Dispensability of APRIL to the development of systemic lupus erythematosus in NZM 2328 mice

Chaim O. Jacob, Shunhua Guo, Noam Jacob, Rahul D. Pawar, Chaim Putterman, William J. Quinn, Michael P. Cancro, Thi Sau Migone, William Stohl

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Abstract

Objective To determine the role of APRIL in the development of systemic lupus erythematosus (SLE) in mice. Methods Wild-type (WT) NZM 2328, NZM. April -/-, NZM.Baff -/-, and NZM.Baff -/-. April -/- mice were evaluated for lymphocyte phenotype by flow cytometry, for serum total IgG and IgG autoantibody levels by enzyme-linked immunosorbent assay, for glomerular deposition of IgG and C3 by immunofluorescence, for renal changes by histopathology, and for clinical disease by laboratory assessment (severe proteinuria). Results In comparison to WT mice, NZM.April -/- mice harbored increased spleen B cells, T cells, and plasma cells (PCs), increased serum levels of IgG antichromatin antibodies, and decreased numbers of bone marrow (BM) PCs. Glomerular deposition of IgG and C3 was similar in NZM.April -/- mice and WT mice, renal changes on histopathology tended to be more severe in NZM.April -/- mice than in WT mice, and development of clinical disease was identical in NZM.April -/- mice and WT mice. BM (but not spleen) PCs and serum IgG antichromatin and anti-double-stranded DNA antibody levels were lower in NZM.Baff -/-.April -/- mice than in NZM.Baff -/- mice, whereas renal immunopathology in each cohort was equally mild. Conclusion APRIL is dispensable for the development of full-blown SLE in NZM mice. Moreover, the elimination of both APRIL and BAFF had no discernible effect on the development of renal immunopathology or clinical disease beyond that of elimination of BAFF alone. The reduction in BM PCs in hosts doubly deficient in APRIL and BAFF beyond that in hosts deficient only in BAFF raises concern that combined antagonism of APRIL and BAFF may lead to greater immunosuppression without a concomitant increase in therapeutic efficacy.

Original languageEnglish (US)
Pages (from-to)1610-1619
Number of pages10
JournalArthritis and Rheumatism
Volume64
Issue number5
DOIs
StatePublished - May 2012

Fingerprint

Systemic Lupus Erythematosus
Plasma Cells
Immunoglobulin G
Kidney
Bone Marrow Cells
Spleen
Serum
Disease Eradication
Antibodies
Proteinuria
Autoantibodies
Immunosuppression
Fluorescent Antibody Technique
Flow Cytometry
B-Lymphocytes
Bone Marrow
Enzyme-Linked Immunosorbent Assay
Lymphocytes
T-Lymphocytes
Phenotype

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy
  • Rheumatology
  • Pharmacology (medical)

Cite this

Dispensability of APRIL to the development of systemic lupus erythematosus in NZM 2328 mice. / Jacob, Chaim O.; Guo, Shunhua; Jacob, Noam; Pawar, Rahul D.; Putterman, Chaim; Quinn, William J.; Cancro, Michael P.; Migone, Thi Sau; Stohl, William.

In: Arthritis and Rheumatism, Vol. 64, No. 5, 05.2012, p. 1610-1619.

Research output: Contribution to journalArticle

Jacob, CO, Guo, S, Jacob, N, Pawar, RD, Putterman, C, Quinn, WJ, Cancro, MP, Migone, TS & Stohl, W 2012, 'Dispensability of APRIL to the development of systemic lupus erythematosus in NZM 2328 mice', Arthritis and Rheumatism, vol. 64, no. 5, pp. 1610-1619. https://doi.org/10.1002/art.33458
Jacob, Chaim O. ; Guo, Shunhua ; Jacob, Noam ; Pawar, Rahul D. ; Putterman, Chaim ; Quinn, William J. ; Cancro, Michael P. ; Migone, Thi Sau ; Stohl, William. / Dispensability of APRIL to the development of systemic lupus erythematosus in NZM 2328 mice. In: Arthritis and Rheumatism. 2012 ; Vol. 64, No. 5. pp. 1610-1619.
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abstract = "Objective To determine the role of APRIL in the development of systemic lupus erythematosus (SLE) in mice. Methods Wild-type (WT) NZM 2328, NZM. April -/-, NZM.Baff -/-, and NZM.Baff -/-. April -/- mice were evaluated for lymphocyte phenotype by flow cytometry, for serum total IgG and IgG autoantibody levels by enzyme-linked immunosorbent assay, for glomerular deposition of IgG and C3 by immunofluorescence, for renal changes by histopathology, and for clinical disease by laboratory assessment (severe proteinuria). Results In comparison to WT mice, NZM.April -/- mice harbored increased spleen B cells, T cells, and plasma cells (PCs), increased serum levels of IgG antichromatin antibodies, and decreased numbers of bone marrow (BM) PCs. Glomerular deposition of IgG and C3 was similar in NZM.April -/- mice and WT mice, renal changes on histopathology tended to be more severe in NZM.April -/- mice than in WT mice, and development of clinical disease was identical in NZM.April -/- mice and WT mice. BM (but not spleen) PCs and serum IgG antichromatin and anti-double-stranded DNA antibody levels were lower in NZM.Baff -/-.April -/- mice than in NZM.Baff -/- mice, whereas renal immunopathology in each cohort was equally mild. Conclusion APRIL is dispensable for the development of full-blown SLE in NZM mice. Moreover, the elimination of both APRIL and BAFF had no discernible effect on the development of renal immunopathology or clinical disease beyond that of elimination of BAFF alone. The reduction in BM PCs in hosts doubly deficient in APRIL and BAFF beyond that in hosts deficient only in BAFF raises concern that combined antagonism of APRIL and BAFF may lead to greater immunosuppression without a concomitant increase in therapeutic efficacy.",
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AU - Jacob, Chaim O.

