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HS1.2 Allelic Frequencies Control IG Maturation and B Cells Numbers
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S.18. HS1.2 Allelic Frequencies Control IG Maturation and B Cells Numbers Franco Pandolfi 1, Rossella Cianci 1, Vincenzo Giambra 2, Giacomo Tampella 3, Marco Cattalini 3, Serena Lolli 1, Alessandro Plebani 3, Domenico Frezza 2. 1Catholic University, Rome, Italy; 2Tor Vergata University, Rome, Italy; 3University of Brescia, Brescia, Italy IgH chain 3'Regulatory Regions (RR) has a role in Ig synthesis. HS1.2 is the only polymorphic allele of the3’ RRs. It Allelic frequencies are changed in diseases with abnormal Ig production. We have recently demonstrated that frequency of allele *2 low and allele *1 high associate with selective IgA defect and relatively low IgM levels (Giambra et al. J. Immunol. Dec 15th 2009). We here expand the finding showing that the above mentioned frequencies also associates with relatively low percentages of B cells. The reference range for CD19 cells is 15% of lymphocytes. We analyzed subjects below or above this range. The results show an inverted trend in the 2 groups suggesting the correlation of low B-cells with increase of allele *1 and decrease allele *2 frequency. High number of B cells corresponds to: decread allele *1, increased allele *2. The difference of the frequency for the two alleles in the two groups is significant with a p value of 0.0289 and O.R. of 3.604. The association between allelic variability in 3'RR-1 and immunity is unclear, but HS1,2 allele *2 has a binding site for NF-κB, while allele *1 not. It has been shown that BAFF, April and BTK regulate B-cell survival via NF-κB, and therefore in allele *1 homozygosity, the missed sites for NF-κB may lead to Ig maturation and affect B cells survival and Ig switch. We suggest that the different alleles of HS1.2 play a role in Ig concentration and B-cell maturation. doi:10.1016/j.clim.2010.03.340
S.19. Multiple Genes within the Idd9.1 Region Regulate iNKT Cells and Type 1 Diabetes in NOD Mice Yi-Guang Chen, David Serreze. The Jackson Laboratory, Bar Harbor, ME Previously the Idd9.1 type 1 diabetes (T1D) susceptibility locus was mapped to a ∼18.4 Mb region on Chromosome 4. To further refine it, we generated 3 NOD congenic lines carrying different intervals of the B10-derived Idd9.1 region. The congenic intervals in these lines are defined by the same proximal marker rs13477946 (120.4 Mb) but the distal ends are distinct (Line-1: D4Mit72 at 128.6 Mb; Line-2: rs13459077 at 132.4 Mb; Line-3: D4Mit69 at 135.9 Mb). Incidence studies showed that both Lines-1 and 3 were more resistant than standard NOD mice to T1D development. Surprisingly, no protection was observed in Line-2. These results indicate that at least three genes in the previously reported Idd9.1 region interactively regulate T1D onset with two NOD and one B10derived susceptibility alleles. Further studies indicated that T1D development in these 3 lines was partially associated with the number and function of iNKT-cells. Compared to standard NOD mice, increased numbers of both thymic and splenic iNKTcells were observed in Line-1 but not Line-2. Marginally improved splenic but not thymic iNKT-cell numbers were shown in Line-3. Enhanced presentation of endogenous ligands
Abstracts contributed to increased iNKT-cell development in Line-1. Functionally, iNKT-cells in Line-1 produced elevated levels of IFNγ and IL-4 relative to those in standard NOD mice upon in vivo stimulation with α-GalCer. In contrast, the functional improvement of iNKT-cells was not observed in Lines-2 and 3. doi:10.1016/j.clim.2010.03.341
