Pathogenic autoantibodies in the NZB mouse are specific for erythrocyte Band 3 protein

Barker, Robert N.; Oliveira, Gabriela Gonçalves de; Elson, C. J.; Lydyard, PM

doi:10.1002/eji.1830230750

Cited by 58 publications

(56 citation statements)

References 28 publications

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Section: Elevated Rbc Turnover In Cd22 Tm1msn Cd22-deficient Mice Is supporting

confidence: 86%

“…2C), along with a non-significant trend towards increased levels of IgG anti-RBC antibodies. As expected, anti-RBC Ab levels in NZB sera were relatively low, reflecting previous observations that the majority of pathogenic antibodies in NZB mice are bound to circulating RBC in vivo [30,31].Cd22 tm1Msn CD22-deficient mice therefore develop anti-RBC antibodies but these have insufficient affinity for RBCs to be detected by DELAT. However, even very low affinity antibodies can mediate RBC clearance in vivo [32].…”

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confidence: 84%

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Increased red cell turnover in a line of CD22‐deficient mice is caused by Gpi1^c: A model for hereditary haemolytic anaemia

et al. 2012

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CD22, an inhibitory co-receptor of the BCR, has been identified as a potential candidate gene for the development of autoimmune haemolytic anaemia in mice. In this study, we have examined Cd22 tm1Msn CD22-deficient mice and identified an increase in RBC turnover and stress erythropoiesis, which might be consistent with haemolysis. We then, however, eliminated CD22 deficiency as the cause of accelerated RBC turnover and established that enhanced RBC turnover occurs independently of B cells and anti-RBC autoantibodies. Accelerated RBC turnover in this particular strain of CD22-deficient mice is red cell intrinsic and appears to be the consequence of a defective allele of glucose phosphate isomerase, Gpi1 c . This form of Gpi1 was originally derived from wild mice and results in a substantial reduction in enzyme activity. We have identified the polymorphism that causes impaired catalytic activity in the Gpi1 c allele, and biochemically confirmed an approximate 75% reduction of GPI1 activity in Cd22 −/− RBCs. The Cd22 −/− .Gpi1 c congenic mouse provides a novel animal model of GPI1-deficiency, which is one of the most common causes of chronic non-spherocytic haemolytic anaemia in humans.Keywords: Anaemia r CD22 r Erythrocytes r Glucose-6-phosphate isomerase r Polymorphism Supporting Information available online IntroductionClearance of RBCs by anti-RBC auto-Ab gives rise to the condition known as autoimmune haemolytic anaemia (AIHA). The pathoCorrespondence: Dr. Kenneth G.C. Smith e-mail: kgcs2@cam.ac.uk logical mechanisms underlying the generation of anti-RBC autoantibodies are incompletely understood, but are likely to involve defects in both T-and B-cell tolerance [1,2]. New Zealand Black (NZB) mice spontaneously develop AIHA at around 6 months of age [3], which is characterised by a progressive anaemia of varying severity, accompanied by reticulocytosis and splenomegaly, the results of on-going stress erythropoiesis. There is a clear genetic contribution to AIHA in NZB mice, and a number of quantitative C 2012 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu Eur. J. Immunol. 2012. 42: 3212-3222 Cellular immune response 3213 trait loci (QTLs) that either promote or protect from disease have been identified [4][5][6][7]. One such anaemia-promoting QTL, designated Aia3 (autoimmune anemia 3), is present on NZB proximal chromosome 7 and peaks in the vicinity of the Cd22 gene, around 9 cM from the centromere [7]. Of the many genes present within this interval, Cd22 is an attractive candidate for promoting Coombs auto-Ab production and AIHA [7]. As discussed below, NZB mice express a defective form of this receptor, and loss of CD22 function is associated with auto-Ab generation in some mouse models [8][9][10]. Other potential candidates include Cd79a, which encodes a component of the BCR signalling complex, and Fcgbp, which encodes an IgG-binding protein.CD22 is an inhibitory co-receptor of the BCR and, like other co-receptors, modulates the Ag receptor signal in response to cues from the local microen...

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Section: Elevated Rbc Turnover In Cd22 Tm1msn Cd22-deficient Mice Is supporting

confidence: 86%

supporting

confidence: 84%

Increased red cell turnover in a line of CD22‐deficient mice is caused by Gpi1^c: A model for hereditary haemolytic anaemia

et al. 2012

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“…injection of rat RBC to naive mice, a model developed by Playfair and Marshall-Clarke in 1973 [6]. A cross-reactive epitope, contained within the phylogenetically conserved erythrocyte anion channel, AE-1, also known as Band 3 [7], precipitates pathogenic autoantibody responses, resulting in loss of tolerance to self-RBC surface antigens [8]. Immunized mice develop autoantibodies specific for both rat and self-RBC, but this process also stimulates a lymphocyte-mediated regulatory mechanism that eventually suppresses the production of those autoantibodies specific for self-RBC while retaining the antibody response to rat RBC [9].…”

Section: Introductionmentioning

confidence: 99%

Indoleamine 2,3 dioxygenase contributes to transferable tolerance in rat red blood cell inducible model of experimental autoimmune haemolytic anaemia

