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  • 1.
    Andersen, Marie Louise M.
    et al.
    Danmark.
    Vaziri-Sani, Fariba
    Kristianstad University, Research environment Man & Biosphere Health (MABH). Lunds universitet.
    Delli, Ahmed
    Skåne University Hospital .
    Pörksen, Sven
    Danmark.
    Jacobssen, Emma
    Skåne University Hospital .
    Thomsen, Jane
    Danmark.
    Svensson, Jannet
    Danmark.
    Petersen, Jacob Steen
    Danmark.
    Hansen, Lars
    Danmark.
    Lernmark, Ake
    Skåne University Hospital .
    Mortensen, Henrik B
    Danmark.
    Nielsen, Lotte B
    Danmark.
    Association between autoantibodies to the Arginine variant of the Zinc transporter 8 (ZnT8) and stimulated C-peptide levels in Danish children and adolescents with newly diagnosed type 1 diabetes2012In: Pediatric Diabetes, ISSN 1399-543X, E-ISSN 1399-5448, Vol. 13, no 6, p. 454-462Article in journal (Refereed)
    Abstract [en]

    Background

    The zinc transporter 8 (ZnT8) was recently identified as a common autoantigen in type 1 diabetes (T1D) and inclusion of ZnT8 autoantibodies (ZnT8Ab) was found to increase the diagnostic specificity of T1D.

    Objectives

    The main aims were to determine whether ZnT8Ab vary during follow-up 1 year after diagnosis, and to relate the reactivity of three types of ZnT8Ab to the residual stimulated C-peptide levels during the first year after diagnosis. Subjects A total of 129 newly diagnosed T1D patients <15 years was followed prospectively 1, 3, 6, and 12 months after diagnosis.

    Methods

    Hemoglobin A1c, meal-stimulated C-peptide, ZnT8Ab, and other pancreatic autoantibodies were measured at each visit. Patients were genotyped for the rs13266634 variant at the SLC30A8 gene and HLA-DQ alleles. Results The levels of all ZnT8Ab [ZnT8Arg (arginine), ZnT8Trp (tryptophan), ZnT8Gln (glutamine)] tended to decrease during disease progression. A twofold higher level of ZnT8Arg and ZnT8Gln was associated with 4.6%/5.2% (p = 0.02), 5.3%/8.2% (p = 0.02) and 8.9%/9.7% (p = 0.004) higher concentrations of stimulated C-peptide 3, 6, and 12 months after diagnosis. The TT genotype carriers of the SLC30A8 gene had 45.8% (p = 0.01) and 60.1% (p = 0.002) lower stimulated C-peptide 6 and 12 months after diagnosis compared to the CC and the CT genotype carriers in a recessive model.

    Conclusions

    The levels of the Arg variant of the ZnT8 autoantibodies are associated with higher levels of stimulated C-peptide after diagnosis of T1D and during follow-up. Carriers of the TT genotype of the SLC30A8 gene predict lower stimulated C-peptide levels 12 months after diagnosis.

  • 2.
    Andersson, C
    et al.
    Lund University.
    Larsson, K
    Deparment of Paediatrics, Kristianstad hospital.
    Vaziri-Sani, Fariba
    Lund University.
    Lynch, K
    Lund University.
    Carlsson, A
    Lund University.
    Cedervall, E
    Ängelholm hospital.
    Jönsson, B
    Ystad hospital.
    Neiderud, J
    Helsingborg hospital.
    Månsson, M
    Lund University.
    Nilsson, A
    Lund University.
    Lernmark, Å
    Lund University.
    Elding Larsson, H
    Lund Univeristy.
    Ivarsson, SA
    Lund University.
    The three ZNT8 autoantibody variants together improve the diagnostic sensitivity of childhood and adolescent type 1 diabetes2011In: Autoimmunity, ISSN 0891-6934, E-ISSN 1607-842X, Vol. 44, no 5, p. 394-405Article in journal (Refereed)
    Abstract [en]

    Aims: We tested whether autoantibodies to all three ZnT8RWQ variants, GAD65, insulinoma-associated protein 2 (IA-2), insulin and autoantibodies to islet cell cytoplasm (ICA) in combination with human leukocyte antigen (HLA) would improve the diagnostic sensitivity of childhood type 1 diabetes by detecting the children who otherwise would have been autoantibody-negative.

    Methods: A total of 686 patients diagnosed in 1996–2005 in Skåne were analyzed for all the seven autoantibodies [arginin 325 zinc transporter 8 autoantibody (ZnT8RA), tryptophan 325 zinc transporter 8 autoantibody (ZnT8WA), glutamine 325 Zinc transporter 8 autoantibody (ZnT8QA), autoantibodies to glutamic acid decarboxylase (GADA), Autoantibodies to islet-antigen-2 (IA-2A), insulin autoantibodies (IAA) and ICA] in addition to HLA-DQ genotypes.

    Results: Zinc transporter 8 autoantibody to either one or all three amino acid variants at position 325 (ZnT8RWQA) was found in 65% (449/686) of the patients. The frequency was independent of age at diagnosis. The ZnT8RWQA reduced the frequency of autoantibody-negative patients from 7.5 to 5.4%—a reduction by 28%. Only 2 of 108 (2%) patients who are below 5 years of age had no autoantibody at diagnosis. Diagnosis without any islet autoantibody increased with increasing age at onset. DQA1-B1*X-0604 was associated with both ZnT8RA (p = 0.002) and ZnT8WA (p = 0.01) but not with ZnT8QA (p = 0.07). Kappa agreement analysis showed moderate (>0.40) to fair (>0.20) agreement between pairs of autoantibodies for all combinations of GADA, IA-2A, ZnT8RWQA and ICA but only slight ( < 0.19) agreement for any combination with IAA.

    Conclusions: This study revealed that (1) the ZnT8RWQA was common, independent of age; (2) multiple autoantibodies were common among the young; (3) DQA1-B1*X-0604 increased the risk for ZnT8RA and ZnT8WA; (4) agreement between autoantibody pairs was common for all combinations except IAA. These results suggest that ZnT8RWQA is a necessary complement to the classification and prediction of childhood type 1 diabetes as well as to randomize the subjects in the prevention and intervention of clinical trials.

  • 3.
    Andersson, C
    et al.
    Lund Univeristy.
    Vaziri-Sani, Fariba
    Lunds universitet.
    Delli, AJ
    Lund University.
    Lindblad, B
    The Queen Silvia Children's Hospital .
    Carlsson, A
    Lund University.
    Forsander, G
    The Queen Silvia Children's Hospital .
    Ludvigsson, J
    Linköping University.
    Marcus, C
    Karolinska Institute.
    Samuelsson, U
    Linköping Univeristy Hospital.
    Ivarsson, SA
    Lund University.
    Lernmark, Å
    Lund University.
    Elding Larsson, H
    Lund Univeristy.
    Triple specificity of ZnT8 autoantibodies in relation to HLA and other islet autoantibodies in childhood and adolescent type 1 diabetes2013In: Pediatric Diabetes, ISSN 1399-543X, E-ISSN 1399-5448, Vol. 14, no 2, p. 97-105Article in journal (Refereed)
    Abstract [en]

    Objective

    To establish the diagnostic sensitivity of and the relationships between autoantibodies to all three Zinc transporter 8 (Zinc transporter 8 autoantibody to either one, two, or all three amino acid variants at position 325, ZnT8A) variants to human leukocyte antigen (HLA)-DQ and to autoantibodies to glutamic acid decarboxylase (GADA), insulinoma-associated protein 2 (IA-2A), and insulin (IAA).

    Methods

    We analyzed 3165 patients with type 1 diabetes (T1D) in the Better Diabetes Diagnosis study for HLA-DQ genotypes and all six autoantibodies (ZnT8RA, arginine 325 Zinc transporter 8 autoantibody; ZnT8WA, tryptophan 325 Zinc transporter 8 autoantibody; ZnT8QA, glutamine 325 Zinc transporter 8 autoantibody; GADA, IA-2A, and IAA).

    Results

    ZnT8A was found in 65% of the patients and as many as 108 of 3165 (3.4%) had 1–3 ZnT8A alone. None had ZnT8QA alone. Together with GADA (56%), IA-2A (73%), and IAA (33%), 93% of the T1D patients were autoantibody positive. All three ZnT8A were less frequent in children below 2 yr of age (p < 0.0001). All three ZnT8A were associated with DQA1-B1*X-0604 (DQ6.4) and DQA1-B1*03-0302 (DQ8). ZnT8WA and ZnT8QA were negatively associated with DQA1-B1*05-02 (DQ2).

    Conclusions

    Analysis of ZnT8A increased the diagnostic sensitivity of islet autoantibodies for T1D as only 7% remained islet autoantibody negative. The association between DQ6.4 and all three ZnT8A may be related to ZnT8 antigen presentation by the DQ6.4 heterodimer.

  • 4.
    Araujo de Pina Cabral, DB
    et al.
    Brasilien.
    Dantas, JR
    Brasilien.
    Skärstrand, H
    Lund University.
    Barone, B
    Brasilien.
    Carvalho, F
    Brasilien.
    Tortora, R
    Brasilien.
    Milech, A
    Brasilien.
    Vaziri-Sani, Fariba
    Lunds universitet.
    Oliveira, JE
    Brasilien.
    Zajdenverg, L
    Brasilien.
    Rodacki, M
    Brasilien.
    Prospective evaluation of glutamine and phospholipids levels in first degree relatives of patients with Type 1 Diabetes from a multiethnic population2015In: Diabetology and Metabolic Syndrome, ISSN 1758-5996, E-ISSN 1758-5996, Vol. 7, no 52Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: A dysregulation in the metabolism of lipids may be an early marker of autoimmunity in Type 1 Diabetes (T1D). It would be of general importance to identify metabolic patterns that would predict the risk for T1D later in life. The aim of this study was to perform a prospective evaluation of glutamine and phospholipids levels in Brazilian first degree relatives (FDR) of patients with T1D in a mean interval of 5 years.

