Analysis of CD45 variants effecting alternative splicing
The CD45 (leukocyte common) antigen is a haemopoietic cell specific tyrosine phosphatase essential for antigen receptor signalling in lymphocytes. Multiple isoforms of CD45 are expressed in a cell type and activation-specific manner, but the exact function of the different isoforms remains obscure. In humans, naive T cells express high molecular weight isoforms (containing CD45RA), but following activation switch to expression of low molecular weight (CD45R0 and CD45RB) isoforms. Human CD45 variant alleles which alter CD45 isoform expression have been identified and associated with infectious and autoimmune diseases. Two contrasting allelic variants have been analysed. The exon 4 77G allele is present at a low frequency in Caucasoids and prevents splicing from high to low molecular weight isoforms. An increased frequency of this allele is found in multiple sclerosis, HIV and Hepatitis C infected individuals. The exon 6 138G allele is found at a high frequency in Far Eastern populations and promotes splicing towards low molecular weight isoforms. This allele is protective in Graves' disease and Hepatitis B infection. Both alleles are associated with altered phenotype and in vitro functional response of T cells. Similarly CD45 transgenic mice exhibit altered T cell phenotype and function. These data demonstrate that subtle changes in isoform expression lead to an alteration in cell phenotype and that both combinations of isoforms and the total level of expression are important for CD45 function.