Lupus is an autoimmune disease affecting many organs. It occurs when patients' antibodies, produced by immune B cells which are part of the body's second line of immune defense, mistakenly attack the body's own cells. Determining how these B cell antibodies fail to learn to differentiate the body's own cells from foreign antigens remains a major challenge that the Rockefeller University investigators will address. Previous studies have indicated that a high percentage (50 to 75 percent) of developing B cells in bone marrow mistake the body's own cells as foreign antigens (referred to as "self antigens"). In most people, however, these B cells are eliminated either before they leave the bone marrow, or when they first begin circulating in blood. This weeding out of errant B cells can occur at one of two checkpoints: either within the bone marrow, or when the B cells leave the bone marrow and enter the bloodstream. The investigators hypothesize that in patients who develop lupus, the checkpoint in the bone marrow fails; B cells evolving in bone marrow do not learn to recognize and become tolerant of the body's own cells. The researchers also hypothesize that treatment exerts its effect by inducing B cells to become tolerant of the body's cells.
The investigators will explore these hypotheses in two ways. First, in newly diagnosed and untreated lupus patients, the researchers will clone and express patients' antibodies from single B cells that are isolated from immature and mature B cells, and from "memory" B cells that remember the identity of an antigen once they encounter it. The investigators will test these antibodies to see if they react against the patients' cells, and compare these antibody actions to those previously observed in studies of healthy people. This should help to determine whether the development of lupus is associated with abnormal B cell tolerance (intolerance to the body's own cells) which results in the release of these abnormal self-reactive B cells into the blood.
If this hypothesis is confirmed, the investigators will assess the effects of therapy on B cells in the same patients. Lupus patients undergo periods of remission and relapse following initial therapy. The investigators will once again study patients' immature, mature, and memory B cell antibodies following initial therapy, and determine whether the clinical severity and course of the disease is associated with increased tolerance by the antibodies to patients' own cells.