| 1. |
- Holmdahl, Rikard
(författare)
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Dissection of the genetic complexity of arthritis using animal models.
- 2003
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Ingår i: Journal of Autoimmunity. - 0896-8411. ; 21:2, s. 99-103
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Forskningsöversikt (refereegranskat)abstract
- The exploding progress in genomic technology and knowledge now opens the possibility to actually identify the molecular mechanisms in disease. However, inflammatory diseases such as rheumatoid arthritis (RA) and multiple sclerosis (MS), are complex and polygenic and remain a challenge. One possible shortcut could be the use of inbred animals as models for RA and MS for the genetic analysis. These models have been extensively characterized and show a similar degree of complexity as the corresponding human diseases. Using these models linkage analysis followed by isolation of the loci in congenic strains have been shown to be highly efficient and have provided fundamental new knowledge on the genetic control of these diseases. The genetically controlled congenic strains are also useful as scientific tools. They can be used for the identification of the disease-associated genes and, thereby, the essential disease pathways that have been selected by nature. We know that this is possible since we have succeeded in identifying the genes within two of the congenic regions; the MHC class II gene Aq controlling immune response and the Ncf1 gene controlling oxidative burst. Both of these genes are associated with T cell activation and arthritis severity.
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| 2. |
- Moralejo, Daniel H, et al.
(författare)
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Genetic dissection of lymphopenia from autoimmunity by introgression of mutated Ian5 gene onto the F344 rat.
- 2003
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Ingår i: Journal of Autoimmunity. - 0896-8411. ; 21:4, s. 315-324
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Tidskriftsartikel (refereegranskat)abstract
- Peripheral T cell lymphopenia (lyp) in the BioBreeding (BB) rat is linked to a frameshift mutation in Ian5, a member of the Immune Associated Nucleotide (Ian) gene family on rat chromosome 4. This lymphopenia leads to type 1 (insulin-dependent) diabetes mellitus (T1DM) at rates up to 100% when combined with the BB rat MHC RT1 u/u genotype. In order, to better study the lymphopenia phenotype without possible confounding effects of diabetes or other autoimmune disease, we generated congenic F344.lyp rats by introgression of lyp on diabetes-resistant MHC RT1 lv1/lv1 F344 rats. Analysis of thymic CD4 and CD8 T lymphocytes revealed no difference in the percentage of CD4(-)CD8(+)and CD4(+)CD8(-)subsets in lyp/lyp compared to +/+ F344 rats. The same subsets was however dramatically reduced in blood (P=0.005), spleen (P=0.019) and mesenteric lymph nodes (MLN) (P<0.0001). Compared to F344 +/+ rats double positive CD4(+)CD8(+)T cells were increased only in lyp/lyp spleen (P=0.034) while double n
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| 3. |
- Wester Rosenlöf, Lena, et al.
(författare)
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Chronicity of pristane-induced arthritis in rats is controlled by genes on chromosome 14
- 2003
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Ingår i: Journal of Autoimmunity. - 0896-8411. ; 21:4, s. 305-313
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Tidskriftsartikel (refereegranskat)abstract
- To, address; he possibility, that genes specifically control the chronic phase of arthritis we have isolated a congenic fragment from the resistant E3; rat cm the, susceptible DA rat background. The isolated fragment covers the Pia6 quantitative trait locus on chromosome 14, which previously has been identified to be linked to chronic pristane induced arthritis (PIA) in gene segregation experiments; of an (E3 x DA) F-2-cross. Heterozygous. Pia6 congenic rats (DA.Pia6) were protected from chronic active arthritis specifically, as determined by macroscopic scoring, histopathology and release of cartilage oligomeric matrix protein (-reflecting ongoing cartilage destruction). The difference was seen only during the chronic active phase of arthritis starting approximately 5 weeks after onset of arthritis. Interestingly, the plasma concentration of the lipocalins alpha(1)-acid glycoprotein and alpha(1)-microglobulin was found significantly altered in naive congenic rats compared to the DA rat. The concentration of alpha(1)-microglobulin was found to be significantly higher throughout the disease course, while alpha(1)-acid glycoprotein had a lower concentration in naive rats, which was highly significant in the chronic phase. The altered concentrations of these proteins already before development of chronic arthritis may provide a clue to the pathogenic process controlled by the Pia6 genes. We conclude that the active relapsing chronic arthritis is under a unique genetic control that is different from the control of acute arthritis and postulate that the liver plays an important role in this relagation. (C) 2003 Elsevier Ltd. All rights reserved..
