Thomas Rothstein, MD, PhD

The Feinstein Institute for Medical Research, NY

2012 B Cells

Human B1 Cells and Lupus Autoantibodies

The Study and What it Means for Patients

“We’re studying whether B1 cells, a small B cell population whose identity in humans we recently described, produce harmful autoantibodies in lupus. If so, therapies could be developed targeting B1 cells without damaging healthy B cells that defend against infection.”

Summary:
We recently discovered a new type of B cell in humans, termed B1 cells. Based on our early data we believe that B1 cells may be the main source of damaging autoantibodies in lupus. We will test our theory by isolating B1 cells from lupus patients and examining whether they do indeed produce antibodies against the body. If our suspicion is correct that these B1 cells, and not other types of lymphocytes, are the source of lupus autoantibodies, we will have provided a new understanding of how lupus disease is produced and have identified a new therapeutic target that can be attacked without impairing other immune cells.

If we show that B1 cells are the major source of autoantibodies in lupus then it may be possible to develop new therapies that eliminate these harmful cells but leave conventional B cells untouched and able to fight infections. The potential role of human B1 cells in lupus or any other autoimmune disease has never been investigated in lupus before, and our team is excited to get started with the help of a grant from the LRI. We are also grateful to the pharmaceutical company EMD Serono for the unrestricted educational grant they are providing to support our work for the first year.

Scientific abstract:
The role of B-cells and autoreactive immunoglobulin in lupus has been emphasized in recent years but the precise origin of pathogenic autoantibodies has not been worked out. It is said that lupus autoantibodies derive from post-germinal center B-cells because they are isotype-switched and somatically mutated. We recently identified the correct phenotype for human B1-cells (CD20+CD27+CD43+CD70-) and found that it shares CD27 expression with memory B-cells. Further, we have found that B1-cells produce immunoglobulin that is autoreactive, isotype-switched and somatically mutated; thus, B1-cells can make IgG, mutated, autoantibodies. Moreover, B1-cells are increased, and IgG+ B1-cells are markedly increased, in lupus. Thus, we propose that pathogenic autoantibodies are produced by B1-cells. We will test this hypothesis through single cell PCR/expression cloning of immunoglobulin expressed by isotype-switched and non-isotype-switched B1-cells and memory B-cells, as well as by naïve B-cells, from normal controls and lupus patients, and we will then test expressed antibody (and germline revertants) for autoreactivity, polyreactivity, and nephritogenicity. The results of this work are likely to overturn old concepts and support a novel paradigm for the etiology of lupus autoantibodies which will point to a new therapeutic target that can be attacked while leaving adaptive B-cells untouched and functioning normally.

2007 B Cells

An Alternate BCR Signaling Pathway to Autoimmunity

The body’s B cells, or B lymphocytes, mature in the bone marrow. When stimulated by an antigen, they develop into cells that make antibodies. And over the past few years, evidence that they play a central role in the cause and development of lupus-by making antibodies to the body's own DNA-has been growing.

Dr. Rothstein aims to discover what triggers B lymphocytes to produce autoantibodies (self-directed antibodies) in lupus.

Having recently found that activated B cells make the hormone-like molecule osteopontin, he suspects this may be what instigates or maintains the destructive production of autoantibodies in lupus. If correct, he will have identified a brand new pathway for the development of lupus, and opened the door to the development of targeted new therapies.

Note: Upon receiving an overlapping grant from the National Institutes of Health, Dr. Rothstein terminated his grant with the LRI after just several months of work.

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