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  • 1.
    Banday, Viqar Showkat
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Immunologi/immunkemi.
    Thyagarajan, Radha
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Immunologi/immunkemi.
    Lejon, Kristina
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Immunologi/immunkemi.
    Contribution of both B-cell intrinsic alterations as well as non-hematopoietic-derived factors in the enhanced immune response of the NOD mouse2017Inngår i: Autoimmunity, ISSN 0891-6934, E-ISSN 1607-842X, Vol. 50, nr 6, s. 363-369Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The underlying cellular and molecular mechanism for the development of Type 1 diabetes is still to be fully revealed. We have previously demonstrated that the NOD mouse, a model for Type 1 diabetes, display a prolonged and enhanced immune response to both self and non-self-antigens. The molecular explanation for this defect however, has not been determined. In this study we immunized NOD and C57BL/6 (B6) with the conventional antigen i.e. hen egg lysozyme (HEL) and analyzed B cell activation, germinal center reaction and antibody clearance. Corroborating our previous observations NOD mice responded robustly to a single immunization of HEL. Immunofluorescence analysis of the spleen revealed an increased number of germinal centers in unimmunized NOD compared to B6. However, post immunization germinal center numbers were similar in NOD and B6. NOD mice showed lower response to BCR stimulation with anti-IgM, in particular at lower concentrations of anti-IgM. Antibody clearance in vivo did not differ between the strains. To determine the cell type that is responsible for the prolonged and enhance immune response, we reconstituted NOD-RAGs with cells from primed donors in different combinations. NOD B cells were required to reproduce the phenotype; however the non-lymphoid compartment of NOD origin also played a role. Based on our results we propose that preexisting GCs in the NOD promote the robust response and alteration in the BCR signaling could promote survival of stimulated cells. Overall, this mechanism could in turn also contribute to the activation and maintenance of autoreactive B cells in the NOD mouse.

  • 2.
    Daka, Bledar
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    Svensson, Maria K
    Lernmark, Åke
    Mincheva-Nilsson, Lucia
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Klinisk immunologi.
    Hallmans, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning.
    Rolandsson, Olov
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    Low agreement between radio binding assays in analyzing glutamic acid decarboxylase (GAD65Ab) autoantibodies in patients classified with type 2 diabetes.2009Inngår i: Autoimmunity, ISSN 0891-6934, E-ISSN 1607-842X, Vol. 42, nr 6, s. 507-514Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Autoantibodies against glutamic acid decarboxylase (GAD65Ab) are used in the classification of diabetes in adults. We assessed the concordance in GAD65 autoantibody levels within subjects between three different GAD65Ab radio binding assays (RBA). Plasma samples from 112 diabetes patients (median age 50 years) initially classified with type 2 diabetes was randomly selected from a local diabetes registry. Coded samples were analyzed with two RBA employing (35)S-labeled GAD65. The first used the pEx9 plasmid (pEx9 RBA), the second employed the pThGAD65 plasmid (pThGAD65 RBA) to label GAD65 by in vitro transcription translation. We also used a commercial kit employing plasmid pGAD17 labelled with (125)I (pGAD17 RBA). Subsequent analyses followed standard procedures. Two different cut-offs for GAD65Ab positivity were used in all three assays. We calculated the correlation, concordance, and agreement between the assays. The proportion of GAD65Ab positivity differed between assays when low cut-offs were used (pEx9 RBA 25%, pThGAD65 RBA 17.9%, and pGAD17 RBA 12.5%, respectively). When high cut-offs were applied, the concordance between the pEx9 RBA and the pThGAD65 RBA was 97.3 while their concordance to the pGAD17 RBA was lower (88.4 and 87.4, respectively). There was a low agreement between both pEx9 RBA and pGAD17 RBA (0.45, 95% CI 0.20-0.70) and between pThGAD65 RBA and pGAD17 RBA (0.43, 95% CI 0.18-0.68). We found discrepancies in determining the GAD65Ab positivity, which constitutes a problem when GAD65Ab are used clinically. Further methodological GAD65Ab assays studies are warranted.

