HCV infection is strictly related to Mixed Cryoglobulinemia (MC), a lymphoproliferative/autoimmune disorder characterized by circulating immunoglobulin complexes (cryoglobulins). The reasons why only a percentage of HCV patients develops MC are still unknown. Two – not mutually exclusive – hypotheses could be suggested: (i) a reduced uptake/clearance of Igs by phagocytes (ii) an excessive production/secretion of Igs. The clearance of cryoglobulins is mediated by low-affinity FcG receptors (FcGRs). Single nucleotide polymorphisms affecting IgG-binding affinity are described for some receptors and particular aplotypes are related to autoimmunity. On the other hand, MC is characterized by B-cell expansion and abnormal Ig production involving specific cytokines, namely BAFF (B-cell Activating Factor). This study was aimed at evaluating the contribution of genetic host factors in the development of HCV-related MC. We analyzed, with different PCR-based techniques and RFLPs, the prevalence of FcGR polymorphisms (FcGR2A-131 R/A, FcGR2B-232I/T, FcGR3A-176V/F and FcGR3B-NA1/NA2) in 210 HCV+ patients (102 with MC(MC+) and 108 (MC−) without any evidence of lymphoproliferative/autoimmune disorders). The BAFF promoter polymorphism −871C/T, inducing a higher transcription of the BAFF gene, was also analyzed. A significantly higher prevalence of both T/T homozygosis (p < 0.001) and the presence of a T-allele (T/T and T/C, p = 0.004) at site −871 of BAFF promoter was shown in MC+ patients, resulting in a significant increase of BAFF serum concentration (4.12±1.29 vs. 2.09±0.81 ng/ml, p < 0.0001). Real-time-PCR analysis of the BAFF gene expression showed a 2.8-fold higher transcription in MC+. By contrast, no significant difference in prevalence of different FcGRs genotypes was observed. However, a trend towards a higher prevalence of the FcGR3A F/F genotype – showing a reduced affinity for IgG – was shown in MC+ patients (p = 0.09). Interestingly, in 19 MC+ patients undergoing anti-CD20 antibody treatment, the response was strictly related to the F-allele presence, being strongly reduced in F/F homozygous patients. These results underline the importance of the host genetic background in the development of HCV-related MC, suggesting that mechanisms enhancing Ig production and B-cell survival could have a more relevant role than genetic defects in cryoglobulin clearance. This latter mechanism, however seems to be very important in the effectiveness of biological therapies, frequently used in HCV-related MC.
Host genetic determinants in HCV-related mixed cryoglobulinemia
GRAGNANI, LAURA;
2010-01-01
Abstract
HCV infection is strictly related to Mixed Cryoglobulinemia (MC), a lymphoproliferative/autoimmune disorder characterized by circulating immunoglobulin complexes (cryoglobulins). The reasons why only a percentage of HCV patients develops MC are still unknown. Two – not mutually exclusive – hypotheses could be suggested: (i) a reduced uptake/clearance of Igs by phagocytes (ii) an excessive production/secretion of Igs. The clearance of cryoglobulins is mediated by low-affinity FcG receptors (FcGRs). Single nucleotide polymorphisms affecting IgG-binding affinity are described for some receptors and particular aplotypes are related to autoimmunity. On the other hand, MC is characterized by B-cell expansion and abnormal Ig production involving specific cytokines, namely BAFF (B-cell Activating Factor). This study was aimed at evaluating the contribution of genetic host factors in the development of HCV-related MC. We analyzed, with different PCR-based techniques and RFLPs, the prevalence of FcGR polymorphisms (FcGR2A-131 R/A, FcGR2B-232I/T, FcGR3A-176V/F and FcGR3B-NA1/NA2) in 210 HCV+ patients (102 with MC(MC+) and 108 (MC−) without any evidence of lymphoproliferative/autoimmune disorders). The BAFF promoter polymorphism −871C/T, inducing a higher transcription of the BAFF gene, was also analyzed. A significantly higher prevalence of both T/T homozygosis (p < 0.001) and the presence of a T-allele (T/T and T/C, p = 0.004) at site −871 of BAFF promoter was shown in MC+ patients, resulting in a significant increase of BAFF serum concentration (4.12±1.29 vs. 2.09±0.81 ng/ml, p < 0.0001). Real-time-PCR analysis of the BAFF gene expression showed a 2.8-fold higher transcription in MC+. By contrast, no significant difference in prevalence of different FcGRs genotypes was observed. However, a trend towards a higher prevalence of the FcGR3A F/F genotype – showing a reduced affinity for IgG – was shown in MC+ patients (p = 0.09). Interestingly, in 19 MC+ patients undergoing anti-CD20 antibody treatment, the response was strictly related to the F-allele presence, being strongly reduced in F/F homozygous patients. These results underline the importance of the host genetic background in the development of HCV-related MC, suggesting that mechanisms enhancing Ig production and B-cell survival could have a more relevant role than genetic defects in cryoglobulin clearance. This latter mechanism, however seems to be very important in the effectiveness of biological therapies, frequently used in HCV-related MC.I documenti in IRIS sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