AU - Guo, Shunhua

AU - Jacob, Noam

AU - Pawar, Rahul D.

AU - Putterman, Chaim

AU - Quinn, William J.

AU - Cancro, Michael P.

AU - Migone, Thi Sau

AU - Stohl, William

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N2 - Objective To determine the role of APRIL in the development of systemic lupus erythematosus (SLE) in mice. Methods Wild-type (WT) NZM 2328, NZM. April -/-, NZM.Baff -/-, and NZM.Baff -/-. April -/- mice were evaluated for lymphocyte phenotype by flow cytometry, for serum total IgG and IgG autoantibody levels by enzyme-linked immunosorbent assay, for glomerular deposition of IgG and C3 by immunofluorescence, for renal changes by histopathology, and for clinical disease by laboratory assessment (severe proteinuria). Results In comparison to WT mice, NZM.April -/- mice harbored increased spleen B cells, T cells, and plasma cells (PCs), increased serum levels of IgG antichromatin antibodies, and decreased numbers of bone marrow (BM) PCs. Glomerular deposition of IgG and C3 was similar in NZM.April -/- mice and WT mice, renal changes on histopathology tended to be more severe in NZM.April -/- mice than in WT mice, and development of clinical disease was identical in NZM.April -/- mice and WT mice. BM (but not spleen) PCs and serum IgG antichromatin and anti-double-stranded DNA antibody levels were lower in NZM.Baff -/-.April -/- mice than in NZM.Baff -/- mice, whereas renal immunopathology in each cohort was equally mild. Conclusion APRIL is dispensable for the development of full-blown SLE in NZM mice. Moreover, the elimination of both APRIL and BAFF had no discernible effect on the development of renal immunopathology or clinical disease beyond that of elimination of BAFF alone. The reduction in BM PCs in hosts doubly deficient in APRIL and BAFF beyond that in hosts deficient only in BAFF raises concern that combined antagonism of APRIL and BAFF may lead to greater immunosuppression without a concomitant increase in therapeutic efficacy.

AB - Objective To determine the role of APRIL in the development of systemic lupus erythematosus (SLE) in mice. Methods Wild-type (WT) NZM 2328, NZM. April -/-, NZM.Baff -/-, and NZM.Baff -/-. April -/- mice were evaluated for lymphocyte phenotype by flow cytometry, for serum total IgG and IgG autoantibody levels by enzyme-linked immunosorbent assay, for glomerular deposition of IgG and C3 by immunofluorescence, for renal changes by histopathology, and for clinical disease by laboratory assessment (severe proteinuria). Results In comparison to WT mice, NZM.April -/- mice harbored increased spleen B cells, T cells, and plasma cells (PCs), increased serum levels of IgG antichromatin antibodies, and decreased numbers of bone marrow (BM) PCs. Glomerular deposition of IgG and C3 was similar in NZM.April -/- mice and WT mice, renal changes on histopathology tended to be more severe in NZM.April -/- mice than in WT mice, and development of clinical disease was identical in NZM.April -/- mice and WT mice. BM (but not spleen) PCs and serum IgG antichromatin and anti-double-stranded DNA antibody levels were lower in NZM.Baff -/-.April -/- mice than in NZM.Baff -/- mice, whereas renal immunopathology in each cohort was equally mild. Conclusion APRIL is dispensable for the development of full-blown SLE in NZM mice. Moreover, the elimination of both APRIL and BAFF had no discernible effect on the development of renal immunopathology or clinical disease beyond that of elimination of BAFF alone. The reduction in BM PCs in hosts doubly deficient in APRIL and BAFF beyond that in hosts deficient only in BAFF raises concern that combined antagonism of APRIL and BAFF may lead to greater immunosuppression without a concomitant increase in therapeutic efficacy.

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