    FINDINGS: Brazilian FDR (n = 30) of patients with T1D were evaluated and blood was sampled to measure the levels of glutamine and phospholipids in the fasting serum by quantitative colorimetric method. The tests were repeated after a mean interval of 5 years and compared to a control group (n = 20). The FDR presented lower levels of phospholipids than controls (p = 0.028), but not of glutamine (p = 0.075). Phospholipids levels decreased over time (p = 0.028) in FDR and were associated with Glutamic acid decarboxylase autoantibody (GADA) titers (p = 0.045), autoantibody positivity (p = 0.008) and PTPN22 polymorphisms (p = 0.014).

    CONCLUSIONS: In this Brazilian multiethnic population, there was a significant decrease in phospholipids levels in FDR in patients with T1D during a 5-year prospective follow-up, as well as a significant association between these metabolite, GADA and PTPN22 polymorphisms. For Glutamine no difference was found. These findings suggest that a dysregulation in the metabolism of lipids may precede the onset of the autoimmunity in T1D.

  • 5.
    Araujo, Débora Batista
    et al.
    Brasilien.
    Skärstrand, Hanna
    Lund University.
    Barone, Bianca
    Brasilien.
    Dantas, Joana Rodrigues
    Brasilien.
    Kupfer, Rosane
    Brasilien.
    Zajdenverg, Lenita
    Brasilien.
    Milech, Adolpho
    Brasilien.
    Vaziri-Sani, Fariba
    Brasilien.
    Oliveira, José Egídio Paulo de
    Brasilien.
    Rodacki, Melanie
    Brasilien.
    Zinc transporter 8 autoantibodies in patients with type 1 diabetes from a multiethnic population and their first degree relatives2014In: Arquivos brasileiros de endocrinologia e metabologia, ISSN 0004-2730, E-ISSN 1677-9487, Vol. 58, no 7, p. 737-743Article in journal (Refereed)
    Abstract [en]

    OBJECTIVE: Zinc transporter 8 autoantibodies (ZnT8A) have been poorly studied in non-Caucasian individuals. We aimed to investigate the prevalence of ZnT8 autoantibodies in patients with T1D and their first degree relatives (FDR) from a multiethnic population, as well as its relation with the insulin (INS) or the protein tyrosine phosphatase non-receptor 22 (PTPN22) gene polymorphisms.

    SUBJECTS AND METHODS: ZnT8A were analyzed in sera from T1D patients (n = 72, mean age of 30.3 ± 11.4 years) of variable duration (15.7 ± 11.8 years) and their FDR (n = 78, mean age of 18.3 ± 9.1 years) by a triple mix Radioligand Binding Assay (RBA) for the ZnT8 autoantibody (ZnT8-RWQ) variants. SNP (single nucleotide polymorphism) for INS and PTPN22 were genotyped.

    RESULTS: The prevalence of ZnT8A was higher in T1D patients than FDR, for ZnT8TripleA (24% vs. 4%,p = 0.001), ZnT8RA (24% vs. 4%, p < 0.001) and ZnT8QA (15% vs. 3%, p = 0.004). All FDR with ZnT8A (n = 3) had at least another positive antibody. Heterozygosis for PTPN22 was associated with a higher frequency of ZnT8TripleA (p = 0.039) and ZnT8RA (p = 0.038).

    CONCLUSIONS: ZnT8A is observed in non-Caucasian patients with T1D, even years after the disease onset, as well as in their FDR. In those, there was an overlap between ZnT8A and other T1D antibodies. ZnT8A was associated with PTPN22 polymorphisms. Further longitudinal studies are necessary to elucidate the importance of these findings in the natural history of T1D patients with multiethnic background.

  • 6.
    Brorsson, Caroline
    et al.
    Danmark.
    Vaziri-Sani, Fariba
    Lund University.
    Bergholdt, Regine
    Danmark.
    Eising, Stefanie
    Danmark.
    Nilsson, Anita
    Lund University.
    Svensson, Jannet
    Danmark.
    Lernmark, Ake
    Lund University.
    Pociot, Flemming
    Danmark.
    Correlations between islet autoantibody specificity and the SLC30A8 genotype with HLA-DQB1 and metabolic control in new onset type 1 diabetes2011In: Autoimmunity, ISSN 0891-6934, E-ISSN 1607-842X, Vol. 44, no 2, p. 107-114Article in journal (Refereed)
    Abstract [en]

    We hypothesised that the correlation between autoantibody specificity for the ZnT8 Arg325Trp isoforms and the type 2 diabetes-associated rs13266634 may affect beta-cell function at type 1 diabetes (T ID) onset. To study this, we tested 482 newly diagnosed diabetic probands and 478 healthy siblings from the Danish population-based T1D registry for autoantibodies to ZnT8 (ZnT8A) in addition to GAD65 and IA-2. The prevalence and titres of autoantibodies were correlated with genotypes for rs13266634 and HLA-DQB1, age at diagnosis (AAD) and insulin dose-adjusted HbA1c (IDAA1c), as a proxy for residual beta-cell function. We replicated the correlation between rs13266634 genotypes and specificity for the ZnT8-Argenine (ZnT8R) and ZnT8-Tryptophan (ZnT8W) isoforms previously reported. ZnT8A overlapped substantially with autoantibodies to glutamate decarboxylase 65 (GADA) and IA-2 (IA-2A) and correlated significantly with IA-2A prevalence (p < 2e-16). No effect on IDAA1c was demonstrated for ZnT8A or rs13266634. We found a correlation between ZnT8R positivity and HLA-DQB1*0302 genotypes (p = 0.016), which has not been shown previously. Furthermore, significantly lower ZnT8R and GADA prevalence and titres was found among probands with AAD < 5 years (prevalence: p = 0.004 and p = 0.0001; titres: p = 0.002 and p = 0.001, respectively). The same trend was observed for IA-2A and ZnT8W; however, the difference was non-significant. Our study confirms ZnT8 as a major target for autoantibodies at disease onset in our Danish T1D cohort of children and adolescents, and we have further characterised the relationship between autoantibody specificity for the ZnT8 Arg325Trp epitopes and rs13266634 in relation to established autoantibodies, AAD, measures of beta-cell function and HLA-DQB1 genotypes in T1D.

  • 7.
    Delli, Ahmed J.
    et al.
    Lund University.
    Vaziri-Sani, Fariba
    Lund University.
    Lindblad, Bengt
    University of Gothenburg.
    Elding Larsson, H
    Lund Univeristy.
    Carlsson, Annellie
    Lund University.
    Forsander, Gun
    Sahlgrenska University Hospital.
    Ivarsson, Sten A.
    Lund University.
    Ludvigsson, Johnny
    Linköping University.
    Kockum, Ingrid
    Karolinska Institute.
    Marcus, Claude
    Karolinska Institute.
    Samuelsson, Ulf
    Linköping University Hospital.
    Örtqvist, Eva
    Karolinska Institute.
    Groop, Leif
    Lund University.
    Bondinas, George P.
    Grekland.
    Papadopoulos, George K.
    Grekland.
    Lernmark, Ake
    Lund University.
    Zinc Transporter 8 Autoantibodies and Their Association With SLC30A8 and HLA-DQ Genes Differ Between Immigrant and Swedish Patients With Newly Diagnosed Type 1 Diabetes in the Better Diabetes Diagnosis Study2012In: Diabetes, ISSN 0012-1797, E-ISSN 1939-327X, Vol. 61, no 10, p. 2556-2564Article in journal (Refereed)
    Abstract [en]

    We examined whether zinc transporter 8 autoantibodies (ZnT8A; arginine ZnT8-RA, tryptophan ZnT8-WA, and glutamine ZnT8-QA variants) differed between immigrant and Swedish patients due to different polymorphisms of SLC30A8, HLA-DQ, or both. Newly diagnosed autoimmune (>= 1 islet autoantibody) type 1 diabetic patients (n = 2,964, <18 years, 55% male) were ascertained in the Better Diabetes Diagnosis study. Two subgroups were identified: Swedes (n = 2,160, 73%) and immigrants (non-Swedes; n = 212, 7%). Non-Swedes had less frequent ZnT8-WA (38%) than Swedes (50%), consistent with a lower frequency in the non-Swedes (37%) of SLC30A8 CT+TT (RW+WW) genotypes than in the Swedes (54%). ZnT8-RA (57 and 58%, respectively) did not differ despite a higher frequency of CC (RR) genotypes in non-Swedes (63%) than Swedes (46%). We tested whether this inconsistency was due to HLA-DQ as 2/X (2/2; 2/y; y is anything but 2 or 8), which was a major genotype in non-Swedes (40%) compared with Swedes (14%). In the non-Swedes only, 2/X (2/2; 2/y) was negatively associated with ZnT8-WA and ZnT8-QA but not ZnT8-RA. Molecular simulation showed nonbinding of the relevant ZnT8-R peptide to DQ2, explaining in part a possible lack of tolerance to ZnT8-R. At diagnosis in non-Swedes, the presence of ZnT8-RA rather than ZnT8-WA was likely due to effects of HLA-DQ2 and the SLC30A8 CC (RR) genotypes.

