publications, contact information

Research Interests

A balance between lymphocyte survival and death is crucial for the resolution of normal immune responses and for preventing autoimmune disease and lymphoid malignancies. A number of membrane receptors and their corresponding ligands have been identified that signal cells to die. Among these death receptor/ligand pairs, Fas and FasL feature prominently in immune homeostasis. The importance of the Fas cell-death pathway is well illustrated by the extent and severity of immune defects observed in mice with germline loss of function mutations in fas or fasl. These mice suffer from massive T-lymphocyte accumulation, exhibit chronic T- and B-cell activation, develop systemic autoimmune disease and have a greatly increased risk of developing B-cell malignancies. Humans with germline Fas mutations develop a similar spectrum of immune system defects. In normal individuals, the Fas death pathway has been shown to be the primary mechanism for the elimination of antigen-activated T lymphocytes and therefore plays a prominent role in resolving immune responses and preventing overstimulation of the immune system. The goal of my group is to gain a further understanding, at the molecular level, of how the Fas cell death pathway limits autoreactivity and exerts its anti-oncogenic activity in B cells.
In normal individuals, death receptor-mediated cell death occurs by apoptosis, a controlled non-inflammatory death mechanism dependent on caspase activation. Signaling via Fas is one of the major mechanisms in T cells for activating caspases and insuring apoptotic death. We have shown that when the Fas pathway is inherently absent or experimentally inactivated, T cells can still die but they use alternative less efficient pathways that are caspase-independent and result in death by necrosis rather than apoptosis. Necrotic death is not associated with nuclear processing and can lead to the release of proinflammatory cellular contents and potentially to autosensitization. We have identified three different non-apoptotic death pathways in T cells and currently are investigating at the molecular level how these pathways signal cells to die.
In addition to being a major pathway for removing excess cells generated during an immune response, the Fas apoptosis pathway also may have a role in eliminating non-lethally damaged cells. Stress in the form of ionizing radiation and exposure to oxidants results in DNA damage and upregulation of Fas expression, especially among B lymphocytes. We propose that defective removal of mutated B cells may be a contributing factor in the increased incidence of B cell malignancies in Fas/FasL deficient mice and humans. To test this proposal, we have bred BALB-gld/gld and control mice that carry a plasmid with a lacZ reporter transgene. LacZ, which is easily recovered from genomic DNA, provides a sensitive system to measure spontaneous, treatment-induced and age-related DNA mutation frequencies in whole tissues and lymphocyte subsets. We are using this system to study DNA mutation frequencies in lymphocytes from mice exposed to irradiation and various forms of chronic oxidative stress.
Patients with germline Fas mutations and autoimmune lymphoproliferative syndrome frequently have greatly elevated levels of circulating interleukin-10 (IL-10), an abnormality that correlates with disease severity. We also observed significantly increased levels of serum IL-10 in ~60% of BALB-gld/gld mice with well-developed lymphoproliferative disease. In addition, activated CD4+ T cells from BALB-gld/gld mice secreted higher than normal levels of IL-10. Because IL-10 can function as a B-cell growth and differentiation factor and also have immunosuppressive effects on T cells, it is possible that dysregulation of IL-10 may contribute to the development of systemic autoimmunity and B cell lymphomagenesis. IL-10 levels may be raised in Fas-deficient individuals as a result of immune dysregulation or possibly as a compensatory mechanism to regulate immune system hyperactivity. To investigate these possibilities, we developed BALB-gld/gld, IL-10-/- mice. Preliminary studies with these mice have resulted in a number of interesting observations. First, the absence of IL-10 accelerates and exacerbates lymphoproliferative disease and B cell activation and increases the production of proinflammatory cytokines. These changes suggest that IL-10 may be important for modulation of the disease phenotype. Second, new disease symptoms were observed that normally are not seen in mice with mutations in fasl or IL-10 alone. These included an inflammatory eye disease, testicular inflammation and infertility. These findings are particularly interesting as the eye and testes are sites of immune privilege and therefore normally are protected from immune attack. We now are investigating the possibility that immune privilege is dependent on both IL-10 and FasL activity.

Selected Publications Top

Davidson W. F., Giese, T and Fredrickson T.N. 1998. Spontaneous Development of Plasmacytoid Tumors in Mice with Defective Fas-Fas Ligand Interactions. J.Exp.Med. 187: 1825-1838.

Lopes, M.F. et al. 1999. Increased Susceptibility of Fas Ligand-deficient gld Mice to Trypanosoma cruzi Infection Due to a Th2-biased Host Immune Response. Eur. J. Immunol. 29: 81-89.

Carey, G. B. et. al. 2000. B-cell Receptor and Fas-mediated Signals for Life and Death. Immunol. Rev. 176: 105-115.

Borges, V. M. et. al. 2001. Fas Ligand Triggers Pulmonary Silicosis. J. Exp. Med. 194: 155-163.

Contact Information Top

Email: davidsonw@usa.redcross.org
Tel: (301) 517-0324
FAX: (301) 517-0344
Mailing address:
Immunology Department
Holland Laboratory
American Red Cross
15601 Crabbs Branch Way
Rockville MD 20855