S.20. Genetic Study of IgA Nephropathy and Lupus Nephritis: No Overlap in Genetic Risk Factors Mai Vuong 1, Iva Gunnarsson 1, Sigrid Lundberg 1, Lars Wramner 3, Anders Fernstrom 4, Ann-Christine Syvänen 5, Lieu Do 2, Stefan Jacobson 1, Leonid Padyukov 1. 1Karolinska Institute, Stockholm, Sweden; 2Hanoi Medical University, Hanoi, Vietnam; 3Sahlgrenska University Hospital, Goteborg, Sweden; 4Linkoping University Hospital, Linkoping, Sweden; 5Uppsala University, Uppsala, Sweden Background: Recently, IRF5, STAT4 genes and TRAF1-C5 locus have been shown to be important candidate genes in systemic lupus erythematosus (SLE). We found association of IgA nephropathy with variants of TGFB1. The aim of the study was to compare the significance of genetic variants from the TGFB1, IRF5, STAT4 genes and TRAF1-C5 locus in association with susceptibility to IgA nephropathy and lupus nephritis in two Swedish cohorts. Patients and Methods: We genotyped thirteen SNPs in four genetic loci for 1026 DNA samples from patients with biopsy proven IgA nephropathy, SLE (with and without lupus nephritis) and healthy age- and sex- matched controls from the same population in Sweden. Results: Genotype and allelic frequencies for SNPs from selected genes did not significantly differ between lupus nephritis patients and SLE patients without nephritis. In addition, haplotype analysis for seven selected SNPs did not reveal the differences for two SLE patient groups with and without nephritis. Moreover, none of these SPNs did show the significant difference between IgA nephropathy patients and healthy controls. Genotype and allelic frequencies of STAT4 and TRAF1-C5 loci were not different between SLE with and without nephritis, or between IgA nephropathy patients and healthy controls. IRF5 and STAT4 variants remain significantly different between SLE cases and healthy controls, however. Conclusion: Our data demonstrate no overlap in genetic susceptibility between IgA nephropathy and SLE and reveal no specific importance of SLE associated SNPs for lupus nephritis. No association of TRAF1-C5 polymorphism with susceptibility to SLE in this Swedish population. doi:10.1016/j.clim.2010.03.342
S.21. A Novel Murine Model of Asthma in Mice Selected for Maximum Acute Inflammatory Response Momtchilo Russo 1, Juciane Castro 1, Lucas Faustino 1, Eliane Gomes 1, Orlando Ribeiro 2. 1University of São Paulo, Sao Paulo, Brazil; 2Instituto Butantan, Sao Paulo, Brazil Asthma is characterized by chronic inflammation of airway mucosa and airway hyperresponsiveness (AHR). Asthmatic patients can respond to allergen provocation in
S.18. HS1.2 Allelic Frequencies Control IG Maturation and B Cells Numbers Franco Pandolfi 1, Rossella Cianci 1, Vincenzo Giambra 2, Giacomo Tampella 3, Marco Cattalini 3, Serena Lolli 1, Alessandro Plebani 3, Domenico Frezza 2. 1Catholic University, Rome, Italy; 2Tor Vergata University, Rome, Italy; 3University of Brescia, Brescia, Italy IgH chain 3'Regulatory Regions (RR) has a role in Ig synthesis. HS1.2 is the only polymorphic allele of the3’ RRs. It Allelic frequencies are changed in diseases with abnormal Ig production. We have recently demonstrated that frequency of allele *2 low and allele *1 high associate with selective IgA defect and relatively low IgM levels (Giambra et al. J. Immunol. Dec 15th 2009). We here expand the finding showing that the above mentioned frequencies also associates with relatively low percentages of B cells. The reference range for CD19 cells is 15% of lymphocytes. We analyzed subjects below or above this range. The results show an inverted trend in the 2 groups suggesting the correlation of low B-cells with increase of allele *1 and decrease allele *2 frequency. High number of B cells corresponds to: decread allele *1, increased allele *2. The difference of the frequency for the two alleles in the two groups is significant with a p value of 0.0289 and O.R. of 3.604. The association between allelic variability in 3'RR-1 and immunity is unclear, but HS1,2 allele *2 has a binding site for NF-κB, while allele *1 not. It has been shown that BAFF, April and BTK regulate B-cell survival via NF-κB, and therefore in allele *1 homozygosity, the missed sites for NF-κB may lead to Ig maturation and affect B cells survival and Ig switch. We suggest that the different alleles of HS1.2 play a role in Ig concentration and B-cell maturation. doi:10.1016/j.clim.2010.03.340
