Characterization of Antinuclear Autoantibodies Present in the Serum from Nonobese Diabetic (NOD) Mice

Humphreys‐Beher, Michael G.; Brinkley, Linda L.; Purushotham, Karnam R.; Wang, Pao-Li; Nakagawa, Yoichi; Dusek, David; Kerr, Micah; Chegini, Naser; Chan, Edward K. L.

doi:10.1006/clin.1993.1137

Cited by 55 publications

(31 citation statements)

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“…The emergence of anti-Sm autoantibodies was somewhat unexpected, as these are considered specific for SLE in human SLE and murine lupus models (19). Some groups, however, have reported ANA in NOD mice, with a variable penetrance (20,21). Other groups found no ANA in unmanipulated NOD mice, but detected antinuclear and anti-Sm Abs after treatment with bacillus Calmette-Guérin (Mycobacterium bovis) (22).…”

Section: Discussionmentioning

confidence: 99%

Genetic Control of Autoimmunity: Protection from Diabetes, but Spontaneous Autoimmune Biliary Disease in a Nonobese Diabetic Congenic Strain

Koarada

Fertig

et al. 2004

The Journal of Immunology

108

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At least 20 insulin-dependent diabetes (Idd) loci modify the progression of autoimmune diabetes in the NOD mouse, an animal model of human type 1 diabetes. The NOD.c3c4 congenic mouse, which has multiple B6- and B10-derived Idd-resistant alleles on chromosomes 3 and 4, respectively, is completely protected from autoimmune diabetes. We demonstrate in this study, however, that NOD.c3c4 mice develop a novel spontaneous and fatal autoimmune polycystic biliary tract disease, with lymphocytic peribiliary infiltrates and autoantibodies. Strains having a subset of the Idd-resistant alleles present in the NOD.c3c4 strain show component phenotypes of the liver disease: NOD mice with B6 resistance alleles only on chromosome 3 have lymphocytic liver infiltration without autoantibody formation, while NOD mice with B10 resistance alleles only on chromosome 4 show autoantibody formation without liver infiltration. The liver disease is transferable to naive NOD.c3c4 recipients using splenocytes from affected NOD.c3c4 mice, demonstrating an autoimmune etiology. Thus, substitution of non-NOD genetic intervals into the NOD strain can prevent diabetes, but in turn cause an entirely different autoimmune syndrome, a finding consistent with a generalized failure of self-tolerance in the NOD genetic background. The complex clinical phenotypes in human autoimmune conditions may be similarly resolved into largely overlapping biochemical pathways that are then modified, potentially by alleles at a few key chromosomal regions, to produce specific autoimmune syndromes.

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Section: Discussionmentioning

confidence: 99%

Genetic Control of Autoimmunity: Protection from Diabetes, but Spontaneous Autoimmune Biliary Disease in a Nonobese Diabetic Congenic Strain

Koarada

Fertig

et al. 2004

The Journal of Immunology

108

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“…However, depending on the amounts and possibly subclass of RF, and also the amount and type (glycoform) of the target IgG, either normal clearance of the RF-IgG occurs via all FcRs, or pathogenic immune complexes could be generated, which could contribute to renal disease [34] or arthritis [4,5]. It is possible that the complexes containing G0% IgG are, however, catabolized more slowly and thus more likely to contribute to the disease processes such as the SLE-like disease in MRL/lpr and the build up of the anti-nuclear antibodies that possibly contribute to the Sjögren's-like disease that develops with age in NOD [38,39].…”

