Presenting Author:

Agnieszka (Agnes) Laskowski, Ph.D.

Principal Investigator:

Steven Kosak, Ph.D.

Department:

Cell and Molecular Biology

Keywords:

B lymphocytes, T lymphocytes, Lupus, Autoimmunity, Genomic Organization, Epigenome, and Gene Expression.

Location:

Ryan Family Atrium, Robert H. Lurie Medical Research Center

C2 - Clinical Women's Health Research

Novel Target and Treatment Strategy for Human Female Dominant Lupus

Lupus involves the inappropriate activation of the adaptive immune system against self-antigens, leading to inflammation and damage to various tissues of the body. Current treatment involves long-term use of corticosteroids and cytotoxic agents, and general immunosuppression and anti-inflammatory agents to temporarily alleviate secondary symptoms once the active phase of the disease has been initiated. These non-specific and delayed treatment strategies contribute to tissue damage, as well as vulnerability to infection and other complications. Importantly, the current drug schedules also fail to achieve the ultimate goals of remission and cure. The central objective of this project is to identify selective and potent small molecule inhibitors that target dysfunctional B and T lymphocytes in women during the active phase of lupus. Lupus is nine times more common in females than in males. The preponderance of female lupus patients suggests a genetic predisposition of having two X chromosomes contributing to the onset of the disease. This predisposition is further supported by the increased incidence of lupus in males with Klinefelter’s syndrome (47, XXY), in which lupus prevalence is equivalent to normal females (46, XX). From mouse genetic studies it has been shown that the presence of two X chromosomes specifically exacerbates lupus autoimmune responses and this increased autoimmunity is not connected to gonad presence. Together these studies support a strong genetic association with increased susceptibility to the onset and maintenance of autoimmunity in women. From our analysis of the three-dimensional organization of chromosomes in human female nuclei, we have identified abnormalities in chromosome X organization in lupus patient lymphocytes. Specifically, natural regulatory T cells (nTregs), responsible for attenuation of the adaptive immune response, have the most significantly disrupted chromosome X organization. In healthy cells, we find that co-localization (coalescence) of the active X (Xa) with the inactive X (Xi) leads to altered epigenetic marks on the X chromosomes. Lupus cells show a reduced rate of chromosome X coalescence. We hypothesize that altered levels of this phenomenon, trans-chromosomal X regulation, leads to lymphocyte dysfunction in women and results in their susceptibility to lupus. For this project, we aim to fully characterize this aberrant regulatory mechanism. The primary focus will be on altered expression levels of genes critical for lymphocyte function located on the X chromosome during the disease state. The second goal is to identify small molecule inhibitors that specifically and effectively increase the gene regulatory effects of trans-chromosomal X regulation. Successful completion of this project will identify a novel proactive treatment strategy for lupus by inhibiting initiation of the active phase through maintenance of proper X-linked gene expression critical for lymphocyte development and function.