Open AccessApoptosis resistance of nonobese diabetic peripheral lymphocytes linked to theIdd5diabetes susceptibility region
Author(s) -
Francesco Colucci,
MarieLouise Bergman,
Carlos PenhaGonçalves,
Corrado Cilio,
Dan Holmberg
Publication year - 1997
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.94.16.8670
Subject(s) - biology , immunology , apoptosis , nod , nod mice , cytotoxic t cell , centimorgan , locus (genetics) , diabetes mellitus , cancer research , genetics , gene , endocrinology , chromosome , in vitro , gene mapping
Defects in lymphocyte apoptosis may lead to autoimmune disorders and contribute to the pathogenesis of type 1 diabetes. Lymphocytes of nonobese diabetic (NOD) mice, an animal model of autoimmune diabetes, have been found resistant to various apoptosis signals, including the alkylating drug cyclophosphamide. Using an F2 intercross between the apoptosis-resistant NOD mouse and the apoptosis-susceptible C57BL/6 mouse, we define a major locus controlling the apoptosis-resistance phenotype and demonstrate its linkage (logarithm of odds score = 3.9) to a group of medial markers on chromosome 1. The newly defined gene cannot be dissociated fromCtla4 andCd28 and in fact marks a 20-centimorgan region encompassingIdd5 , a previously postulated diabetes susceptibility locus. Interestingly, we find that the CTLA-4 (cytotoxic T lymphocyte-associated antigen 4) and the CD28 costimulatory molecules are defectively expressed in NOD mice, suggesting that one or both of these molecules may be involved in the control of apoptosis resistance and, in turn, in diabetes susceptibility.