Dahal

Hall

Barker

et al. 2013

Clinical and Experimental Immunology

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SummaryAutoimmune haemolytic anaemia (AIHA) is caused by autoantibodies against red blood cell (RBC) surface antigens that render RBC susceptible to Fc-mediated phagocytosis and complement-mediated lysis. Experimental AIHA can be induced by injection of rat RBC to naive mice, but a lymphocyte-mediated regulatory mechanism eventually suppresses the production of autoantibodies specific for mouse RBC. Critically, this tolerogenic response can be transferred to naive mice by splenocytes from the rat RBCimmunized mouse. Here we investigate whether indoleamine 2,3 dioxygenase (IDO) or the initiators of IDO cascade, including the cytotoxic T lymphocyte antigen (CTLA)-4 receptor and its soluble isoform, contribute to this tolerogenic mechanism. Splenocytes from experimental AIHA mice were transferred adoptively to naive mice under the cover of anti-CTLA-4, antisoluble CTLA-4 antibodies or IDO inhibitor 1-methyl tryptophan (1-MT). Recipient mice were immunized with rat RBC and levels of antibody against self-RBC and rat-RBC were monitored. Our results indicate that transfer of tolerance to naive recipients is dependent upon IDO-mediated immunosuppression, as mice receiving previously tolerized splenocytes under the cover of 1-MT were refractory to tolerance and developed haemolytic disease upon further challenge with rat RBC. Initiators of IDO activity, CTLA-4 or soluble CTLA-4 did not mediate this tolerogenic process but, on their blockade, boosted antigen-specific effector immune responses.

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“…3 RBC-bound immunoglobulin G (IgG) autoantibodies can be detected by Coombs' test from 3 months of age and the mice develop signs of anaemia 2-3 months later. 4 These autoantibodies are now known to be specific for Band 3, the RBC anion channel protein, 5 and depend on T cells for their production since treatment with anti-CD4 monoclonal antibody prevents NZB mice from becoming Coombs' positive. 6 CD4 + T cells can be classified into two types, Th1 and Th2, depending on the cytokines they produce.…”

Section: Introductionmentioning

confidence: 99%

T‐helper 1 dominated responses to erythrocyte Band 3 in NZB mice

et al. 1996

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SUMMARYBand 3, the red blood cell (RBC) anion channel protein, is the target autoantigen for the pathogenic RBC autoantibodies and T-helper (Th) cells in New Zealand Black (NZB) mice with autoimmune haemolytic anaemia (AIHA). To determine the subpopulation of these Th cells, they were stimulated with Band 3 and the profile of the cytokines elaborated by the responding cells was measured. NZB T cells stimulated with Band 3 produced high levels of the Th1 cytokine, interferon-g (IFN-g), but little or no interleukin-4 (IL-4), IL-5 or IL-10. Similar patterns were produced by NZB T cells responding to a spectrin preparation from the RBC membrane skeleton, or to mycobacterial heat-shock protein (hsp) 65 following immunization of mice with hsp 65 in incomplete adjuvant. By contrast, T cells from CBA mice similarly immunized with hsp 65 produced high levels of IL-4 and IL-5 in response to hsp 65. Examination of the isotype of the RBC-bound immunoglobulins in NZB mice revealed that immunoglobulin G2a (IgG2a) autoantibodies were the first to be detected in most mice and that later in the disease, IgG3 autoantibodies were often prominent. It is concluded that, contrary to expectation, the development of RBC autoantibodies in NZB mice is associated with Th1 cytokine-dominated responses.

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Pathogenic autoantibodies in the NZB mouse are specific for erythrocyte Band 3 protein

Cited by 58 publications

References 28 publications

Increased red cell turnover in a line of CD22‐deficient mice is caused by Gpi1^c: A model for hereditary haemolytic anaemia

Increased red cell turnover in a line of CD22‐deficient mice is caused by Gpi1^c: A model for hereditary haemolytic anaemia

Indoleamine 2,3 dioxygenase contributes to transferable tolerance in rat red blood cell inducible model of experimental autoimmune haemolytic anaemia

T‐helper 1 dominated responses to erythrocyte Band 3 in NZB mice

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Pathogenic autoantibodies in the NZB mouse are specific for erythrocyte Band 3 protein

Cited by 58 publications

References 28 publications

Increased red cell turnover in a line of CD22‐deficient mice is caused by Gpi1c: A model for hereditary haemolytic anaemia

Increased red cell turnover in a line of CD22‐deficient mice is caused by Gpi1c: A model for hereditary haemolytic anaemia

Indoleamine 2,3 dioxygenase contributes to transferable tolerance in rat red blood cell inducible model of experimental autoimmune haemolytic anaemia

T‐helper 1 dominated responses to erythrocyte Band 3 in NZB mice

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Increased red cell turnover in a line of CD22‐deficient mice is caused by Gpi1^c: A model for hereditary haemolytic anaemia

Increased red cell turnover in a line of CD22‐deficient mice is caused by Gpi1^c: A model for hereditary haemolytic anaemia