  • 8. Flannick, Jason
    et al.
    Thorleifsson, Gudmar
    Beer, Nicola L.
    Jacobs, Suzanne B. R.
    Grarup, Niels
    Burtt, Noel P.
    Mahajan, Anubha
    Fuchsberger, Christian
    Atzmon, Gil
    Benediktsson, Rafn
    Blangero, John
    Bowden, Don W.
    Brandslund, Ivan
    Brosnan, Julia
    Burslem, Frank
    Chambers, John
    Cho, Yoon Shin
    Christensen, Cramer
    Douglas, Desiree A.
    Duggirala, Ravindranath
    Dymek, Zachary
    Farjoun, Yossi
    Fennell, Timothy
    Fontanillas, Pierre
    Forsen, Tom
    Gabriel, Stacey
    Glaser, Benjamin
    Gudbjartsson, Daniel F.
    Hanis, Craig
    Hansen, Torben
    Hreidarsson, Astradur B.
    Hveem, Kristian
    Ingelsson, Erik
    Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Isomaa, Bo
    Johansson, Stefan
    Jorgensen, Torben
    Jorgensen, Marit Eika
    Kathiresan, Sekar
    Kong, Augustine
    Kooner, Jaspal
    Kravic, Jasmina
    Laakso, Markku
    Lee, Jong-Young
    Lind, Lars
    Uppsala universitet.
    Lindgren, Cecilia M.
    Linneberg, Allan
    Masson, Gisli
    Meitinger, Thomas
    Mohlke, Karen L.
    Molven, Anders
    Morris, Andrew P.
    Potluri, Shobha
    Rauramaa, Rainer
    Ribel-Madsen, Rasmus
    Richard, Ann-Marie
    Rolph, Tim
    Salomaa, Veikko
    Segre, Ayellet V.
    Skaerstrand, Hanna
    Steinthorsdottir, Valgerdur
    Stringham, Heather M.
    Sulem, Patrick
    Tai, E. Shyong
    Teo, Yik Ying
    Teslovich, Tanya
    Thorsteinsdottir, Unnur
    Trimmer, Jeff K.
    Tuomi, Tiinamaija
    Tuomilehto, Jaakko
    Vaziri-Sani, Fariba
    Lunds universitet.
    Voight, Benjamin F.
    Wilson, James G.
    Boehnke, Michael
    McCarthy, Mark I.
    Njolstad, Pal R.
    Pedersen, Oluf
    Groop, Leif
    Cox, David R.
    Stefansson, Kari
    Altshuler, David
    Loss-of-function mutations in SLC30A8 protect against type 2 diabetes2014In: Nature Genetics, ISSN 1061-4036, E-ISSN 1546-1718, Vol. 46, no 4, p. 357-363Article in journal (Refereed)
    Abstract [en]

    Loss-of-function mutations protective against human disease provide in vivo validation of therapeutic targets1-3, but none have yet been described for type 2 diabetes (T2D). Through sequencing or genotyping of -150,000 individuals across 5 ancestry groups, we identified 12 rare protein-truncating variants in SLC30A8, which encodes an islet zinc transporter (ZnT8) 4 and harbors a common variant (p. Trp325Arg) associated with T2D risk and glucose and proinsulin levels5-7. Collectively, carriers of protein-truncating variants had 65% reduced T2D risk (P = 1.7 x 10(-6)), and non-diabetic Icelandic carriers of a frameshift variant (p. Lys34Serfs* 50) demonstrated reduced glucose levels (-0.17 s. d., P = 4.6 x 10(-4)). The two most common proteintruncating variants (p. Arg138* and p. Lys34Serfs* 50) individually associate with T2D protection and encode unstable ZnT8 proteins. Previous functional study of SLC30A8 suggested that reduced zinc transport increases T2D risk(8,9), and phenotypic heterogeneity was observed in mouse Slc30a8 knockouts(10-15). In contrast, loss-of-function mutations in humans provide strong evidence that SLC30A8 haploinsufficiency protects against T2D, suggesting ZnT8 inhibition as a therapeutic strategy in T2D prevention.

  • 9.
    Ingemansson, Sofie
    et al.
    Lund University.
    Vaziri-Sani, Fariba
    Lund University.
    Lindblad, Ulf
    University of Gothenburg.
    Gudbjornsdottir, Soffia
    The Nordic Research Academy for Global Health.
    Törn, Carina
    Lund University.
    Long-term sustained autoimmune response to beta cell specific zinc transporter (ZnT8, W, R, Q) in young adult patients with preserved beta cell function at diagnosis of diabetes2013In: Autoimmunity, ISSN 0891-6934, E-ISSN 1607-842X, Vol. 46, no 1, p. 50-61Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to examine whether autoantibodies to: ZnT8-Tryptophan (ZnT8WA), ZnT8-Arginine (ZnT8RA) or ZnT8-Glutamine (ZnT8QA) correlated with C-peptide or other autoantibodies and to assess diagnostic sensitivity of ZnT8WRQA. Specimens from 270 newly diagnosed diabetic subjects (age 15-34 years) and after 5 years duration of disease were examined. Four linear regression models were used to dissect the importance of different factors from diagnosis for the respective difference of (logZnT8WA), (logZnT8RA) and (logZnT8QA); A) unadjusted model for: initial C-peptide, age, BMI, gender, clinical classification, ICA, GADA, IA-2A, (ZnT8WA/ZnT8RA/ZnT8QA); B) C-peptide corrected for clinical factors; C) C-peptide corrected for autoantibodies; D) C-peptide corrected for all factors. The least decrease of ZnT8WA was observed in patients with high initial C-peptide in all models A) p = 0.054; B) p = 0.021; C) p = 0.047 and D) p = 0.017. A less statistically significant decrease of ZnT8RA was observed in patients with high initial C-peptide in A) p = 0.038 and C) p = 0.047, but this finding was not confirmed in B or D. The decrease of ZnT8QA levels was not related to C-peptide in any model but correlated to age D) p = 0.049. Furthermore, patients with unclassifiable diabetes showed the least decrease in D) p = 0.035. ZnT8WA, ZnT8RA or ZnT8QA were identified as a single autoantibody in 3.8% (10/266) of patients, thereby increasing diagnostic sensitivity from 79.3% (211/266) to 83.1% (221/266). In conclusion, high initial C-peptide was the most important factor even after adjusting for other factors in patients positive for ZnT8WA or ZnT8RA to remain autoantibody positive 5 years after diagnosis.

  • 10.
    Kanatsuna, N
    et al.
    Lund University.
    Delli, A
    Lund University.
    Andersson, C
    Lund University.
    Nilsson, A-L
    Lund University.
    Vaziri-Sani, Fariba
    Lund University.
    Larsson, K
    Kristianstad Hospital.
    Carlsson, A
    Lund University.
    Cedervall, E
    Ängelholm Hospital.
    Jönsson, B
    Ystad Hospital.
    Neiderud, J
    Helsingborg Hospital.
    Elding Larsson, H
    Lund University.
    Ivarsson, S-A
    Lund University.
    Törn, C
    Lund University.
    Fex, M
    Lund University.
    Lernmark, Å
    Lund University.
    Doubly reactive INS-IGF2 autoantibodies in children with newly diagnosed autoimmune (type 1) diabetes2015In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 82, no 4, p. 361-369Article in journal (Refereed)
    Abstract [en]

    The splice variant INS-IGF2 entails the preproinsulin signal peptide, the insulin B-chain, eight amino acids of the C-peptide and 138 unique amino acids from an ORF in the IGF2 gene. The aim of this study was to determine whether levels of specific INS-IGF2 autoantibodies (INS-IGF2A) were related to age at diagnosis, islet autoantibodies, HLA-DQ or both, in patients and controls with newly diagnosed type 1 diabetes. Patients (n = 676), 0-18 years of age, diagnosed with type 1 diabetes in 1996-2005 and controls (n = 363) were analysed for specific INS-IGF2A after displacement with both cold insulin and INS-IGF2 to correct for non-specific binding and identify double reactive sera. GADA, IA-2A, IAA, ICA, ZnT8RA, ZnT8WA, ZnT8QA and HLA-DQ genotypes were also determined. The median level of specific INS-IGF2A was higher in patients than in controls (P < 0.001). Irrespective of age at diagnosis, 19% (126/676) of the patients had INS-IGF2A when the cut-off was the 95th percentile of the controls (P < 0.001). The risk of INS-IGF2A was increased among HLA-DQ2/8 (OR = 1.509; 95th CI 1.011, 2.252; P = 0.045) but not in 2/2, 2/X, 8/8, 8/X or X/X (X is neither 2 nor 8) patients. The association with HLA-DQ2/8 suggests that this autoantigen may be presented on HLA-DQ trans-heterodimers, rather than cis-heterodimers. Autoantibodies reactive with both insulin and INS-IGF2A at diagnosis support the notion that INS-IGF2 autoimmunity contributes to type 1 diabetes.

  • 11. Kanatsuna, Norio
    et al.
    Taneera, Jalal
    Vaziri-Sani, Fariba
    Lund University.
    Wierup, Nils
    Larsson, Helena Elding
    Delli, Ahmed
    Skarstrand, Hanna
    Balhuizen, Alexander
    Bennet, Hedvig
    Steiner, Donald F.
    Torn, Carina
    Fex, Malin
    Lernmark, Ake
    Autoimmunity against INS-IGF2 Protein Expressed in Human Pancreatic Islets2013In: Journal of Biological Chemistry, ISSN 0021-9258, E-ISSN 1083-351X, Vol. 288, no 40, p. 29013-29023Article in journal (Refereed)
    Abstract [en]

    Insulin is a major autoantigen in islet autoimmunity and progression to type 1 diabetes. It has been suggested that the insulin B-chain may be critical to insulin autoimmunity in type 1 diabetes. INS-IGF2 consists of the preproinsulin signal peptide, the insulin B-chain, and eight amino acids of the C-peptide in addition to 138 amino acids from the IGF2 gene. We aimed to determine the expression of INS-IGF2 in human pancreatic islets and autoantibodies in newly diagnosed children with type 1 diabetes and controls. INS-IGF2, expressed primarily in beta cells, showed higher levels of expression in islets from normal compared with donors with either type 2 diabetes (p = 0.006) or high HbA1c levels (p < 0.001). INS-IGF2 autoantibody levels were increased in newly diagnosed patients with type 1 diabetes (n = 304) compared with healthy controls (n = 355; p < 0.001). Displacement with cold insulin and INS-IGF2 revealed that more patients than controls had doubly reactive insulin-INS-IGF2 autoantibodies. These data suggest that INS-IGF2, which contains the preproinsulin signal peptide, the B-chain, and eight amino acids of the C-peptide may be an autoantigen in type 1 diabetes. INS-IGF2 and insulin may share autoantibody-binding sites, thus complicating the notion that insulin is the primary autoantigen in type 1 diabetes.

