Genetic regulation of anti-erythrocyte autoantibodies and splenomegaly in autoimmune hemolytic anemia-prone New Zealand Black mice

Ochiai, Kimiko; Ozaki, Shoichi; Tanino, Akihiro; Watanabe, Shinji; Ueno, Tomoo; Mitsui, Kentaro; Toei, Junichi; Inada, Yûji; Hirose, Sachiko; Shirai, Toshikazu; Nishimura, Hiroyuki

doi:10.1093/intimm/12.1.1

Cited by 28 publications

(24 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…[17][18][19][20]. In particular, a couple of loci on mouse chromosome 4 have been identified by several investigators to be linked to autoantibody production or other features of B cell hyperactivity (21)(22)(23)(24)(25)(26)(27)(28). When 1 of these loci, Sle2 of NZM2410/NZW origin, was introgressed onto the normal C57BL/6 (B6) background, it precipitated several B cell phenotypes including polyclonal hypergammaglobulinemia and elevated B1 cell formation (29)(30)(31).…”

mentioning

confidence: 99%

CD19 hyperexpression augments Sle1‐induced humoral autoimmunity but not clinical nephritis

Shi¹,

Xie²,

Chang³

et al. 2007

Arthritis & Rheumatism

View full text Add to dashboard Cite

Objective. B cell hyperactivity is a common denominator in murine and human systemic lupus erythematosus. Some susceptibility genes in lupus are associated with B cell hyperactivity, but others are clearly not. While the Sle1 lupus susceptibility locus of NZM2410/NZW origin leads to chromatin-focused autoimmunity, genetically engineered overexpression of CD19 leads to "generalized" B cell hyperactivity. We undertook this study to determine the degree to which generalized B cell hyperactivity can amplify lupus pathogenesis.Methods. To elucidate the impact of generalized B cell hyperactivity on Sle1-triggered autoimmunity, B6 mice bearing the human CD19 transgene were rendered congenic for the Sle1 z genetic locus and phenotyped for serologic, cellular, and pathologic evidence of lupus.Results. As expected, B6.Sle1.hCD19 Tg/Tg mice, homozygous at Sle1 and bearing the hCD19 transgene, exhibited high levels of IgM and IgG anti-DNA/ antiglomerular autoantibodies, skewed B cell subsets, and profoundly activated B and T cells. Despite exhibiting glomerular IgM, IgG, and complement deposits, these mice did not exhibit accelerated mortality or any clinical evidence of renal dysfunction.Conclusion. Generalized B cell hyperactivity may augment humoral autoimmunity, but this may not suffice to engender end-organ disease in lupus. These findings allude to the presence of an additional distal checkpoint that dissociates pathogenic autoantibody formation and renal immunoglobulin deposition from the progression to clinical nephritis in lupus."Generalized B cell hyperactivity" has been documented in several murine models of lupus (1,2). This phenomenon is evidenced by the activated surface phenotype of B cells, heightened spontaneous secretion of antibodies by cultured B cells, and the expanded population of B1 cells seen in most murine models of lupus (3-8). Transfer studies involving allotype-marked bone marrow (as well as pre-B cells) and tetraparental chimera experiments have also indicated that these phenotypes are genetically encoded in a B cell-intrinsic manner (9-13). Generalized B cell hyperactivity has also been documented in patients with lupus (14-16). The advent of microsatellite-based linkage analysis has shed light on the genetic basis of B cell hyperactivity in lupus. Linkage analysis in several murine models has uncovered multiple lupus susceptibility loci (for review, see refs. 17-20). In particular, a couple of loci on mouse chromosome 4 have been identified by several investigators to be linked to autoantibody production or other features of B cell hyperactivity (21-28). When 1 of these loci, Sle2 of NZM2410/NZW origin, was introgressed onto the normal C57BL/6 (B6) background, it precipitated several B cell phenotypes including polyclonal hypergammaglobulinemia and elevated B1 cell formation (29-31).In addition to the above lessons gleaned from mapping studies in lupus, additional molecular insights have also arisen from "engineered" mouse models that exhibit lupus-like disease. For example, aberrant express...

show abstract

mentioning

confidence: 99%

CD19 hyperexpression augments Sle1‐induced humoral autoimmunity but not clinical nephritis

Shi¹,

Xie²,

Chang³

et al. 2007

Arthritis & Rheumatism

View full text Add to dashboard Cite

show abstract

“…However, other QTL that map to the 80-90 Mbp chromosome 4 interval include loci that control the immune response (Ifa and Ifb), splenomegaly (Sbw2, Orgwg6 and Spm1), and anti-red blood cell IgG antibodies (Arigg3), which have been implicated in mouse models of autoimmune haemolytic anaemia and systemic lupus erythrematosus [7][8][9]. Significantly, a mouse anti-erythrocyte autoantibody modifier locus (Aem3) and anti-nuclear autoantibody locus (Bana2) co-localise to the suggestive E/NE bone marrow cell ratio QTL on chromosome 10, and a human haematocrit level QTL has also been mapped to chromosome 6q23-24, syntenic to mouse chromosome 10 QTL [1].…”