Section: Discussionmentioning

confidence: 99%

Differential clearance of glycoforms of IgG in normal and autoimmune-prone mice

Newkirk

Novick

Stevenson

et al. 1996

Clinical and Experimental Immunology

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SUMMARYIn order to understand better the origins of the elevated levels of the glycoform of IgG that lacks galactose on both arms of the oligosaccharide chain (G0%) located in the Fc, which occurs in man and mouse with age, and in particular in autoimmune disease, we investigated the clearance of two glycosylated forms of IgG2a and IgG1 in normal (BALB/c) and autoimmune-prone (MRL/lpr, MRL/, and non-obese diabetic (NOD)) mice. To investigate the possibility of different rates of catabolism, enzymatically generated glycoforms of monomeric IgG1 and IgG2a (fully glycosylated or G0%), were iodinated and injected into the tail vein of the mice. We found that the G0% IgG2a remained in circulation significantly longer than the fully glycosylated variants, in all of the mouse strains tested. In contrast, the two forms of IgG1 had similar kinetics in all the autoimmune-prone mice, whereas in BALB/c, there was a longer half-life (t 1/2 ) for G0% IgG1. These data suggest that there may be differences in the ability of the IgG glycoforms to bind to the Fc°receptors, in particular Fc°RI. The clearance rates were found to vary among the strains studied, with MRL/lpr having the fastest catabolic rates for all glycoforms and IgG subclasses tested. This appeared to be due to the presence of circulating IgG and IgM rheumatoid factors (RF). There were significantly increased frequencies and titres for both IgM and IgG RF in MRL/lpr mice compared with the other strains. In contrast, interferon-gamma, known to induce the Fc°RI, was found to be similar in the sera, in all of the strains of mice examined. These results suggest that RF probably play an important biological function in the MRL/lpr mice and aid in the clearance of circulating IgG. Our study shows that the state of glycosylation of IgG affects the t 1/2 in vivo, and that by removing the terminal sugars (sialic acid and galactose), the antibody (IgG2a) will remain in circulation significantly longer. These observations may thus provide a partial explanation for the increase in relative percentage of this glycoform that occurs with age.

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“…C57BL/6 carrying either the NOD-derived genetic interval on chromosome 3 encompassing Idd3 , 10, 17, 18, or the Idd6 genetic intervals on chromosome 6 retained normal disease-free physiology. Conversely, NOD mice, containing chromosome regions of Hu et al ., 1992Hu and Humphreys-Beher, 1995;Humphreys-Beher et al ., 1993, 1994Kerr et al ., 1995;Yamamoto et al ., 1996Yamamoto et al ., , 1997Robinson et al ., 1996Robinson et al ., , 1997Robinson et al ., , 1998aRobinson et al ., , 1998bRobinson et al ., , 1998cYamachika et al ., 1998Yamachika et al ., , 2000Kong et al ., 1998a. c Konttinen et al ., 1994;Wu et al ., 1997. d Haneji et al ., 1997.…”

Section: (A) Geneticcontrol Of Autoimmunity Innod Mice Andhumanpatientsmentioning

confidence: 99%

Progress in Understanding Autoimmune Exocrinopathy Using the Non-obese Diabetic Mouse: An Update

Cha

Peck

Humphreys‐Beher

2002

Critical Reviews in Oral Biology & Medicine

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Sjögren's Syndrome (SS) is a chronic autoimmune disease characterized by histological and functional alterations of salivary and lacrimal glands that result in a severe dryness of the mouth and the eyes. The etiology of SS has remained undefined despite investigators' significant efforts to identify the mechanisms of initiation. Based on histopathology, several animal models are available-such as MRL/lpr, NZW/NZB, NFS/sld, graft vs. host, transgenic mouse expressing viral surface antigen, and the nonobese diabetic (NOD) mouse-for investigation of the etiology of SS. Biochemical and immunological similarities between human SS and autoimmune exocrinopathy (AEC) in the NOD mouse, including the loss of secretory function, establish the NOD mouse as an appropriate model to unravel the underlying pathophysiology of SS. Recently, several NOD congenic partner strains have been developed to investigate the roles of genetic intervals, cytokines, and autoantibodies in the disease pathogenesis. Studies on NOD-scid suggest that the pathogenesis of SS occurs in two phases: an asymptomatic phase, in which epithelial cells of exocrine tissues undergo dedifferentiation accompanied by elevated apoptosis; and a second phase in which autoaggression is mounted against target organ autoantigens, resulting in the activation of T-and B-cells, and the generation of autoantibodies. The presence of autoantibodies on the cell-surface signaling receptor, the muscarinic 3 receptor, in both SS patients and the NOD mice correlates with the hallmark clinical symptom of secretory dysfunction. Additionally, the NOD mouse model provides an important example of how both Th1 and Th2 cytokines, as well as non-immune genetic loci, are involved in the maintenance of and progression to the overt disease state. Ultimately, analysis of these data provides insight into potentially novel therapeutic interventions.

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Characterization of Antinuclear Autoantibodies Present in the Serum from Nonobese Diabetic (NOD) Mice

Cited by 55 publications

References 0 publications

Genetic Control of Autoimmunity: Protection from Diabetes, but Spontaneous Autoimmune Biliary Disease in a Nonobese Diabetic Congenic Strain

Genetic Control of Autoimmunity: Protection from Diabetes, but Spontaneous Autoimmune Biliary Disease in a Nonobese Diabetic Congenic Strain

Differential clearance of glycoforms of IgG in normal and autoimmune-prone mice

Progress in Understanding Autoimmune Exocrinopathy Using the Non-obese Diabetic Mouse: An Update

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