  • 12.
    Karpman, D
    et al.
    Lunds universitet.
    Manea, M
    Lunds universitet.
    Vaziri-Sani, Fariba
    Lunds universitet.
    Stahl, A L
    Lunds universitet.
    Kristoffersson, A C
    Lunds universitet.
    Platelet activation in hemolytic uremic syndrome2006In: Seminars in Thrombosis and Hemostasis, ISSN 0094-6176, E-ISSN 1098-9064, Vol. 32, no 2, p. 128-145Article in journal (Refereed)
    Abstract [en]

    Platelet consumption in platelet-fibrin aggregates leading to thrombocytopenia and small vessel obstruction are major features of the hemolytic uremic syndrome (HUS). Although thrombocytopenia has been correlated to poor prognosis, the mechanisms by which thrombocytopenia develops in HUS have not been completely elucidated. However, plausible explanations have been platelet contact with thrombogenic surfaces and/or direct contact with an aggregating agent. This article summarizes several mechanisms of platelet activation, interactions with leukocytes, chemokine release, complement activation, and antimicrobial defense. Specific mechanisms are outlined by which platelets may be activated, leading to thrombocytopenia during HUS. In diarrhea-associated HUS Shiga toxin has been shown to injure the endothelium, thus exposing the subendothelium, releasing tissue factor, and rendering the vessel wall prothrombotic. Shiga toxin also binds to and activates platelets. The toxin may activate endothelial cells and platelets simultaneously. In atypical HUS the alternative complement pathway is activated because of mutations in complement regulatory proteins. Mutated factor H does not bind to endothelium and platelets efficiently, enabling complement activation on these cells. In thrombotic thrombocytopenic purpura, intravascular platelet clotting Occurs due to dysfunction of the von Willebrand factor (VWF)-cleaving protease ADAMTS13. Thrombi are formed by binding of platelets to ultralarge VWF multimers.

  • 13.
    Kjellerås, Jennifer
    et al.
    Lunds universitet.
    Vaziri-Sani, Fariba
    Lunds universitet.
    Agardh, Daniel
    Lunds universitet.
    Improved efficacy by using the pTnT-rhtTG plasmid for the detection of celiac disease specific tissue transglutaminase autoantibodies in radioligand binding assays2011In: Scandinavian Journal of Clinical and Laboratory Investigation, ISSN 0036-5513, E-ISSN 1502-7686, Vol. 71, no 8, p. 701-704Article in journal (Refereed)
    Abstract [en]

    Background: Tissue transglutaminase (tTG) autoantibodies are serological markers for celiac disease. The aim was to study the efficacy of the pTnT-rhtTG plasmid and subsequent diagnostic accuracy of tTG autoantibodies for childhood celiac disease using radioligand binding assays.

    Methods: Coupled in vitro transcription and translation of tTG were performed by pTnT-rhtTG as well as by the pGEMt Easy-rhtTG vectors using the TNT SP6 Coupled Reticulocyte Lysate System in the presence of [(35)S] methionine. Sera from 190 celiac disease children and 74 controls were measured for tTG autoantibodies in two separate radioligand binding assays using anti-human IgA agarose and protein A sepharose beads for the detection of IgA-tTG and IgG-tTG, respectively.

    Results: Median incorporation of [(35)S] methionine into the pTnT-rhtTG was 26% compared to 16% for the pGEMt Easy-rhtTG plasmid (p = 0.0016). Using pTnT-rhtTG (as compared to pGEMt Easy-rhtTG), sensitivities were IgA-tTG = 96.3% (95.7%) and IgG-tTG = 95.8% (97.3%) and specificities were IgA-tTG = 91.9% (90.5%) and IgG-tTG = 94.6% (98.4%). According to receiver operator characteristics for the pTnT (pGEMt Easy) assays, area under the curves were IgA-tTG = 98.4% (98.4%) and IgG-tTG = 97.7% (97.2%), respectively.

    Conclusion: The pTnT-rhtTG plasmid increased the efficacy of tTG antigen usage without reducing the diagnostic accuracy of IgA-tTG and IgG-tTG for childhood celiac disease. The pTnT-rhtTG plasmid is therefore recommended over the pGEMt Easy-rhtTG for the assessment of IgA-tTG and IgG-tTG using radioligand binding assays.

  • 14. Nielsen, Lotte B.
    et al.
    Vaziri-Sani, Fariba
    Lunds universitet.
    Poerksen, Sven
    Andersen, Marie-Louise M.
    Svensson, Jannet
    Bergholdt, Regine
    Pociot, Flemming
    Hougaard, Philip
    de Beaufort, Carine
    Castano, Luis
    Mortensen, Henrik B.
    Lernmark, Ake
    Hansen, Lars
    Relationship between ZnT8Ab, the SLC30A8 gene and disease progression in children with newly diagnosed type 1 diabetes2011In: Autoimmunity, ISSN 0891-6934, E-ISSN 1607-842X, Vol. 44, no 8, p. 616-623Article in journal (Refereed)
    Abstract [en]

    Autoantibodies against the newly established autoantigen in type 1 diabetes, zinc transporter 8, ZnT8, are presented as two types, ZnT8RAb and ZnT8WAb. The rs13266634 variant of the SLC30A8 gene has recently been found to determine the type of ZnT8Ab. The aim of this study was to explore the impact of this genetic variant and the ZnT8Ab on the residual beta-cell function during disease progression the first year after disease diagnosis in children with newly diagnosed type 1 diabetes. This cohort consists of 257 children aged < 16 years, all patients were newly diagnosed with type 1 diabetes. A Boost-test was carried out at 1, 6, and 12 months to characterize the residual beta-cell function. Carriers of the CC and CT genotype groups of the rs13266634 SNP of the SLC30A8 gene had higher stimulated C-peptide levels the first year after onset compared with those of the TT genotype group (29%, p = 0.034). CC genotype carriers were highly associated with the presence of ZnT8RAb subtype during disease progression (compared with TT, p < 0.0001). On the other hand, the TT genotype was associated with the presence of ZnT8WAb subtype during disease progression (compared with CC, p < 0.0001). The C allele of the SLC30A8 gene is associated with preserved beta-cell function in type 1 diabetes patients. The genetic determination of the rs13266634 variant on the ZnT8Ab specificity is sustained the first 12 months after the diagnosis of type 1 diabetes in a pediatric cohort.

  • 15.
    Nilsson, A-L
    et al.
    Östersund hospital.
    Vaziri-Sani, Fariba
    Lund University.
    Broberg, P
    Lund University.
    Elfaitouri, A
    Uppsala University.
    Pipkorn, R
    Tyskland.
    Blomberg, J
    Uppsala University.
    Ivarsson, S-A
    Lund University.
    Elding Larsson, H
    Lund Univeristy.
    Lernmark, Å
    Lund University.
    Serological evaluation of possible exposure to Ljungan virus and related parechovirus in autoimmune (type 1) diabetes in children2015In: Journal of Medical Virology, ISSN 0146-6615, E-ISSN 1096-9071, Vol. 87, no 7, p. 1130-1140Article in journal (Refereed)
    Abstract [en]

    Exposure to Ljungan virus (LV) is implicated in the risk of autoimmune (type 1) diabetes but possible contribution by other parechoviruses is not ruled out. The aim was to compare children diagnosed with type 1 diabetes in 2005-2011 (n = 69) with healthy controls (n = 294), all from the Jämtland County in Sweden, using an exploratory suspension multiplex immunoassay for IgM and IgG against 26 peptides of LV, human parechoviruses (HPeV), Aichi virus and poliovirus in relation to a radiobinding assay (RBA) for antibodies against LV and InfluenzaA/H1N1pdm09. Islet autoantibodies and HLA-DQ genotypes were also determined. 1) All five LV-peptide antibodies correlated to each other (P < 0.001) in the suspension multiplex IgM- and IgG-antibody assay; 2) The LV-VP1_31-60-IgG correlated with insulin autoantibodies alone (P = 0.007) and in combination with HLA-DQ8 overall (P = 0.022) as well as with HLA-DQ 8/8 and 8/X subjects (P = 0.013); 3) RBA detected LV antibodies correlated with young age at diagnosis (P < 0.001) and with insulin autoantibodies (P < 0.001) especially in young HLA-DQ8 subjects (P = 0.004); 4) LV-peptide-VP1_31-60-IgG correlated to RBA LV antibodies (P = 0.009); 5) HPeV3-peptide-IgM and -IgG showed inter-peptide correlations (P < 0.001) but only HPeV3-VP1_1-30-IgG (P < 0.001) and VP1_95-124-IgG (P = 0.009) were related to RBA LV antibodies without relation to insulin autoantibody positivity (P = 0.072 and P = 0.486, respectively). Both exploratory suspension multiplex IgG to LV-peptide VP1_31-60 and RBA detected LV antibodies correlated with insulin autoantibodies and HLA-DQ8 suggesting possible role in type 1 diabetes. It remains to be determined if cross-reactivity or concomitant exposure to LV and HPeV3 contributes to the seroprevalence.

