The Study Of Low Fertility And Immune Deficiency Of Pearl Mice

Hermansky-Pudlak syndrome type2(HPS2)is an autosomal recessive inheritable disease characterized by partial albinism,lung fibrosis,prolonged bleeding tendency and immunodeficiency.This disease is caused by the disorder of biosynthesis and function of lysosomes and endosome-lysosome related organelles,and there is no effective treatment for now.HPS2 patients suffered the mutation of Ap3b1 gene,which encodes the ?-3A subunit of adaptor protein-3 complex(AP-3).The disruption of the AP-3 hinder the shuttle of cargo proteins from the trans-Golgi network to endosome-lysosome related organelles ubiquitously.Pearl mouse is a kind of animal model for human HPS2,and also suffered mutation of Ap3bl gene.Draw on the previous study of our laboratory,the litter size of female pearl mice were obviously smaller than normal control and the arrangement of endometrial epithelial cells were loose.It has been reported that the ?-catenin is involved in the cell junction through the E-cadherin and it's dephosphorylation and position was regulated by PCP-2,PCP-2 could interacted with AP-3.We speculated the lose of AP-3 could influenced the intracellular distribution of ?-catenin,but in fact it was normal in the uterus of adult pearl mice.Meanwhile,we found the content of immunoglobulin G(IgG)in pearl mice's uterus was lower.We also found the heavy chain of IgG was seriously low in the serum of pearl mice,but the light chain was not decreased gravely.In consideration of IgG is the only immunoglobulin can through the placenta,the decrease of IgG may affect the litter size of pearl mice.Although there are some reports about the immunodeficiency of HPS2 patients,there isn't particular report about its humoral immune deficiency.In order to determine the humoral immune deficiency symptoms in pearl mice,we tested the IgG,IgM and IgA levels in pearl mice's serum.The results showed that the IgG,IgM levels of pearl mice were significant lower than that of wild-type mice,while the average level of IgA was higher than control group.Besides,the mRNA level of IgG in pearl mice's spleens was also detected lower,but the IgM and IgA levels were raised gradually as the growth of the age and finally surpassed the normal level.These results indicated that the pearl mice may suffered humoral immune deficiency even immunoglobulin class switch recombination deficiency.Because the immunoglobulins were produced by the activited B lymphocytes,we counted the proportion of mature B lymphocytes in pearl mice's spleen,and found there was no significant difference between pearl and control mice,indicating that the development of pearl mice's B cell is basically normal.Histological and morphological abnormalities were also not found in spleens of pearl mice.So the AP-3 may affected the activation or class switch recombination of B lymphocytes.CD40-CD40L interaction plays a major role in the activation program of B lymphocytes.We detected the transcription level of CD40 and it's ligand(CD40L)in spleens of pearl mice,and found the mRNA level of CD40L was significantly lower,which may lead to a reduction of B cell's activation capacity.Activation induced cytidine deaminase(AID)could initiate the class switch recombination.In pearl mice,we found the mRNA level of AID was only half of the normal mice in spleens.Indicating the start of class switch recombination of pearl mice may be affected.The investigation of the fertility of pearl mice trigger the observation of the humoral immune deficiency.Through the study of the phenotype and reasons of pearl mice's humoral immune deficiency,we may provided some references for diagnosis and treatment for HPS2 patients.And the research of the lower production of immunoglobulins in pearl mice's B lymphocytes may enrich our knowledge of the function of AP-3 complex.