Expression of the CD45 Ag in hemopoietic cells is essential for normal development and function of lymphocytes, and both mice and humans lacking expression exhibit SCID. Human genetic variants of CD45, the exon 4 C77G and exon 6 A138G alleles, which alter the pattern of CD45 isoform expression, are associated with autoimmune and infectious diseases. We constructed transgenic mice expressing either an altered level or combination of CD45 isoforms. We show that the total level of CD45 expressed is crucial for normal TCR signaling, lymphocyte proliferation, and cytokine production. Most importantly, transgenic lines with a normal level, but altered combinations of CD45 isoforms, CD45RABC/+ and CD45RO/+ mice, which mimic variant CD45 expression in C77G and A138G humans, show more rapid onset and increased severity of experimental autoimmune encephalomyelitis. CD45RO/+ cells produce more TNF-α and IFN-γ. Thus, for the first time, we have shown experimentally that it is the combination of CD45 isoforms that affects immune function and disease.

Summary: CD45 is known to regulate signalling through many different surface receptors in diverse haemopoietic cell types. Here we report for the first time that CD45^–/– bone marrow dendritic cells (BMDC) are more activated than CD45^+/+ cells and that tumour necrosis factor (TNF) and interleukin‐6 (IL‐6) production by BMDC and splenic dendritic cells (sDC), is increased following stimulation via Toll‐like receptor (TLR)3 and TLR9. Nuclear factor‐κB activation, an important downstream consequence of TLR3 and TLR9 signalling, is also increased in CD45^–/– BMDC. BMDC of CD45^–/– mice also produce more TNF and IL‐6 following stimulation with the cytokines TNF and interferon‐α. These results show that TLR signalling is increased in CD45^–/– dendritic cells and imply that CD45 is a negative regulator of TLR and cytokine receptor signalling in dendritic cells.

In the present study, we demonstrate for the first time that the potent neurotoxin vipoxin from the venom of Vipera ammodytes meridionalisexhibits hemolytic and anticoagulant properties. By...

Background: A polymorphism in exon 4 (C77G) of CD45 that alters CD45 splicing has been associated with autoimmune and infectious diseases in humans. Objective: To investigate the effect of C77G in hepatitis C virus (HCV) infected individuals and study the phenotype and function of peripheral blood mononuclear cells (PBMC) from healthy and hepatitis C infected C77G carriers. Results: C77G individuals showed an increased proportion of primed CD45RA and effector memory CD8 T cells and more rapid activation of the lymphocyte specific protein tyrosine kinase (Lck) following CD3 stimulation. Transgenic mice with CD45 expression mimicking that in human C77G variants had more activated/memory T cells, more rapid proliferative responses, and activation of Lck. Conclusions: Changes in CD45 isoform expression can alter immune function in human C77G variants and CD45 transgenic mice. The C77G allele may influence the outcome of HCV infection.