The Diamond Laboratory is interested in the regulation of the B cell repertoire and the pathogenicity of autoantibodies. 

These are many diseases characterized by the presence of autoantibodies although the contribution of the autoreactive B cells and autoantibodies to tissue injury in these diseases are often unclear. In particular, we study DNA-reactive B cells in the autoimmune disease systemic lupus erythematosus. We are interested in the alterations within B cells that lead to the survival and activation of DNA-reactive B cells and in the alterations in other cells of the immune system that affect B cell function and can also lead to the survival and activation of DNA-reactive B cells.  We are especially interested in the regulation of autoreactive B cells that acquire their autoreactivity by somatic mutation during a germinal center response and in determining whether the processes that govern the selection of the B cell repertoire early in B cell development are the same as those that govern selection after activation. These studies are designed to provide new strategies to protect against autoimmune disease.

We are also interested in whether autoantibodies in individuals with autoimmune disease, or, indeed, protective antibodies in non-autoimmune individuals might frequently cause brain injury if they penetrate the blood-brain barrier. It is our hypothesis that antibodies may frequently contribute to acquired changes in cognition or behavior.

Research Description

Regulation of B cell repertoire

We are interested in the regulation autoreactive B cells as they mature to immunocompetence.  We are particularly interested in the B cell receptor signaling pathway.  It is our hypothesis that B cell hyporesponsiveness to antigen during early development allows autoreactive B cell to enter the native B cell repertoire. We have evidence that antigen mediates positive selection as well as negative selection of transitional B cells.  We are interested in delineating those conditions in which positive selection predominates and those conditions in which negative selection is triumphant.

We are investigating the regulation of B cells that respond to antigen and acquire autoreactivity.  We have shown that a process termed receptor editing causes post-germinal center B cells to express a new light chain in an effort to transform an autoreactive B cell receptor into one that is not autoreactive.
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Hormonal effects on B cell development and selection

Most autoimmune disease are more common in women and there is strong evidence that estrogen contributes to this female predisposition to autoimmune disease.  We are studying the impact of estrogen on B cell receptor signaling and B cell maturation to a marginal zone phenotype.  We are further trying to understand if estrogen alters the germinal center response as it has been shown to regulate both RAG and AID expression.

Dendritic cell regulation of B cell function

We have been studying how alterations in function of dendritic cells can determine B cell selection and maturation.  These studies provide information on a important link between the innate and the adaptive immune systems and will help identify new pathways for therapeutic intervention in autoimmune disease.

Antibodies and brain function

We have become very interested in a subset of anti-DNA antibodies that cross-reacts with NMDA receptors and alters function in adult brain following a breach in the blood-brain barrier and alters fetal brain development as a consequence of in utero exposure to maternal antibodies.  We have recently extended our studies of anti-brain antibodies to ask whether these might account for some cases of autism and post-traumatic stress disorder. 
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