Immunity & Tolerance

A series of immunization and autoantibody tests of serum was developed and used by Dr Carola Vinuesa and her team at the John Curtin School to screen two libraries of ~200 G3 pedigrees of mutagenized B6 mice intercrossed with B10.BR. Approximately every seventh pedigree yielded a true-breeding variant strain with spontaneous production of antinuclear autoantibodies (ANAs), a key clinical test for systemic lupus and other autoimmune disorders. These are currently being mapped and analysed, and the causal mutation in the first ANA mutant that was found has recently been identified by sequencing all the cDNAs in the 0.5 Mb mapped interval. It is a missense allele of a ubiquitously expressed protein of previously unknown function, highly conserved from humans to invertebrates, and causes a recessive, T cell autonomous hyperactivation and excessive cytokine production syndrome with many of the cardinal clinical features of systemic lupus erythematosus. Sequencing the corresponding human gene in lupus patients is in progress.

Approximately every fourth pedigree yielded putative variants in one or other aspect of humoral immunity and memory. Most of these are still be propagated to define heritability pattern and phenotype, but those furthest advanced have mostly bred true.

Vinuesa C & Goodnow CC (2004)
Illuminating autoimmune regulators through controlled variation of the mouse genome sequence.
Immunity (in press).