  • 16.
    Nilsson, Anna-Lena
    et al.
    Östersund Hospital.
    Vaziri-Sani, Fariba
    Lund University.
    Andersson, Cecilia
    Lund University.
    Larsson, Karin
    Kristianstad Hospital.
    Carlsson, Anneli
    Lund University.
    Cedervall, Elisabeth
    Ängelholm Hospital.
    Jönsson, Björn
    Ystad Hospital.
    Neiderud, Jan
    Helsingborg Hospital.
    Elding Larsson, Helena
    Lund University.
    Ivarsson, Sten-Anders
    Lund University.
    Lernmark, Ake
    Lund University.
    Relationship between Ljungan virus antibodies, HLA-DQ8, and insulin autoantibodies in newly diagnosed type 1 diabetes children2013In: Viral immunology, ISSN 0882-8245, E-ISSN 1557-8976, Vol. 26, no 3, p. 207-215Article in journal (Refereed)
    Abstract [en]

    Environmental factors, including viral infections, may explain an increasing and fluctuating incidence of childhood type 1 diabetes (T1D). Ljungan virus (LV) isolated from bank voles have been implicated, but it is unclear whether LV contributes to islet autoimmunity, progression to clinical onset, or both, of T1D. The aim was to test whether LV antibodies (LVAb) were related to HLA-DQ and islet autoantibodies in newly diagnosed T1D patients (n = 676) and controls (n = 309). Patients, 0-18 years of age, diagnosed with T1D in 1996-2005 were analyzed for LVAb, HLA-DQ genotypes, and all seven known islet autoantibodies (GADA, IA-2A, IAA, ICA, ZnT8RA, ZnT8WA, and ZnT8QA). LVAb at 75th percentile, defined as cut off, was 90 (range 6-3936) U/mL and 4th quartile LVAb were found in 25% (170/676) of which 64% were < 10 (n = 108, p < 0.0001), and 27% were < 5 (n = 45; p < 0.0001) years old. The 4th quartile LVAb in children < 10 years of age correlated to HLA DQ2/8, 8/8, and 8/X (p < 0.0001). Furthermore, in the group with 4th quartile LVAb, 55% were IAA positive (p = 0.01) and correlation was found between 4th quartile LVAb and IAA in children < 10 years of age (p = 0.035). It is concluded that 1) LVAb were common among the young T1D patients and LVAb levels were higher in the younger age groups; 2) 4th quartile LVAb correlated with IAA; and 3) there was a correlation between 4th quartile LVAb and HLA-DQ8, particularly in the young patients. The presence of LVAb supports the notion that prior exposure to LV may be associated with T1D.

  • 17.
    Nilsson, Sara C.
    et al.
    Lunds universitet.
    Karpman, Diana
    Clinical Sciences Lund.
    Vaziri-Sani, Fariba
    Clinical Sciences Lund.
    Kristoffersson, Ann-Charlotte
    Clinical Sciences Lund.
    Salomon, Remi
    Frankrike.
    Provot, Francois
    Frankrike.
    Fremeaux-Bacchi, Veronique
    Frankrike.
    Trouw, Leendert A.
    Frankrike.
    Blom, Anna M.
    Lunds universitet.
    A mutation in factor I that is strongly associated with atypical hemolytic uremic syndrome does not affect the function of factor I in complement regulation2007In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 44, no 1-3, p. 221-221Article in journal (Other academic)
    Abstract [en]

    Factor I (FI) is the major complement inhibitor that degrades C3b and C4b in the presence of cofactors C4b binding protein (C4BP), factor H (FH), membrane cofactor protein (MCP) or complement receptor 1 (CR1). Recently, mutations and polymorphisms in complement regulator molecules FH and MCP but also in FI have been associated with atypical hemolytic uremic syndrome (aHUS). HUS is a disorder characterized by hemolytic anemia, thrombocytopenia and acute renal failure. In this study we report three unrelated patients with an identical heterozygous mutation, G261D, in FI heavy chain who developed severe aHUS at different time points in their lives. Two patients also have polymorphisms in FH previously associated with risk of developing aHUS. Testing in particular one patient and control serum samples we did not observe major differences in complement hemolytic activity, FI plasma levels or the capability to degrade C4b or C3b. A recombinant protein was produced in order to analyze the functional consequences of the mutation. Mutant FI had a slightly different migration pattern during electrophoresis under reducing conditions. An alteration due to alternative splicing or glycosylation was ruled out, thus the altered migration may be due to proximity of the mutation to a cysteine residue. The recombinant mutant FI degraded C3b and C4b in a manner comparable to wild type protein. In conclusion, despite the strong association between the heterozygous mutation in FI and aHUS we did not observe any abnormalities in the function of FI regarding complement regulation.

  • 18.
    Nilsson, Sara C
    et al.
    Lund University.
    Karpman, Diana
    Lund University.
    Vaziri-Sani, Fariba
    Lunds universitet.
    Kristoffersson, Ann-Charlotte
    Lund University.
    Salomon, Rémi
    Frankrike.
    Provot, Francois
    Frankrike.
    Fremeaux-Bacchi, Veronique
    Frankrike.
    Trouw, Leendert A
    Lund University.
    Blom, Anna M
    Lund University.
    A mutation in factor I that is associated with atypical hemolytic uremic syndrome does not affect the function of factor I in complement regulation2007In: Molecular Immunology, ISSN 0161-5890, E-ISSN 1872-9142, Vol. 44, no 8, p. 1835-1844Article in journal (Refereed)
    Abstract [en]

    Factor I (FI) is the major complement inhibitor that degrades C3b and C4b in the presence of cofactors such as factor H (FH) and membrane cofactor protein (MCP). Recently, mutations and polymorphisms in complement regulator molecules FH and MCP but also in FI have been associated with atypical hemolytic uremic syndrome (aHUS). HUS is a disorder characterized by hemolytic anemia, thrombocytopenia and acute renal failure. In this study, we report three unrelated patients with an identical heterozygous mutation, G261D, in the FI heavy chain who developed severe aHUS at different time points in their lives. Two of the patients also have polymorphisms in FH previously associated with risk of developing aHUS. Testing in particular one patient and control serum samples we did not observe major differences in complement hemolytic activity, FI plasma levels or the capability to degrade C4b or C3b. A recombinant protein was produced in order to analyze the functional consequences of the mutation. Mutant FI had a slightly different migration pattern during electrophoresis under reducing conditions. An alteration due to alternative splicing or glycosylation was ruled out, thus the altered migration may be due to proximity of the mutation to a cysteine residue. The recombinant mutant FI degraded C3b and C4b in a manner comparable to wild-type protein. In conclusion, despite the association between the heterozygous mutation in FI and aHUS we did not observe any abnormalities in the function of FI regarding complement regulation.

  • 19.
    Redondo, Maria J
    et al.
    USA.
    Muniz, Jesse
    USA.
    Rodriguez, Luisa M
    USA.
    Lyer, Dinakar
    USA.
    Vaziri-Sani, Fariba
    Lunds Universitet.
    Haymond, Morey W
    USA.
    Hampe, Christiane S
    USA.
    Metzker, Michael L
    USA.
    Grant, Struan F A
    USA.
    Balasubramanyam, Ashok
    USA.
    Association of TCF7L2 variation with single islet autoantibody expression in children with type 1 diabetes2014In: BMJ open diabetes research & care, ISSN 2052-4897, Vol. 2, no 1, p. 1-6Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: The transcription factor 7-like 2 (TCF7L2) gene has the strongest genetic association with type 2 diabetes. TCF7L2 also associates with latent autoimmune diabetes in adults, which often presents with a single islet autoantibody, but not with classical type 1 diabetes.

    METHODS: We aimed to test if TCF7L2 is associated with single islet autoantibody expression in pediatric type 1 diabetes. We studied 71 prospectively recruited children who had newly diagnosed type 1 diabetes and evidence of islet autoimmunity, that is, expressed ≥1 islet autoantibody to insulin, glutamic acid decarboxylase 65, islet cell autoantigen 512, or zinc transporter 8. TCF7L2 rs7903146 alleles were identified. Data at diagnosis were cross-sectionally analyzed.

    RESULTS: We found that 21.1% of the children with autoimmune type 1 diabetes expressed a single islet autoantibody. The distribution of TCF7L2 rs7903146 genotypes in children with a single autoantibody (n=15) was 40% CC, 26.7% CT and 33.3% TT, compared with children with ≥2 islet autoantibodies (50% CC, 42.9% CT and 7.1% TT, p=0.024). Furthermore, compared with children with ≥2 autoantibodies, single-autoantibody children had characteristics reflecting milder autoimmune destruction of β-cells. Restricting to lean children (body mass index<85th centile; n=36), 45.5% of those expressing a single autoantibody were rs7903146 TT homozygotes, compared with 0% of those with ≥2 autoantibodies (p<0.0001).

    CONCLUSION: These results suggest that, in children with only mild islet autoimmunity, mechanisms associated with TCF7L2 genetic variation contribute to diabetogenesis, and this contribution is larger in the absence of obesity.

  • 20. Salami, F
    et al.
    Abels, M
    Hyöty, H
    Vaziri-Sani, Fariba
    Lunds universitet.
    Aronsson, Ca
    Vehik, K
    Delli, A
    Hagopian, Wa
    Rewers, M
    Ziegler, Ag
    Simell, O
    Akolkar, B
    Krischer, J
    She, J
    Lernmark, A
    Detection of Lactobacilli in monthly mail-in stool samples from 3-18 months old infants at genetic risk for type 1 diabetes2012In: International Journal of Probiotics and Prebiotics, ISSN 1555-1431, Vol. 7, no 3-4, p. 135-144Article in journal (Refereed)
    Abstract [en]

    The feasibility to detect lactobacilli in mail-in infant stools collected monthly from 3-18 months old children was investigated. The aim was to determine total lactobacilli and Lactobacillus plantarum (L. plantarum) content (ng/g feces) in 50 infants each from Colorado (648 samples), Finland (624 samples) and Sweden (685 samples) who participated in the TEDDY (The Environmental Determinants of Diabetes in the Young) study. Total lactobacilli content varied markedly between 5 and 16,800 ng/g feces in the three clinical sites within and between individuals especially in infants. L.plantarum also varied markedly intra- and inter-individually from <0.5 - 736 ng/g feces. A higher variability of total lactobacilli was found before 10 months of age than after in the three different clinical sites. Sweden had the lowest total lactobacilli content compared to Colorado and Finland while the L.plantarum content was higher in Sweden. Mail-in stool samples from infants should prove useful in analyzing probiotics in childhood.

  • 21.
    Shulman, L M
    et al.
    Israel.
    Hampe, C S
    USA.
    Ben-Haroush, A
    Israel.
    Perepliotchikov, Y
    Israel.
    Vaziri-Sani, Fariba
    Lund University.
    Israel, S
    Israel.
    Miller, K
    Israel.
    Bin, H
    Israel.
    Kaplan, B
    Israel.
    Laron, Z
    Israel.
    Antibodies to islet cell autoantigens, rotaviruses and/or enteroviruses in cord blood and healthy mothers in relation to the 2010-2011 winter viral seasons in Israel: a pilot study2014In: Diabetic Medicine, ISSN 0742-3071, E-ISSN 1464-5491, Vol. 31, no 6, p. 681-685Article in journal (Refereed)
    Abstract [en]

    Aims

    To determine whether antivirus and/or islet cell antibodies can be detected in healthy pregnant mothers without diabetes and/or their offspring at birth in two winter viral seasons.

