Biomedical subjects

Chunfang Zhao

Publications and source records attributed to Chunfang Zhao.

3 recordsLinked to original sources

PubMed2006

A role for Mlh3 in somatic hypermutation.

Somatic hypermutation (SHM) and class switch recombination (CSR) allow B cells to make high affinity antibodies of various isotypes. Both processes are initiated by activation-induced cytidine deaminase (AID) to generate dG:dU mismatches in the immunoglobulin genes that are resolved differently in SHM and CSR to introduce point mutations and recombination, respectively. The MutL homolog MLH3 has been implicated in meiosis and DNA mismatch repair (MMR). Since it interacts with MLH1, which plays a role in SHM and CSR, we examined these processes in Mlh3-deficient mice. Although deficiencies in other MMR proteins result in defects in SHM, Mlh3(-/-) mice exhibited an increased frequency of mutations in their immunoglobulin variable regions, compared to wild type littermates. Alterations of mutation spectra were observed in the Jh4 flanking region in Mlh3(-/-) mice. Nevertheless, Mlh3(-/-) mice were able to switch to IgG3 or IgG1 with similar frequencies to control mice. This is the first instance where a loss of a DNA repair protein has a positive impact on the rate of SHM, suggesting that Mlh3 normally inhibits the accumulation of mutations in SHM.

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PubMed2006

Salmonella typhimurium infection triggers dendritic cells and macrophages to adopt distinct migration patterns in vivo.

The presence of an anti-bacterial T cell response and evidence of bacterial products in inflamed joints of reactive arthritis patients suggests an antigen transportation role in this disease for macrophages and dendritic cells. We have investigated the functional properties and in vivo migration of macrophages and DC after infection with Salmonella enterica serovar Typhimurium (S. typhimurium). BM-derived macrophages and DC displayed enhanced expression of costimulatory molecules (CD40 and CD86) and increased production of pro-inflammatory cytokines (TNF-alpha, IL-6 and IL-12p40) and nitric oxide after infection. Upon adoptive transfer into mice, infected DC migrated to lymphoid tissues and induced an anti-Salmonella T cell response, whereas infected macrophages did not. Infection of DC with S. typhimurium was associated with strong up-regulation of the chemokine receptor CCR7 and acquisition of responsiveness to chemokines acting through this receptor. Moreover, S. typhimurium-infected CCR7-deficient DC were unable to migrate to lymph nodes after adoptive transfer, although they did reach the spleen. Our data demonstrate distinct roles for macrophages and DC as antigen transporters after S. typhimurium infection and a dependence on CCR7 for migration of DC to lymph nodes after bacterial infection.

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PubMed2006

The mismatch repair protein Msh6 influences the in vivo AID targeting to the Ig locus.

Somatic hypermutation (SHM) and class switch recombination (CSR) are initiated by activation-induced cytidine deaminase (AID), which preferentially deaminates deoxycytidines at WRC (W = A/T, R = A/G) motifs in vitro. The mechanisms responsible for targeting AID and for organizing the queue of enzymes involved in vivo have been elusive. Here, we examined point mutant knockin Msh6 mice (Msh6(TD/TD)), which lack the second phase of SHM but retain all the proteins involved, and found that AID was frequently targeted to non-WRC motifs. Unexpectedly, by comparing SHM and CSR in wild-type, Msh6(TD/TD), and age-matched Msh6(-/-) mice, we discovered that the presence of Msh6 protein influenced the AID targeting in phase one of SHM and mediated the proper targeting of recombination sites in CSR in vivo. Our data suggest that Msh6 plays a scaffolding role in the first phase of SHM, in addition to its enzymatic role in the second phase of SHM.

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