  • 3. Hansson, Ida
    et al.
    Lynch, Kristian F
    Hallmans, Göran
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Näringsforskning.
    Lernmark, Åke
    Rolandsson, Olov
    Umeå universitet, Medicinska fakulteten, Institutionen för folkhälsa och klinisk medicin, Allmänmedicin.
    High-titer GAD65 autoantibodies detected in adult diabetes patients using a high efficiency expression vector and cold GAD65 displacement.2011Inngår i: Autoimmunity, ISSN 0891-6934, E-ISSN 1607-842X, Vol. 44, nr 2, s. 129-136Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Adult type 2 diabetes patients with GAD65 autoantibodies (GADA) are known as latent autoimmune diabetes in adults (LADA). It has been suggested that GADA in LADA patients preferentially bind to the N-terminal end of GAD65. Using the N-terminal end extension of ³⁵S-GAD65 generated by the pEx9 plasmid, we tested the hypothesis that GADA in LADA patients preferentially react with ³⁵S-GAD65 from the pEx9 plasmid compared to the normal length pThGAD65 plasmid. Healthy control subjects (n = 250) were compared with type 1 (n = 23), type 2 (n = 290), and unspecified (n = 57) diabetes patients. In addition, radio-binding assays for GADA with ³⁵S-GAD65 generated from both the pEx9 and pThGAD65 plasmids were used in displacement assays with an excess of recombinant human GAD65 (2 μg/mL) to correct for non-specific binding. ³⁵S-GAD65 produced by either pEx9 or pThGAD65 did not differ in binding among the healthy controls and among the type 1 diabetes patients. Among the type 2 and unspecified patients, there were 4/290 and 3/57 patients, respectively, with binding to the pEx9 but not to the pThGAD65 generated ³⁵S-GAD65. In the displacement assay, we discovered 14 patients with very high-titer GADA among the type 1 (n = 3, 12,272-29,915 U/mL), type 2 (n = 7; 12,398-334,288 U/mL), and unspecified (n = 4; 20,773-4,053,580 U/mL) patients. All samples were fully displaced following appropriate dilution. We conclude that pThGAD65 is preferred for the coupled in vitro transcription translation of ³⁵S-GAD65 and that displacement with recombinant GAD65 may detect very high-titer GADA with possible clinical relevance.

  • 4.
    Leijon, Kristina
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Freitas, A
    Unite d'lmmunobiologie, lnsritut Pasteur, Paris, France.
    Holmberg, Dan
    Umeå universitet, Medicinska fakulteten, Institutionen för molekylärbiologi (Medicinska fakulteten).
    Analysis of VH gene utilisation in the non-obese diabetic mouse1993Inngår i: Autoimmunity, ISSN 0891-6934, E-ISSN 1607-842X, Vol. 15, nr 1, s. 11-18Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The immunoglobulin (Ig) heavy chain variable (VH) gene complexity and the VH gene utilisation pattern of the non-obese diabetic (NOD) mouse were investigated. We found that the NOD mouse displays a VH gene complexity which appears to be identical to that of the C57BL/6 mouse. Thus, Southern hybridisation using probes specific for 9 of the murine VH gene families revealed identical restriction fragment length polymorphism (RFLP) patterns in both mouse strains. As indicated by immunofluorescence analysis using allotype specific monoclonal antibodies the NOD mice were also found to carry the IgCH-1b allele. Collectively, these data suggest that the NOD mice carry an IgVH locus identical to that carried by C57BL/6. In contrast to the apparent identity at the level of germline VH gene repertoires, the pattern of VH gene utilisation differed considerably between these two mouse strains. Thus, in NOD mice the neonatal preference of D-proximal VH genes was found to be more pronounced than in C57BL/6 mice. Moreover, in contrast to adult C57BL/6 mice a D-proximal bias was evident also in adult NOD mice. On the basis of these findings we discuss the possibility that the distorted development of B cell repertoires in the NOD mouse could be directly or indirectly related to the T cell mediated, autoimmune process in the NOD mouse.

