Loss of P2RX7 Receptor Activity in MRL lpr/lpr T Lymphocytes Correlates with the Expression of B220

Date of Award

2009

Document Type

Thesis

Degree Name

Bachelors

Department

Natural Sciences

First Advisor

Clore, Amy

Keywords

PRX7 Receptor, B220 Molecule, Immunology, Lupus

Area of Concentration

Biology

Abstract

During the immune response, T lymphocytes activated by a particular antigen undergo a very important expansion phase. These lymphocytes must be rapidly depleted at the end of the response in order to maintain the critical homeostasis governing the immune system (Hildeman et al., 2002). This negative regulation is effected, partly, by the apoptotic receptor Fas and of its ligand, FasL, expressed at the surface of activated T lymphocytes. In MRL lpr/lpr mice, as in patients affected by the autoimmune lymphoproliferative syndrome (ALPS), the mutation of the fas gene is responsible for the development of systematic autoimmune pathologies such as systemic lupus erythematosus (SLE) and of secondary lymphatic organ hyperplasia due to the accumulation of activated T lymphocytes of the abnormal immunophenotype CD90+ CD4- CD8- B220+ (double negative, T DN) (Lee et al., 2005). The B220 molecule is a differentiation marker for B lymphocytes. Its presence on the surface of T DN lymphocytes indicates that the lymphocytes have received an apoptosis signal, but that they managed to escape the autoregulation process due to their fas gene mutation (Griffith et al., 1995). While 11 susceptibility loci for SLE have been characterized, the underlying causes of the disease remain unknown. In the MRL lpr/lpr mouse model, it has been previously demonstrated that the faults in the immune system's homeostasis pathway linked to the Fas receptor were one of the causes for the disease's onset (Lee et al., 2005). In the course of the present work, we studied the possible role of the purinergic receptor, P2rx7, in SLE development in the MRL lpr/lpr mouse model using flow cytometry, western blotting and real-time RT-PCR. In both auto-immune MRL lpr/lpr mice and their wildtype counterparts, MRL +/+, the results indicate that the P2rx7 receptor is inactive in lymphocytic subpopulations expressing tyrosine phosphatase B220, such as in activated T lymphocyte that have received an apoptotic signal, as well as B lymphocytes. It appears that neither transcriptional or translational regulation, nor the presence of a mutation on the P2rx7 gene can explain the receptor's inactivity. The in vitro induction of B220 expression at the T lymphocytes surface in the MRL lpr/lpr mice diminishes P2rx7 receptor's activity. Reciprocally, inhibition of tyrosine phosphatase activity for CD45 isoforms including B220 lead to an augmentation of P2rx7 activity in lymphocytes expressing B220. Consequently, B220 and/or other isoforms of CD45 are implicated in the inactivation of P2rx7 in T B220+ lymphocytes as well as in B lymphocytes, and this relationship may play a role in the development of the lupic phenotype.

Rights

This bibliographic record is available under the Creative Commons CC0 public domain dedication. The New College of Florida, as creator of this bibliographic record, has waived all rights to it worldwide under copyright law, including all related and neighboring rights, to the extent allowed by law.

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