Section: Discussionmentioning

confidence: 99%

“…For example, QTL that are linked to anti-red blood cell and antinuclear antibody production and splenomegaly have been mapped in mouse models of AHA and SLE [7][8][9]. Similarly, QTL have been identified that determine mouse stem, progenitor and mature white blood cell numbers [10][11][12][13][14][15][16][17][18].…”

Section: Introductionmentioning

confidence: 99%

Mouse bone marrow and peripheral blood erythroid cell counts are regulated by different autosomal genetic loci

Jawad¹,

Giotopoulos²,

Fitch³

et al. 2007

Blood Cells, Molecules, and Diseases

View full text Add to dashboard Cite

1 SummaryErythropoiesis is under fine control and genetic loci that effect it are likely to be important in a range of conditions. To assess the relative contributions of different genetic loci to parameters of erythropoiesis we have measured RBC counts in the peripheral circulation and committed erythroid cells (RBC and small normoblasts) in the bone marrow in a cohort of (CBA/H x C57BL/6) F2 mice to map quantitative trait loci (QTL). Candidate genes were assessed using bioinformatics and DNA sequencing.Different autosomal loci affect bone marrow (chromosomes 5, 11, and 19) and peripheral blood (chromosome 4) erythroid cell counts but there may be a common chromosome X locus. Spleen weight QTL were found on chromosomes 3, 15 and 17. Surprisingly, erythropoietin (EPO) is the best candidate quantitative trait gene (QTG) in the chromosome 5 locus that affects bone marrow but not peripheral blood erythroid cell counts. Epo gene expression is known to be genetically regulated in mice, but our data suggests a tissue-specific role for epo in mouse erythropoiesis that is also genetically determined. The identity of the other QTG will be important both to further knowledge of the control of erythropoiesis and as potential modifier genes for haematological disorders.

show abstract

“…Loci from NZB/NZW crosses are designated Nba, Sle, and Lbw (47,54,55,59,60,74). HA loci from NZB crosses are designated Aem (75). Loci from BXSB crosses are designated Bxs (53,56,80).…”

Section: Discussionmentioning

confidence: 99%

Linkage Analysis of Systemic Lupus Erythematosus Induced in Diabetes-Prone Nonobese Diabetic Mice byMycobacterium bovis

Jordan

Silveira

Shepherd

et al. 2000

The Journal of Immunology

View full text Add to dashboard Cite

Systemic lupus erythematosus induced by Mycobacterium bovis in diabetes-prone nonobese diabetic mice was mapped in a backcross to the BALB/c strain. The subphenotypes—hemolytic anemia, antinuclear autoantibodies, and glomerular immune complex deposition—did not cosegregate, and linkage analysis for each trait was performed independently. Hemolytic anemia mapped to two loci: Bah1 at the MHC on chromosome 17 and Bah2 on distal chromosome 16. Antinuclear autoantibodies mapped to three loci: Bana1 at the MHC on chromosome 17, Bana2 on chromosome 10, and Bana3 on distal chromosome 1. Glomerular immune complex deposition did not show significant linkage to any genomic region. Mapping of autoantibodies (Coombs’ or antinuclear autoantibodies) identified two loci: Babs1 at the MHC and Babs2 on distal chromosome 1. It has previously been reported that genes conferring susceptibility to different autoimmune diseases map nonrandomly to defined regions of the genome. One possible explanation for this clustering is that some alleles at loci within these regions confer susceptibility to multiple autoimmune diseases—the “common gene” hypothesis. With the exception of the H2, this study failed to provide direct support for the common gene hypothesis, because the loci identified as conferring susceptibility to systemic lupus erythematosus did not colocalize with those previously implicated in diabetes. However, three of the four regions identified had been previously implicated in other autoimmune diseases.

show abstract

Genetic regulation of anti-erythrocyte autoantibodies and splenomegaly in autoimmune hemolytic anemia-prone New Zealand Black mice

Cited by 28 publications

References 27 publications

CD19 hyperexpression augments Sle1‐induced humoral autoimmunity but not clinical nephritis

CD19 hyperexpression augments Sle1‐induced humoral autoimmunity but not clinical nephritis

Mouse bone marrow and peripheral blood erythroid cell counts are regulated by different autosomal genetic loci

Linkage Analysis of Systemic Lupus Erythematosus Induced in Diabetes-Prone Nonobese Diabetic Mice byMycobacterium bovis

Contact Info

Product

Resources

About