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| 4. |
- Alarcon-Riquelme, Marta E., et al.
(författare)
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Finding genes for SLE : complex interactions and complex populations
- 2003
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Ingår i: Journal of Autoimmunity. - 0896-8411 .- 1095-9157. ; 21:2, s. 117-120
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Many years of work, multiplex family collection and endless genotyping finally give fruit. The original aim cannot be lost. The aim is not only to identify mutations involved in susceptibility for systemic lupus erythematosus (SLE) but to elucidate the disease pathogenesis as well. After genetics comes the biology. We review our recent findings on the genetics of lupus, provide possible mechanisms for disease susceptibility and present some facts on the problematic of identifying susceptibility mutations for complex diseases in complex human populations.
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| 5. |
- Schloot, N, et al.
(författare)
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Comparison of cytokine ELISpot assay formats for the detection of islet antigen autoreactive T cells : Report of the third immunology of diabetes society T-cell workshop
- 2003
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Ingår i: Journal of Autoimmunity. - 0896-8411 .- 1095-9157. ; 21:4, s. 365-376
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Tidskriftsartikel (refereegranskat)abstract
- The identification of sensitive assay formats capable of distinguishing islet autoreactive T cells directly ex vivo in blood is a major goal in type 1 diabetes research. Recently, much interest has been shown in the cytokine enzyme linked immunospot assay (CK ELISpot), an assay potentially capable of fulfilling these difficult criteria. To address the utility of this assay in detecting autoreactive T cells, a 'wet' workshop was organized using the same fresh blood sample and coded antigens. Five different laboratories participated, using three distinct CK ELISpot assay formats. Samples from two subjects were pre-tested for responses to sub-optimal concentrations of tetanus toxoid, representing a low frequency recall response, and peptides from diabetes associated autoantigens GAD65, IA-2 and HSP60. All participants measured interferon-? production and combinations of interleukins-4, -5, -10 and -13. In the workshop 4 of 5 laboratories detected low frequency recall responses in both subjects and 3 of 5 detected at least one of the autoreactive peptide responses concordant with pre-testing. Significant assay format related differences in sensitivity and signal-to-noise ratio were observed. The results demonstrate the potential for detection of low-level autoreactive T cell responses and identify assay characteristics that will be useful for studies in type 1 diabetes. ⌐ 2003 Elsevier Ltd. All rights reserved.
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| 6. |
- Bergman, Marie-Louise, et al.
(författare)
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CTLA-4-/- mice display T cell-apoptosis resistance resembling that ascribed to autoimmune-prone non-obese diabetic (NOD) mice
- 2001
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Ingår i: Journal of Autoimmunity. - : Elsevier. - 0896-8411 .- 1095-9157. ; 16:2, s. 105-113
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Tidskriftsartikel (refereegranskat)abstract
- The genes conferring susceptibility to autoimmune (insulin-dependent) diabetes mellitus (IDDM) are, in most cases, not defined. Among the loci so far identified as associated with murine IDDM (Idd1-19), only the nature of Idd1 has been assessed. Here we show that thymocytes and peripheral lymphocytes of the non-obese diabetic (NOD) mouse are relatively resistant to apoptosis induced by gamma-irradiation. By linkage analysis of F2 progeny mice, we map this trait to a locus on chromosome 1 containing the Idd5 diabetes susceptibility region. By the use of congenic mice, we confirm the linkage data and map this locus to a 6 cM region on proximal chromosome 1. Ctla4, being localized in this chromosomal region and mediating crucial functions in T cell biology, is a logical candidate gene in the Idd5 susceptibility region. In line with this, we demonstrate that T cells from Ctla4(-/-)deficient mice show a similar resistance to gamma-irradiation-induced apoptosis as observed in the NOD mice. This reinforces the notion that CTLA-4 contributes to the pathogenesis of autoimmune diabetes.
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| 7. |
- Corthay, Alexandre, et al.
