Research Assistant Professor of Medicine
BRBII/III, Suite 757, Room 751
421 Curie Boulevard
Philadelphia, PA 19104-4283
Office: 215-573-4394
Fax: 215-573-7599
Email: rocarri2@mail.med.upenn.edu
Dr. Caricchio's Immunology Graduate Group (BGS)
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Systemic lupus erythematosus (SLE), the prototype of autoimmune diseases, is primarily a disease of young women. The peak incidence occurs between the ages of 15 and 40 and during these years, the female to male ratio is 10 to 1. Despite an extensive search over the past three decades, the cause of SLE remains unknown.
It is clear though that the immune response in lupus is antigen driven, yet how these ubiquitous autoantigens come to be recognized by the immune system in SLE remains unknown. Recent observations have led a number of investigators to propose that apoptotic cells may be the source of nuclear immunogens. This fascinating hypothesis remains to be confirmed. We intend to study autoantigen translocation through a novel and powerful approach, the use of GFP-tagged autoantigens, which will allow me to determine in real time endogenous autoantigen trafficking, to define protein specificity and to deduce the cytoskeleton structures involved. Moreover we intend to investigate the immunological relevance of this phenomenon by determining if autoantigens displayed by apoptotic cells are recognized by immune competent cells. The experiments will thus provide important insights into the source of autoantigens, and into the role of apoptosis in exposing lupus antigens to the autoreactive cells. These studies may lead to a better understanding of how autoimmunization in a lupus prone individual takes place and therefore may also lead to a rational therapy for targeting apoptotic cells and their products in SLE.
RealTime imaging of Ro52kD-GFP and Tubulin-YFP expressing cells:
Ro52KD (1C) |
Tubulin (3B) |
Tubulin (3C) |
Apoptosis has emerged in recent years to explain how self-antigens might become “available” to a self-primed immune system. We and others have observed that subversion of apoptotic clearance mechanisms, leads to lupus-like manifestations.
In this context, of particular interest are nucleosomes, the basic structure of chromatin, which not only are unique and invariable byproducts of apoptosis, but are also often the first antibody specificity to arise in lupus, long before the appearance of anti-DNA or anti-histones. Nevertheless the mechanism of autoantibody production from nucleosome autoreactivity is still unclear, and more importantly the in vivo factors inciting immunogens are yet to be demonstrated.
Our laboratory exploits the use of ko mice that cannot generate apoptotic nucleosomes because chromatin fragmentation is impaired, as a tool to investigate in vivo the relevance of nucleosomes in triggering or perpetuating the autoimmune response in SLE. We have also developed transgenic mice in which apoptotic nucleosomes are traceable in vivo , to investigate the origin of this important self-reactive apoptotic waste in SLE.
Finally our laboratory is also investigating the role of blebs, a byproduct of apoptotis, as a source of self-antigen material for antigen presentation by dendritic cells.