  • 5. Lowe, R M
    et al.
    Graham, J
    Sund, G
    Kockum, I
    Landin-Olsson, M
    Schaefer, J B
    Törn, C
    Lernmark, A
    Dahlquist, Gisela
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk vetenskap, Pediatrik.
    The length of the CTLA-4 microsatellite (AT)N-repeat affects the risk for type 1 diabetes. Diabetes Incidence in Sweden Study Group.2000Inngår i: Autoimmunity, ISSN 0891-6934, E-ISSN 1607-842X, Vol. 32, nr 3, s. 173-80Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    CTLA-4 is important to down-regulating T cell responses and has been implicated in type 1 (insulin dependent) diabetes mellitus in both linkage and association studies. The aim of our study was to relate the polymorphic (AT)n microsatellite in the 3' untranslated sequence of the CTLA-4 gene to diabetes risk. We studied 616 consecutively diagnosed 0-34 year-old Swedish patients and 502 matched controls by PCR-based genotyping fo determine the length of the 3'-end (AT)n repeat region of the CTLA-4 gene and categorizing alleles as predominantly monomorphic short (S) or highly polymorphic (in length) long (L) alleles. The odds of type 1 diabetes of subjects with the L/L genotype was estimated to be 1.84 times that of subjects with the S/S genotype (95% CI 1.44-2.73, p=0.002). Further analysis of the long alleles, partitioned into intermediate (I) length and very long (VL) alleles, suggested that L alleles act recessively in conferring diabetes risk (p=0.0009). This study suggests that the 3'-end (AT)n repeat region of the CTLA-4 gene represents a recessive risk factor for type 1 diabetes.

  • 6.
    Renman, Emma
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Ekici, Rifat
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Sundström, Mia
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    Lejon, Kristina
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi.
    HSC70 is a novel binding partner involved in the capture of immunoglobulins on B cells in the NOD mouse2022Inngår i: Autoimmunity, ISSN 0891-6934, E-ISSN 1607-842X, Vol. 55, nr 8, s. 520-528Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    B cells have been shown to be essential for Type 1 diabetes development in the non-obese diabetic mouse, where their contribution as antigen presenting cells has been emphasised. Other important functions for B cells include surface capture of immunoglobulins and transportation of immune complexes, with subsequent endocytosis, antigen processing and antigen presentation. We have previously demonstrated that NOD B cells capture IgM and IgG immune complexes through an unknown surface molecule. In this study, we revealed the presumptive immunoglobulin-binding molecule to be HSC70. Moreover, we detected increased levels of HSC70 on NOD B cells. HSC70 has been shown to play a role in antigen processing and presentation as well as being important in several autoimmune diseases, including rheumatoid arthritis and systemic lupus erythematosus. Due to its protein stabilising properties, increased HSC70 could contribute to enhanced self-antigen collection and presentation and thereby contribute to the development of Type 1 diabetes.

    Fulltekst (pdf)
    fulltext
  • 7.
    Thyagarajan, Radha
    et al.
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Immunologi/immunkemi.
    Banday, Viqar
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Immunologi/immunkemi.
    Ding, Zhoujie
    Lejon, Kristina
    Umeå universitet, Medicinska fakulteten, Institutionen för klinisk mikrobiologi, Immunologi/immunkemi.
    Contribution of autoallergy to the pathogenesis in the NOD mice2015Inngår i: Autoimmunity, ISSN 0891-6934, E-ISSN 1607-842X, Vol. 48, nr 5, s. 298-304Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The immunoglobulin isotype IgE is commonly associated with allergy. However, its involvement in autoimmune disease in general, and Type 1 diabetes (T1D) in particular, is still not completely clarified, nonetheless IgE has been observed in patients with T1D. In this article, we aimed to elucidate the contribution of IgE in the pathogenesis of the disease in a spontaneous model for T1D, i.e. the NOD mouse. We observed increased levels of IgE in splenic, lymph node and peripheral blood B cells in the NOD mice compared to the control C57BL/6 (B6) mice. No correlation was found between the IgE levels on B cells and those in the sera of these mice, indicating a B cell intrinsic property mediating IgE capture in NOD. Functionally, the B cells from NOD were similar to B6 in rescuing the IgE-mediated immune response via the low affinity receptor CD23 in a transgenic adoptive transfer system. However, the involvement of IgE in diabetes development was clearly demonstrated, as treatment with anti-IgE antibodies delayed the incidence of the diabetes in the NOD mice compared to the PBS treated group. Pancreas sections from a 13-week-old NOD revealed the presence of tertiary lymphoid structures with T cells, B cells, germinal centers and IgE suggesting the presence of autoantigen specific IgE. Our study provides an insight to the commonly overlooked immunoglobulin IgE and its potential role in autoimmunity.

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