Moir and their LIR colleagues,
in collaboration with scientists from Human Genome Sciences (Rockville,
MD), set out to uncover what drives B-cell abnormalities in HIV
infection. Using gene chip technology developed by Human Genome
Sciences, they probed thousands of genes taken from B cells of HIV-infected
patients. The researchers compared which genes were “turned
on,” or expressed, in the patients whose viral burden was
high with profiles of gene expression in patients whose virus was
controlled by antiretroviral therapy. The research team also examined
gene expression in healthy HIV-negative individuals.
“We found more than 40 genes that were ‘over-expressed’
in the group with high HIV levels compared with the two other groups,”
says Dr. Moir. Most of these genes, she notes, belong to either
one of two major physiologic pathways. Of note, in patients with
HIV levels, certain elements from both pathways helped prime B cells
for apoptosis.
The researchers not only discovered new pathways that are perturbed
during the course of HIV infection, but also illuminated how HIV
affects a key B-cell survival system. The principal player in this
survival system, B Lymphocyte Stimulator (BLyS), was discovered
by Human Genome Sciences. The discovery was first reported in a
scientific journal in 1999. BLyS (also known as BAFF) and BAFF-R
— one of three known docking molecules for BLyS on B cells
— are essential for B-cell development and survival. Dr. Moir
and her team discovered that B cells of patients with high levels
of HIV have reduced levels of BAFF-R on their surfaces, making these
B cells more susceptible to cell death.
The LIR researchers plan to examine whether similar pathways are
triggered in other cells of the immune system that are over-activated
by HIV, including CD8+ T cells, CD4+ T cells and natural killer
(NK) cells.
Whether common or distinct pathways are involved, these new
findings help explain one of the driving forces of HIV immunopathogenesis
and may lead to therapeutic strategies aimed at quelling the aberrant
levels of immune cell activation,” notes Dr. Fauci.
NIAID is a component of the National Institutes of Health, an agency
of the U.S. Department of Health and Human Services. NIAID supports
basic and applied research to prevent, diagnose and treat infectious
diseases such as HIV/AIDS and other sexually transmitted infections,
influenza, tuberculosis, malaria and illness from potential agents
of bioterrorism. NIAID also supports research on transplantation
and immune-related illnesses, including autoimmune disorders, asthma
and allergies.
News releases, fact sheets and other NIAID-related materials are
available on the NIAID Web site at
http://www.niaid.nih.gov.
Reference: S Moir et al. Decreased survival of B cells of HIV-viremic
patients mediated by altered expression of receptors of the TNF
superfamily. Journal of Experimental Medicine 200(5): 587-599 (2004).
This article is available online at http://www.jem.org/cgi/doi/10.1084/jem.20032236.
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