    Methods

    Maternal and cord blood sera from 107 healthy pregnant women were tested for islet cell autoantibodies using radioligand binding assays and for anti-rotavirus and anti-CoxB3 antibody using an enzyme-linked immunosorbent assay.

    Results

    Glutamic acid decarboxylase (GAD)65 autoantibodies and rotavirus antibodies, present in both maternal and cord blood sera, correlated with an odds ratio of 6.89 (95% CI: 1.01-46.78). For five, 22 and 17 pregnancies, antibodies to GAD65, rotavirus and CoxB3, respectively, were detected in cord blood only and not in the corresponding maternal serum. In 10 pregnancies, rotavirus antibody titres in the cord blood exceeded those in the corresponding maternal serum by 2.5-5-fold. Increased antibody titres after the 20(th) week of gestation suggested CoxB3 infection in one of the 20 pregnancies and rotavirus in another.

    Conclusion

    The concurrent presence of GAD65 antibodies in cord blood and their mothers may indicate autoimmune damage to islet cells during gestation, possibly caused by cross-placental transmission of viral infections and/or antivirus antibodies. Cord blood antibody titres that exceed those of the corresponding maternal sample by >2.5-fold, or antibody-positive cord blood samples with antibody-negative maternal samples, may imply an active in utero immune response by the fetus. What's new? <list list-type="bulleted" id="dme12404-list-0001"> It has been hypothesized that viral infections initiate islet cell autoimmunity. Previous research suggests an association of viral infection in utero and islet autoimmunity. We found a significant correlation between glutamic acid decarboxylase 65 autoantibodies and anti-rotavirus in healthy mothers at delivery and in cord blood. The presence of antibodies in cord blood with antibody-negative mothers suggests an independent fetal immune response. Our findings support the hypothesis that viral infections during pregnancy damage fetal islet cells, triggering islet autoimmunity.

  • 22.
    Skärstrand, H
    et al.
    Lund University.
    Dahlin, L. B.
    Lund University.
    Lernmark, Ake
    Lund University.
    Vaziri-Sani, Fariba
    Lunds universitet.
    Neuropeptide Y autoantibodies in patients with long-term type 1 and type 2 diabetes and neuropathy2013In: Journal of diabetes and its complications, ISSN 1056-8727, E-ISSN 1873-460X, Vol. 27, no 6, p. 609-617Article in journal (Refereed)
    Abstract [en]

    Aims: The neurotransmitter Neuropeptide Y (NPY) was previously reported as a minor autoantigen in newly diagnosed type 1 diabetes (T1D) patients. The single nucleotide polymorphism at rs16139 (T1128C, L7P) in the NPY gene was associated with an increased risk for the development of type 2 diabetes (T2D). We aimed to develop a radiobinding assay for NPY-L (Leucine) and NPY-P (Proline) autoantibodies (A) to study the levels and the association with other islet autoantibodies and neuropathy. Methods: Autoantibodies against NPY-L, NPY-P, ZnT8, GAD65 and IA-2 were studied in T1D (n = 48) and T2D (n = 26) patients with duration up to 42 and 31 years. A subgroup of T1D (n = 32) patients re-examined, 5-8 years after first visit, was tested for peripheral (Z-score) and autonomic neuropathy (E/I ratio). Results: NPY-LA and NPY-PA were detected in 23% and 19% in T1D (p<0.001), and 12% and 23% in T2D patients (p<0.001) compared to 2.5% controls (n = 398). The levels of NPYA declined during follow-up in the T1D patients (p < 0.001). The neuropathy was not related to the NPYA or the other islet autoantibodies. Conclusions: Regardless of the absence of an association between NPYA and neuropathy, NPY may contribute to the pathogenesis of T1D and T2D as a minor autoantigen.

  • 23.
    Skärstrand, H
    et al.
    Lund University.
    Krupinska, E
    Lund University.
    Haataja, T J K
    Lund University.
    Vaziri-Sani, Fariba
    Lund University.
    Lagerstedt, J O
    Lund University.
    Lernmark, Å
    Lund University.
    Zinc transporter 8 (ZnT8) autoantibody epitope specificity and affinity examined with recombinant ZnT8 variant proteins in specific ZnT8R and ZnT8W autoantibody-positive type 1 diabetes patients2015In: Clinical and Experimental Immunology, ISSN 0009-9104, E-ISSN 1365-2249, Vol. 179, no 2, p. 220-229Article in journal (Refereed)
    Abstract [en]

    Variant-specific zinc transporter 8 autoantibodies (ZnT8A) against either arginine (R) or tryptophan (W) at amino acid (aa) position 325 of the zinc transporter 8 (ZnT8) has been identified in type 1 diabetes (T1D) patients. Reciprocal cross-over tests revealed differences in half-maximal binding to indicate variable affinity of patient ZnT8 autoantibodies. Insufficient recombinant ZnT8 variant proteins have precluded detailed analyses of ZnT8 autoantibody affinity. The aims in the present study were to (i) generate recombinant ZnT8R- and ZnT8W-aa275-369 proteins; (ii) test the ZnT8R- and ZnT8W-aa275-369 proteins in reciprocal competitive radiobinding assays (RBA) against ZnT8R- and ZnT8W-aa268-369 labelled with (35) S-methionine; and (iii) determine the specificity and affinity of sera specific for either ZnT8 arginine (R) or ZnT8 tryptophan (W) autoantibodies in newly diagnosed T1D patients. The results demonstrate, first, that it was possible to produce recombinant human MBP-ZnT8-aa275-369 protein purified to homogeneity for RBA reciprocal competition experiments. Secondly, high-titre ZnT8WA sera diluted to half maximal binding showed significant specificity for respective variants of either ZnT8R or ZnT8W. Thirdly, ZnT8WA-positive sera showed high affinity for ZnT8W compared to ZnT8RA for ZnT8R. These data demonstrate that T1D patients may have single amino acid-specific autoantibodies directed against either ZnT8R or ZnT8W and that the autoantibody affinity to the respective variant may be different. Further studies are needed to assess the mechanisms by which variant-specific ZnT8A of variable affinity develop and their possible role in the pathogenic process leading to the clinical onset of T1D.

  • 24.
    Skärstrand, H
    et al.
    Lund University.
    Lernmark, Ake
    Lund University.
    Vaziri-Sani, Fariba
    Lunds universitet.
    Antigenicity and Epitope Specificity of ZnT8 Autoantibodies in Type 1 Diabetes2013In: Scandinavian Journal of Immunology, ISSN 0300-9475, E-ISSN 1365-3083, Vol. 77, no 1, p. 21-29Article in journal (Refereed)
    Abstract [en]

    The single nucleotide polymorphism (SNP) rs13266634 encodes either an Arginine (R) or a Tryptophan (W) (R325W) at the amino acid position 325 in the Zinc Transporter 8 (ZnT8) protein. Autoantibodies (Ab) that recognize ZnT8R, ZnT8W or both at the polymorphic site are common in newly diagnosed type 1 diabetes (T1D) patients. The epitope specificity and affinity of ZnT8Ab are poorly understood, but may be of importance for the prediction and clinical classification of T1D. Therefore, the aims were to 1) determine the immunogenicity of short (318331) ZnT8 peptides in mice and 2) test the affinity of short and long (268369) ZnT8 proteins in T1D patients positive for either ZnT8RAb or ZnT8wAb. Sera from BALB/cByJ mice immunized with short R, W or Q (Glutamine) ZnT8 peptides were tested for ZnT8-peptide antibodies in ELISA and radiobinding assay (RBA). Using reciprocal permutation experiment, short synthetic ZnT8R and ZnT8W (318331) and long in vitro transcription translation ZnT8R and ZnT8W (268369) proteins were tested in competitive RBA with R- and W-monospecific T1D sera samples. All mouse sera developed non-epitope-specific peptide antibodies in ELISA and only 6/12 mice had ZnT8-RWQ antibodies in RBA. Both long ZnT8R and ZnT8W (268369), but not any short, proteins displaced labelled ZnT8 (268369) proteins in binding to T1D ZnT8Ab-specific sera. The reciprocal cross-over tests showed that half-maximal displacement varied 2- to 11-fold indicating variable affinity of patient ZnT8Ab, signifying crucial autoantibody epitope spreading. The present approach should make it possible to dissect the importance of the R325W ZnT8 autoantigen epitope in the T1D pathogenesis.

  • 25.
    Skärstrand, H
    et al.
    Lund University.
    Vaziri-Sani, Fariba
    Lunds universitet.
    Andersson, C.
    Lund University.
    Elding Larsson, H
    Lund Univeristy.
    Ivarsson, SA
    Lund University.
    Lernmark, Åke
    Lund University.
    NPY minor autoantibodies in newly diagnosed type 1 diabetes patients2013In: Diabetologia, ISSN 0012-186X, E-ISSN 1432-0428, Vol. 56, p. 19-19Article in journal (Other academic)
  • 26.
    Skärstrand, Hanna
    et al.
    Lund University.
    Vaziri-Sani, Fariba
    Lund University.
    Delli, Ahmed J
    Lund University.
    Törn, Carina
    Lund University.
    Elding Larsson, H
    Lund Univeristy.
    Ivarsson, Sten
    Lund University.
    Agardh, Daniel
    Lund University.
    Lernmark, Ake
    Lund University.
    Neuropeptide Y is a minor autoantigen in newly diagnosed type 1 diabetes patients2015In: Pediatric Diabetes, ISSN 1399-543X, E-ISSN 1399-5448, Vol. 16, no 8, p. 621-628Article in journal (Refereed)
    Abstract [en]

    BACKGROUND: Autoantibodies (A) against Neuropeptide Y (NPY), was reported in 9% newly diagnosed type 1 diabetes (T1D) patients. A single nucleotide polymorphism (SNP) at rs16139 (T1128C) within the NPY-gene identified an amino acid substitution from leucine (L) to proline (P) (L7P) associated with both glucose tolerance and type 2 diabetes. We aimed to determine: (i) the influence of autoantibodies to leucine neuropeptide Y (NPY-LA) and autoantibodies to proline neuropeptide Y (NPY-PA) on the diagnostic sensitivity of type 1 diabetes (T1D), (ii) the association of NPYA with major islet autoantibodies, and (iii) the association of NPYA with HLA-DQ genotypes in newly diagnosed T1D patients.