S.19. Multiple Genes within the Idd9.1 Region Regulate iNKT Cells and Type 1 Diabetes in NOD Mice Yi-Guang Chen, David Serreze. The Jackson Laboratory, Bar Harbor, ME Previously the Idd9.1 type 1 diabetes (T1D) susceptibility locus was mapped to a ∼18.4 Mb region on Chromosome 4. To further refine it, we generated 3 NOD congenic lines carrying different intervals of the B10-derived Idd9.1 region. The congenic intervals in these lines are defined by the same proximal marker rs13477946 (120.4 Mb) but the distal ends are distinct (Line-1: D4Mit72 at 128.6 Mb; Line-2: rs13459077 at 132.4 Mb; Line-3: D4Mit69 at 135.9 Mb). Incidence studies showed that both Lines-1 and 3 were more resistant than standard NOD mice to T1D development. Surprisingly, no protection was observed in Line-2. These results indicate that at least three genes in the previously reported Idd9.1 region interactively regulate T1D onset with two NOD and one B10derived susceptibility alleles. Further studies indicated that T1D development in these 3 lines was partially associated with the number and function of iNKT-cells. Compared to standard NOD mice, increased numbers of both thymic and splenic iNKTcells were observed in Line-1 but not Line-2. Marginally improved splenic but not thymic iNKT-cell numbers were shown in Line-3. Enhanced presentation of endogenous ligands
Abstracts contributed to increased iNKT-cell development in Line-1. Functionally, iNKT-cells in Line-1 produced elevated levels of IFNγ and IL-4 relative to those in standard NOD mice upon in vivo stimulation with α-GalCer. In contrast, the functional improvement of iNKT-cells was not observed in Lines-2 and 3. doi:10.1016/j.clim.2010.03.341
S.20. Genetic Study of IgA Nephropathy and Lupus Nephritis: No Overlap in Genetic Risk Factors Mai Vuong 1, Iva Gunnarsson 1, Sigrid Lundberg 1, Lars Wramner 3, Anders Fernstrom 4, Ann-Christine Syvänen 5, Lieu Do 2, Stefan Jacobson 1, Leonid Padyukov 1. 1Karolinska Institute, Stockholm, Sweden; 2Hanoi Medical University, Hanoi, Vietnam; 3Sahlgrenska University Hospital, Goteborg, Sweden; 4Linkoping University Hospital, Linkoping, Sweden; 5Uppsala University, Uppsala, Sweden Background: Recently, IRF5, STAT4 genes and TRAF1-C5 locus have been shown to be important candidate genes in systemic lupus erythematosus (SLE). We found association of IgA nephropathy with variants of TGFB1. The aim of the study was to compare the significance of genetic variants from the TGFB1, IRF5, STAT4 genes and TRAF1-C5 locus in association with susceptibility to IgA nephropathy and lupus nephritis in two Swedish cohorts. Patients and Methods: We genotyped thirteen SNPs in four genetic loci for 1026 DNA samples from patients with biopsy proven IgA nephropathy, SLE (with and without lupus nephritis) and healthy age- and sex- matched controls from the same population in Sweden. Results: Genotype and allelic frequencies for SNPs from selected genes did not significantly differ between lupus nephritis patients and SLE patients without nephritis. In addition, haplotype analysis for seven selected SNPs did not reveal the differences for two SLE patient groups with and without nephritis. Moreover, none of these SPNs did show the significant difference between IgA nephropathy patients and healthy controls. Genotype and allelic frequencies of STAT4 and TRAF1-C5 loci were not different between SLE with and without nephritis, or between IgA nephropathy patients and healthy controls. IRF5 and STAT4 variants remain significantly different between SLE cases and healthy controls, however. Conclusion: Our data demonstrate no overlap in genetic susceptibility between IgA nephropathy and SLE and reveal no specific importance of SLE associated SNPs for lupus nephritis. No association of TRAF1-C5 polymorphism with susceptibility to SLE in this Swedish population. doi:10.1016/j.clim.2010.03.342
S.21. A Novel Murine Model of Asthma in Mice Selected for Maximum Acute Inflammatory Response Momtchilo Russo 1, Juciane Castro 1, Lucas Faustino 1, Eliane Gomes 1, Orlando Ribeiro 2. 1University of São Paulo, Sao Paulo, Brazil; 2Instituto Butantan, Sao Paulo, Brazil Asthma is characterized by chronic inflammation of airway mucosa and airway hyperresponsiveness (AHR). Asthmatic patients can respond to allergen provocation in