Immunology Graduate Group

Roberto Caricchio, M.D.
Research Assistant Professor of Medicine
Department of Medicine/Rheumatology

Address: 751 BRB II/III, 421 Curie Blvd
Office Phone: 215-573-4394
Lab Phone: 215-573-2946
Fax: 215-573-7599
Email: rocarri2@mail.med.upenn.edu

Dr. Caricchio's Rheumatology page

Education:
M.D., Catholic University of Sacred Heart, Rome (Italy)
B.S., Liceo A. Landi Velletri, Rome (Italy)

Research Interests

The role of apoptosis in Systemic Lupus Erythematosus.

Research Summary

Apoptosis has emerged in recent years to explain how self-antigens might become “available” to a self-primed immune system (Figure 1). Others and we 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 (Figure 2). 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 (Figure 3).

Finally our laboratory is also investigating the role of blebs, a byproduct of apoptosis, as a source of self-antigen material for antigen presentation by dendritic cells (Figure 4).

Recent Publications

Lorenza Frisoni, Lenese Mcphie, Lucrezia Colonna, Uma Sriram, Marc Monestier, *Stefania Gallucci, *Roberto Caricchio. Nuclear autoantigen translocation and autoantibody opsonization lead to increased dendritic cell phagocytosis and presentation of nuclear antigens: a novel pathogenic pathway for autoimmunity? J Immunol. 2005 (in press)
*The authors contributed equally

Cohen PL, Caricchio R. Genetic models for the clearance of apoptotic cells. Rheum Dis Clin North Am. 2004 Aug; 30(3):473-86, viii.

Caricchio R , McPhie L, Cohen PL. UV-B Radiation-induced cell death: critical role of UV dose in inflammation and lupus autoantigen redistribution. J Immunol . 2003 Dec 1;171(11):5778-86.

Cohen PL, Caricchio R , Abraham V, Camenisch TD, Jennette JC, Roubey RA, Earp HS, Matsushima G, Reap EA. Delayed apoptotic cell clearance and lupus-like autoimmunity in mice lacking the c-mer membrane tyrosine kinase. J Exp Med . 2002 Jul 1;196(1):135-40.

Caricchio R , D'Adamio L, Cohen PL. Fas, ceramide and serum withdrawal induce apoptosis via a common pathway in a type II Jurkat cell line. Cell Death Differ . 2002 May;9(5):574-80.

R.S. Scott, E.L. McMahon, S.M. Pop, E.A. Reap, Caricchio R , P.L. Cohen, H.S. Earp, G.K. Matsushima. Phagocytosis and clearance of apoptotic cells is mediated by Mer. Nature Vol.411, pp207-211, 2001

Caricchio R. and Cohen P.L.. Spontaneous and induced apoptosis in SLE: multiple assays fail to reveal consistent abnormalities. Cell. Immunol . 198, 54–60 (1999).

Caricchio R. , Kovalenko D., Kaufmann W.K. and Cohen P.L. The oxidative stress inducer menadione (vitamin K3) requires a functional Fas/Fas ligand system for inducing apoptosis. Clinical Immunol Vol. 93, No. 1, October, pp. 65–74, 1999

Caricchio R. , Reap E. and Cohen P.L. Fas/Fas ligand interactions are involved in UV-B-induced human lymphocyte apoptosis. J. Immunol . 1998, 161:241-251.

Figure 1.

Expression of H2B-GFP before and after UV-B-induced apoptosis. A431 cells were stably transfected with H2B-GFP fusion protein (K/H2B-GFP). H2B-GFP is expressed only within the nuclei. In the right panel an apoptotic K/H2B-GFP cell is shown after UV-B irradiation. The “Blebs and bodies forming” phase is shown. Noticeably, redistribution of SLE self antigens are among the remarkable changes that occur during apoptosis. Images were collected in real time by laser confocal microscopy.

Figure 2.

CAD-null mice do not fragment DNA in vivo. CAD-/- and wild type littermates were treated with two different stimuli: g -irradiation (1500 Rads) and septic shock. After few hrs organs were harvested and DNA was extracted. CAD+/+ mice promptly fragmented DNA in the tissues tested, as shown by the characteristic laddering of the DNA. In contrast, no DNA fragmentation was induced in the CAD-/-. Control DNA extracted from organs of untreated mice is shown for comparison.

Figure 3.

H2B-GFP expression under the K14 promoter. B6 K/ H2B-GFP mice were euthanized. Organs were harvested and froze. Unstained frozen sections were collected on glass slides and fixed in 4% formaldehyde with no further manipulation. Images of various organ sections were collected by laser confocal microscopy. H2B-GFP fusion protein is expressed solely in the nuclei of the tissues investigated and will serve as a “tracer” in vivo of lupus autoAgs H2B and nucleosomes.

Figure 4.

Phagocytosis of apoptotic cells by DCs. K/H2B-GFP cells were cultured in bottom glass dishes, UVB irradiated and after 5 hrs DCs were added to the culture. After 2hrs of co-incubation, laser confocal images were collected of DCs phagocytosing apoptotic K/H2B-GFP cells expressing a fluorescent fusion protein .

 

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