Schenten, Dominik (2003) Analysis of the Function of DNA Polymerase Kappa and M17 in the Immune System. PhD thesis, Universität zu Köln.
In T cell-dependent immune responses, activated B cells undergo a phase of rapid expansion and form distinct histological structures, the germinal centers (GC). GCs are the sites of secondary antibody diversification. Somatic hypermutation (SHM) introduces mutations into the rearranged V genes, whereas class switch recombination (CSR) alters the IgH constant region to modulate effector function. The current model of SHM postulates cytidine deamination by AID, followed by error-prone repair that involves short-patch DNA synthesis by error-prone DNA polymerases. The Pol k (DinB1) gene encodes a specialized mammalian DNA polymerase called DNA polymerase k. The mouse Pol k gene is expressed in most tissues of the body including B cells. The ability of Pol k to generate mutations when extending primers on undamaged DNA templates identifies this enzyme as a candidate for the introduction of nucleotide exchanges during SHM. Here, I show that Polk-deficient mice are viable, fertile and able to mount a normal immune response to the antigen (4-hydroxy-3-nitrophenyl) acetyl-chicken globulin (NPGC). Polk-deficient mice mutate their Ig genes normally. Pol k-/- Pol l-/- Pol i-/- mice also show no defects in SHM, indicating that these error-prone DNA polymerases do not substitute for each other�s function during SHM. However, Polk-deficient embryonic fibroblasts are sensitive to cell death following exposure to ultraviolet radiation, suggesting a role for Polk in translesion DNA synthesis. The human gene HGAL serves as marker in the prognosis of patients with GC-derived diffuse large B cell lymphomas (DLBCL). The mouse gene M17 is the homologue of HGAL. M17 is predominantly expressed in the GCs, indicating a role in GC function. In the present study, I analyzed M17-/- mice to investigate the role of M17 in the GC reaction. M17-/- mice form normal GCs, undergo efficient CSR and SHM and mount a T cell-dependent immune response. Thus, M17 is dispensable for the GC reaction and the current data support a rather indirect role for HGAL as a prognostic marker in the biology of DLBCL.
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