    METHODS: Serum from the HLA-DQ typed T1D patients (n = 673; median age 10 yr) from Skåne, Sweden, were analyzed for autoantibodies against NPY-L and NPY-P in a radioligand binding assay, and against glutamic acid decarboxylase 65 (GAD65), insulin, insulinoma associated protein-2 (IA-2), and zinc transporter 8 (ZnT8) in addition to islet cell antibodies (ICA). A total of 1006 subjects (median age 9 yr) were used as controls.

    RESULTS: A total of 9.2% (n = 62) of the T1D patients were positive for NPY-LA (p < 0.001) and 7.6% (n = 51) for NPY-PA (p < 0.001) compared to 1.1% (n = 11) in controls. The NPY-LA and NPY-PA appeared together (κ = 0.63; p < 0.001) and the median levels correlated (R² = 0.603; p < 0.001). T1D patients diagnosed after 10 yr of age were at an increased risk for NPYA at diagnosis [odds ratio (OR = 2.46; 95% CI 1.46-4.16; p = 0.001)] adjusted for age at diagnosis, gender, autoantibody positivity, and HLA.

    CONCLUSIONS: NPY is a minor autoantigen in children with newly diagnosed T1D. Therefore, NPY autoantibodies may be investigated in T1D autoimmunity.

  • 27.
    Sorensen, J. S.
    et al.
    Danmark.
    Vaziri-Sani, Fariba
    Lunds universitet.
    Maziarz, M.
    USA.
    Kristensen, K.
    Danmark.
    Ellerman, A.
    Danmark.
    Breslow, N.
    USA.
    Lernmark, A.
    Lund University.
    Pociot, F.
    Danmark.
    Brorsson, C.
    Danmark.
    Birkebaek, N. H.
    Danmark.
    Islet autoantibodies and residual beta cell function in type 1 diabetes children followed for 3-6 years2012In: Diabetes Research and Clinical Practice, ISSN 0168-8227, E-ISSN 1872-8227, Vol. 96, no 2, p. 204-210Article in journal (Refereed)
    Abstract [en]

    Aims: To test if islet autoantibodies at diagnosis of type 1 diabetes (T1DM) and after 3-6 years with T1D predict residual beta-cell function (RBF) after 3-6 years with T1D.

    Methods: T1D children (n = 260, median age at diagnosis 9.4, range 0.9-14.7 years) were tested for GAD65, IA-2, ZnT8R, ZnT8W and ZnT8Q autoantibodies (A) at diagnosis, and 3-6 years after diagnosis when also fasting and stimulated RBF were determined.

    Results: For every 1-year increase in age at diagnosis of TID, the odds of detectable C-peptide increased 1.21 (1.09, 1.34) times for fasting C-peptide and 1.28 (1.15, 1.42) times for stimulated C-peptide. Based on a linear model for subjects with no change in IA-2A levels, the odds of detectable C-peptide were 35% higher than for subjects whose IA-2A levels decreased by half (OR = 1.35 (1.09, 1.67), p = 0.006); similarly for ZnT8WA (OR = 1.39 (1.09, 1.77), p = 0.008) and ZnT8QA (OR = 1.55 (1.06, 2.26) p = 0.024). Such relationship was not detected for GADA or ZnT8RA. All OR adjusted for confounders.

    Conclusions: Age at diagnosis with T1D was the major predictor of detectable C-peptide 3-6 years post-diagnosis. Decreases in IA-2A, and possibly ZnT8A, levels between diagnosis and post-diagnosis were associated with a reduction in RBF post-diagnosis.

  • 28.
    Stahl, Anne-Lie
    et al.
    Lund University.
    Vaziri-Sani, Fariba
    Lund University.
    Heinen, Stefan
    Tyskland.
    Kristoffersson, Ann-Charlotte
    Lund University.
    Gydell, Karl-Henrik
    Regional Hospital, Halmstad.
    Raafat, Reem
    USA.
    Gutierrez, Alberto
    Karolinska University.
    Beringer, Ortraud
    Tyskland.
    Zipfel, Peter F.
    Tyskland.
    Karpman, Diana
    Lund University.
    Factor H dysfunction in patients with atypical hemolytic uremic syndrome contributes to complement deposition on platelets and their activation2008In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 111, no 11, p. 5307-5315Article in journal (Refereed)
    Abstract [en]

    Atypical hemolytic uremic syndrome (aHUS) may be associated with mutations in the C-terminal of factor H (FH). FH binds to platelets via the C-terminal as previously shown using a construct consisting of short consensus repeats (SCRs) 15 to 20. A total of 4 FH mutations, in SCR15 (C870R) and SCR20 (V1168E, E1198K, and E1198Stop) in patients with aHUS, were studied regarding their ability to allow complement activation on platelet surfaces. Purified FH-E1198Stop mutant exhibited reduced binding to normal washed platelets compared with normal FH, detected by flow cytometry. Washed platelets taken from the 4 patients with aHUS during remission exhibited C3 and C9 deposition, as well as CD40-ligand (CD40L) expression indicating platelet activation. Combining patient serum/plasma with normal washed platelets led to C3 and C9 deposition, CD40L and CD62P expression, aggregate formation, and generation of tissue factor-expressing microparticles. Complement deposition and platelet activation were reduced when normal FH was preincubated with platelets and were minimal when using normal serum. The purified FH-E1198Stop mutant added to FH-deficient plasma (complemented with C3) allowed considerable C3 deposition on washed platelets, in comparison to normal FH. In summary, mutated FH enables complement activation on the surface of platelets and their activation, which may contribute to the development of thrombocytopenia in aHUS.

  • 29.
    Vaziri-Sani, Fariba
    et al.
    Kristianstad University, School of Education and Environment, Avdelningen för Naturvetenskap. Kristianstad University, Research environment Man & Biosphere Health (MABH). Lunds universitet.
    Brundin, Charlotte
    Lund University.
    Agardh, Daniel
    Lund University.
    Osteoprotegerin autoantibodies do not predict low bone mineral density in middle-aged women2017In: Bone Reports, ISSN 2352-1872, Vol. 7, p. 132-136Article in journal (Refereed)
    Abstract [en]

    Purpose

    Autoantibodies against osteoprotegerin (OPG) have been associated with osteoporosis. The aim was to develop an immunoassay for OPG autoantibodies and test their diagnostic usefulness of identifying women general population with low bone mineral density.

    Methods

    Included were 698 women at mean age 55.1 years (range 50.4–60.6) randomly selected from the general population. Measurement of wrist bone mineral density (g/cm2) was performed of the non-dominant wrist by dual-energy X-ray absorptiometry (DXA). A T-score < − 2.5 was defined as having a low bone mineral density. Measurements of OPG autoantibodies were carried by radiobinding assays. Cut-off levels for a positive value were determined from the deviation from normality in the distribution of 398 healthy blood donors representing the 99.7th percentile.

    Results

    Forty-five of the 698 (6.6%) women were IgG-OPG positive compared with 2 of 398 (0.5%) controls (p < 0.0001) and 35 of the 698 (5.0%) women had a T-score < − 2.5. There was no difference in bone mineral density between IgG-OPG positive (median 0.439 (range 0.315–0.547) g/cm2) women and IgG-OPG negative (median 0.435 (range 0.176–0.652) g/cm2) women (p = 0.3956). Furthermore, there was neither a correlation between IgG-OPG levels and bone mineral density (rs = 0.1896; p = 0.2068) nor T-score (rs = 0.1889; p = 0.2086). Diagnostic sensitivity and specificity of IgG-OPG for low bone mineral density were 5.7% and 92.9%, and positive and negative predictive values were 7.4% and 90.8%, respectively.

    Conclusion

    Elevated OPG autoantibody levels do not predict low bone mineral density in middle-aged women selected from the general population.

  • 30.
    Vaziri-Sani, Fariba
    et al.
    Lunds universitet.
    Delli, Ahmed J.
    Lund University.
    Elding Larsson, H
    Lund Univeristy.
    Lindblad, Bengt
    Queen Silvia Childrens Hospital.
    Carlsson, Annelie
    Lund University.
    Forsander, Gun
    Queen Silvia Childrens Hospital.
    Ivarsson, Sten A.
    Lund University.
    Ludvigsson, Johnny
    Linköping University.
    Marcus, Claude
    Karolinska Institute.
    Lernmark, Ake
    Lund University.
    A novel triple mix radiobinding assay for the three ZnT8 (ZnT8-RWQ) autoantibody variants in children with newly diagnosed diabetes2011In: JIM - Journal of Immunological Methods, ISSN 0022-1759, E-ISSN 1872-7905, Vol. 371, no 1-2, p. 25-37Article in journal (Refereed)
    Abstract [en]

    Background and aims: Autoantibodies against the zinc transporter 8 (ZnT8A) are common in type 1 diabetes (T1D). ZnT8A analyses are complicated by the fact that there are three variants of the autoantigen at amino acid position 325 representing ZnT8-R (Arginine), ZnT8-W (Tryptophan) and ZnT8-Q (Glutamin). The aims of the study were: 1) to develop an autoantigen triple mix Radio-Binding Assay (RBA) for ZnT8A: 2) to identify the individual ZnT8-R,-W,-QA reactivity and 3) to validate the triple mix ZnT8A RBA in children with newly diagnosed T1D.