(författare)
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Evaluation of the percentage of peripheral T cells with two different T cell receptor alpha-chains and of their potential role in autoimmunity
- 2001
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Ingår i: Journal of Autoimmunity. - Rockville, MD : American Association of Immunologists. - 0896-8411 .- 1095-9157. ; 16:4, s. 423-429
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Tidskriftsartikel (refereegranskat)abstract
- Approximately 25% of mature T cells possess two distinct cytoplasmic T cell receptor (TCR) alpha-chains, due to productive gene rearrangements of both alleles. Expression of two different alpha-chains at the cell surface is a potential risk factor for development of autoimmunity. However, it has been difficult to determine the frequency of peripheral T cells with two different alpha-chains at the surface. Our new approach is based on comparing by flow cytometry the percentage of cells that express a given Valpha-chain between wild-type mice and mice that are hemizygous for a disrupted Tcra locus (Tcra+/-) and consequently unable to express two rearranged Tcra genes. We consistently found that approximately 8% of total peripheral T cells express two surface alpha-chains. The importance of dual alpha-T cells in autoimmunity was examined in a mouse model for rheumatoid arthritis, namely collagen-induced arthritis (CIA). No significant difference was observed between Tcra+/- mice and wild-type littermates, considering arthritis incidence, day of disease onset, and maximum arthritic score. We therefore conclude that there is incomplete phenotypic allelic exclusion in TCRalpha, and that the presence of a significant number of potentially multireactive T cells does not increase the susceptibility to develop autoimmune arthritis. © 2001 Academic Press.
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| 8. |
- Dahle, Charlotte, 1956-, et al.
(författare)
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Methods of choice for diagnostic antinuclear antibody (ANA) screening : Benefit of adding antigen-specific assays to immunofluorescence microscopy
- 2004
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Ingår i: Journal of Autoimmunity. - : Elsevier BV. - 0896-8411 .- 1095-9157. ; 22:3, s. 241-248
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Tidskriftsartikel (refereegranskat)abstract
- Objectives. To evaluate and compare the performances of three enzyme-immunoassays (EIAs) and a double radial immunodiffusion (DRID) test in addition to immunofluorescence (IF) microscopy for routine laboratory screening of patient sera sent for antinuclear antibody (ANA) analysis. Methods. 3079 consecutive patient sera sent for routine testing of ANA were analysed by IF microscopy on HEp-2 cells (IF-ANA), three different ANA-EIAs, and a DRID test for antibodies against extractable nuclear antigens. The IF-ANA and DRID tests were regarded as reference methods. Results. By IF-ANA and/or DRID, 375 sera (12%) turned out ANA-positive. A further 171 sera (6%) were positive by EIA, but could not be confirmed either by IF microscopy or DRID. 32 of the 375 ANA-positive (9%) sera were negative by IF microscopy, but had precipitating antibodies against Ro/SS-A (52 and/or 60 kD). Conclusions. Different assays for ANA analysis give overlapping results to a certain extent, but are by no means interchangeable. Thus, different ANA tests reflect different aspects of these autoantibodies. The diagnostic utility of ANA testing still mainly refers to IF-microscopy and precipitin tests. IF-ANA should not be abandoned as the golden standard in clinical routine, until diagnostic and classification criteria for systemic lupus erythematosus and other systemic inflammatory autoimmune diseases have been revised. However, in addition we strongly advocate that a specific test for anti-Ro/SS-A antibodies is always included.
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| 9. |
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| 10. |
- Fossati-Jimack, Liliane, et al.
(författare)
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Selective increase of autoimmune epitope expression on aged erythrocytes in mice : implications in anti-erythrocyte autoimmune responses
- 2002
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Ingår i: Journal of Autoimmunity. - : Academic Press. - 0896-8411 .- 1095-9157. ; 18:1, s. 17-25
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Tidskriftsartikel (refereegranskat)abstract
- We investigated the impact of changes occurring during red blood cell (RBC) ageing on the RBC-binding activity of pathogenic anti-erythrocyte monoclonal antibodies derived from autoimmune-prone New Zealand black (NZB) mice. As assessed by flow cytometric analysis on in vivo biotinylated RBCs, all five NZB-derived anti-RBC mAb exhibited more efficient binding to aged RBCs than to young RBCs, and resulted in a selective elimination of more aged RBCs from the circulating blood. In addition, treatment of RBCs with proteases markedly enhanced the binding of all five anti-RBC mAb, raising the possibility that increased exposure of autoimmune epitopes on aged RBCs may be in part, a result of contacts with proteolytic enzymes during the lifetime of circulating RBCs. In marked contrast, the binding activity of mAb raised in non-autoimmune animals against antigens expressed on RBCs, such as CD44, CD47, CD147 and TER-119, was either decreased or unchanged with RBC ageing, and these epitopes, except for that recognized by anti-CD47 mAb, were highly sensitive to mild treatment with proteases. Our data unravel the unique molecular feature of RBC epitopes involved in autoimmune haemolytic anaemia, suggesting that membrane alterations in aged RBCs might play a significant role in the development of the autoantibody response to RBCs.
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