    Methods: Serum samples were obtained from 2664 (56% males, n = 1436) patients in the Swedish nationwide Better Diabetes Diagnosis (BDD) study representing patients with T1D (97%, n = 2582), T2D (1.7%, n = 46), MODY (1.0%, n = 28) and secondary diabetes (0.3%, n = 8). cDNA coding for the C-terminal end of each variant was prepared by site-directed mutagenesis and subcloned into a high efficiency in vitro transcription translation vector. The ZnT8 variants were labeled with 35S-methionine and used in a standard RBA separating free from autoantibody-bound autoantigen with Protein A-Sepharose.

    Results: ZnT8-TripleA was detected in 1678 (65%) patients with T1D, 4 (9%) T2D, 3 (11%) MODY and in none (0%) of the patients with secondary diabetes. Among the T1D patients ZnT8-RA was detected in 1351 (52%) patients, ZnT8-WA in 1209(47%) and ZnT8-QA in 790(31%) demonstrating that 1661 (64%) had one or several ZnT8A. The ZnT8-TripleA assay showed a false positive rate of 1.9% (n = 49). Only 1.2% (n = 32) of the T1D patients were false negative for ZnT8-TripleA compared to 0/46(0%) of the T2D patients. The precision (intra assay CV) and reproducibility (inter assay CV) of the ZnT8-TripleA assay did not differ from the RBA of the individual ZnT8 variants.

    Conclusion: We conclude that the ZnT8-TripleA assay had low false positive and false negative rates. The ZnT8-TripleA assay would therefore be highly suitable not only to analyze patient with newly diagnosed diabetes but also for screening the general population since this assay demonstrated high sensitivity and very high specificity.

  • 31.
    Vaziri-Sani, Fariba
    et al.
    Lunds universitet.
    Hellwage, J
    Zipfel, P F
    Sjoholm, A G
    Iancu, R
    Karpman, D
    Factor H binds to washed human platelets2005In: Journal of Thrombosis and Haemostasis, ISSN 1538-7933, E-ISSN 1538-7836, Vol. 3, no 1, p. 154-162Article in journal (Refereed)
    Abstract [en]

    Background: Factor H regulates the alternative pathway of complement. The protein has three heparin-binding sites, is synthesized primarily in the liver and copurifies from platelets with thrombospondin-1. Factor H mutations at the C-terminus are associated with atypical hemolytic uremic syndrome, a condition in which platelets are consumed. Objectives The aim of this study was to investigate if factor H interacts with platelets.

    Methods: Binding of factor H, recombinant G or N-terminus constructs and a C-terminus mutant to washed (plasma and complement-free) platelets was analyzed by flow cytometry. Binding of factor H and constructs to thrombospondin-1 was measured by surface plasmon resonance.

    Results: Factor H bound to platelets in a dose-dependent manner. The major binding site was localized to the C-terminus. The interaction was partially blocked by heparin. Inhibition with anti-GPIIb/IIIa, or with fibrinogen, suggested that the platelet GPIIb/IIIa receptor is involved in factor H binding. Factor H binds to thrombospondin-1. Addition of thrombospondin-1 increased factor H binding to platelets. Factor H mutated at the C-terminus also bound to platelets, albeit to a significantly lesser degree.

    Conclusions: This study reports a novel property of factor H, i.e. binding to platelets, either directly via the GPIIb/IIIa receptor or indirectly via thrombospondin-1, in the absence of complement. Binding to platelets was mostly mediated by the C-terminal region of factor H and factor H mutated at the C-terminus exhibited reduced binding.

  • 32.
    Vaziri-Sani, Fariba
    et al.
    Lunds universitet.
    Holmberg, L
    Sjöholm, A G
    Kristoffersson, A C
    Manea, M
    Fremeaux-Bacchi, V
    Fehrman-Ekholm, I
    Raafat, R
    Karpman, D
    Phenotypic expression of factor H mutations in patients with atypical hemolytic uremic syndrome2006In: Kidney International, ISSN 0085-2538, E-ISSN 1523-1755, Vol. 69, no 6, p. 981-988Article in journal (Refereed)
    Abstract [en]

    We investigated the phenotypic expression of factor H mutations in two patients with atypical hemolytic uremic syndrome (HUS). Factor H in serum was assayed by rocket immunoelectrophoresis, immunoblotting, and double immunodiffusion and in tissue by immunohistochemistry. Functional activity was analyzed by hemolysis of sheep erythrocytes and binding to endothelial cells. A homozygous mutation in complement control protein (CCP) domain 10 of factor H was identified in an adult man who first developed membranoproliferative glomerulonephritis and later HUS. C3 levels were very low. The patient had undetectable factor H levels in serum and a weak factor H 150 kDa band. Double immunodiffusion showed partial antigenic identity with factor H in normal serum owing to the presence of factor H-like protein 1. Strong specific labeling for factor H was detected in glomerular endothelium, mesangium and in glomerular and tubular epithelium as well as in bone marrow cells. A heterozygous mutation in CCP 20 of factor H was found in a girl with HUS. C3 levels were moderately decreased at onset. Factor H levels were normal and a normal 150 kDa band was present. Double immunodiffusion showed antigenic identity with normal factor H. Factor H labeling was minimal in the renal cortex. Factor H dysfunction was demonstrated by increased sheep erythrocyte hemolysis and decreased binding to endothelial cells. In summary, two different factor H mutations associated with HUS were examined: in one, factor H accumulated in cells, and in the other, membrane binding was reduced.

  • 33.
    Vaziri-Sani, Fariba
    et al.
    Lunds universitet.
    Oak, Shilpa
    Radtke, Jared
    Lernmark, Ake
    Lynch, Kristian
    Agardh, Carl. -D.
    Cilio, Corrado M.
    Lethagen, Asa L.
    Ortqvist, Eva
    Landin-Olsson, Mona
    Torn, Carina
    Hampe, Christiane S.
    ZnT8 autoantibody titers in type 1 diabetes patients decline rapidly after clinical onset2010In: Autoimmunity, ISSN 0891-6934, E-ISSN 1607-842X, Vol. 43, no 8, p. 598-606Article in journal (Refereed)
    Abstract [en]

    Autoantibodies to the islet-specific zinc transporter isoform 8 (ZnT8) are detected in the majority of type 1 diabetes patients prior to and at clinical diagnosis. The presence of ZnT8Ab after diagnosis has not been investigated. This study analyzed the autoantibody response to ZnT8 in regard to age at onset and disease duration. Two new onset type 1 diabetes patient cohorts with different age distributions at onset (2-17 and 15-34 years of age at onset), a longitudinal subset of the younger type 1 diabetes patient cohort (n = 32), and a cohort of GAD65Ab-positive LADA patients (n = 47) was analyzed for the presence of autoantibodies directed to the two major isoforms, ZnT8-Arginine (ZnT8R) and ZnT8-Tryptophan (ZnT8W). The majority of type 1 diabetes patients tested positive for ZnT8Ab to both isoforms. ZnT8Ab titers were significantly higher in the younger type 1 diabetes patients as compared with the older cohort (ZnT8RAb at a median of 148 and 29 U/ml, respectively, p < 0.001) (ZnT8WAb at a median of 145 and 58 U/ml, respectively, p < 0.01). ZnT8RAb and ZnT8WAb titers were significantly lower in the LADA patients (ZnT8RAb at a median of 14 U/ml, ZnT8WAb at a median of 25 U/ml) as compared with either type 1 diabetes cohorts. In our longitudinal analysis of type 1 diabetes patients after clinical diagnosis, ZnT8Ab levels to both isoforms declined significantly during the initial year of disease (ZnT8RAb from a median of 320-162 U/ml, p = 0.0001; ZnT8WAb from a median of 128-46 U/ml, p = 0.0011). The antibody titers further declined during the following 4 years (p < 0.0001). We conclude that ZnT8Ab presents a useful marker for type 1 diabetes, especially in younger patients at disease diagnosis.

  • 34.
    Warvsten, Anna
    et al.
    Lund University.
    Björnfors, Martin
    Lund University.
    Arvidsson, Michael
    Lund University.
    Vaziri-Sani, Fariba
    Lunds universitet.
    Jönsson, Ida
    Lund University.
    Olsson, Gert E
    SLU, Umeå.
    Ahlm, Clas
    Umeå University.
    Elding Larsson, Helena
    Lund University.
    Lernmark, Åke
    Lund University.
    Nilsson, Anna-Lena
    Lund University.
    Islet autoantibodies present in association with Ljungan virus infection in bank voles (Myodes glareolus) in northern Sweden2017In: Journal of Medical Virology, ISSN 0146-6615, E-ISSN 1096-9071, Vol. 89, no 1, p. 24-31Article in journal (Refereed)
    Abstract [en]

    Bank voles are known reservoirs for Puumala hantavirus and probably also for Ljungan virus (LV), a suggested candidate parechovirus in type 1 diabetes etiology and pathogenesis. The aim of this study was to determine whether wild bank voles had been exposed to LV and if exposure associated to autoantibodies against insulin (IAA), glutamic acid decarboxylase 65 (GADA) or islet autoantigen-2 (IA-2A). Serum samples from bank voles (Myodes glareolus) captured in early summer or early winter of 1997 and 1998, respectively, were analyzed in radiobinding assays for antibodies against Ljungan virus (LVA) and Puumala virus (PUUVA) as well as for IAA, GADA and IA-2A. LVA was found in 25% (189/752), IAA in 2.5% (18/723), GADA in 2.6% (15/615) and IA-2A in 2.5% (11/461) of available bank vole samples. LVA correlated with both IAA (p = 0.007) and GADA (p < 0.001) but not with IA-2A (p = 0.999). There were no correlations with PUUVA, detected in 17% of the bank voles. Compared to LVA negative bank voles, LVA positive animals had higher levels of both IAA (p = 0.002) and GADA (p < 0.001) but not of IA-2A (p = 0.205). Levels of LVA as well as IAA and GADA were higher in samples from bank voles captured in early summer.

    IN CONCLUSION: LVA was detected in bank voles and correlated with both IAA and GADA but not with IA-2A. These observations suggest that exposure to LV may be associated with islet autoimmunity. It remains to be determined if islet autoantibody positive bank voles may develop diabetes in the wild. This article is protected by copyright. All rights reserved.

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