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Aberrant expression of costimulatory molecules in splenocytes of the mevalonate kinase-deficient mouse model of human hyper-IgD syndrome (HIDS)

  • Original Article
  • Published:
Journal of Inherited Metabolic Disease

Abstract

Objective

We sought to determine the activation status and proliferative capacities of splenic lymphocyte populations from a mevalonate kinase-deficient mouse model of hyper-IgD syndrome (HIDS). We previously reported that murine mevalonate kinase gene ablation was embryonic lethal for homozygous mutants while heterozygotes (Mvk +/−) demonstrated several phenotypic features of human HIDS including increased serum levels of IgD, IgA, and TNFα, temperature dysregulation, hematological abnormalities, and splenomegaly.

Methods and results

Flow cytometric analysis of cell surface activation markers on T and B lymphocytes, and macrophage populations, demonstrated aberrant expression of B7 glycoproteins in all splenic cell types studied. Differences in expression levels between Mvk +/− and Mvk +/+ littermate controls were observed in both the basal state (unstimulated) and after Concanavalin A (Con-A) stimulation in vitro of whole splenocyte cultures. In Mvk +/− CD4 and CD8 T cells, alterations in expression of CD25, CD80, CD152, and CD28 were observed. Mvk +/− splenic macrophages expressed altered levels of CD80, CD86, CD40, and CD11c while Mvk +/− B lymphocytes had differential expression of CD40, CD80, and CD86. Mvk +/− splenocyte subpopulations also exhibited altered proliferative capacities in response to in vitro stimulation.

Conclusion

We postulate that imbalances in the expression of cell surface proteins necessary for activation, proliferation, and regulation of the intensity and duration of an immune response may result in defective T cell activation, proliferation, and effector functions in our model and potentially in human HIDS.

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Abbreviations

APC:

Antigen presenting cell

CFSE:

5-6-carboxyfluorescein diacetate, succinimidyl ester

Con-A:

Concanavalin-A

GGDP:

Geranylgeranyl-diphosphate

EAE:

Experimental autoimmune encephalomyelitis

Foxp3:

Forkhead box P3 transcription factor

HIDS:

Human hyper-IgD syndrome

IL-:

Interleukin-

MCP-1:

Macrophage chemoattractant protein 1

MFI:

Mean fluorescence intensity

MHC:

Major histocompatibility antigen

MVK:

Mevalonate kinase

NOD:

Non-obese diabetic

TCR:

T cell antigen receptor

TH:

T helper cell

TNF:

Tumor necrosis factor

Treg:

Regulatory T cell

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Acknowledgement

The authors would like to thank Sherri Wiseman, Tara Rutledge, and Stephanie Guimond for their excellent technical assistance.

Supported in part by a grant from the Research Advisory Committee (RAC) Children’s Hospital of Pittsburgh, NIH HD57864 (KMG), and the Sterol and Isoprenoid Diseases (STAIR) consortium. STAIR is a part of NIH Rare Diseases Clinical Research Network (RDCRN). Funding and/or programmatic support for this project has been provided by a grant (1U54HD061939) from NICHD and the NIH Office of Rare Diseases Research (ORDR). The views expressed in written materials or publications do not necessarily reflect the official policies of the Department of Health and Human Services nor does mention by trade names commercial practices, or organizations imply endorsement by the U.S. Government.

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Author notes

  1. Elizabeth J. Hager

    Present address: Biological Testing Branch, National Cancer Institute, Fairview Center Suite, 205, 1003 West 7th St, Frederick, MD, 21701, USA

Authors and Affiliations

  1. Department of Biological Sciences, DOW ESE Room 742, Michigan Technological University, 1400 Townsend Drive, Houghton, MI, 49931, USA

    Elizabeth J. Hager & K. Michael Gibson

  2. Division of Immunogenetics, Department of Pediatrics, Children’s Hospital of Pittsburgh, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA

    Jon D. Piganelli

  3. Department of Microbiology, Comprehensive Diabetes Center, Shelby 1202, University of Alabama at Birmingham, Birmingham, AL, USA

    Hubert M. Tse

Authors
  1. Elizabeth J. Hager
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  2. Jon D. Piganelli
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  4. K. Michael Gibson
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Corresponding author

Correspondence to K. Michael Gibson.

Additional information

Communicated by: Robert Steiner

Competing interest: None declared.

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Hager, E.J., Piganelli, J.D., Tse, H.M. et al. Aberrant expression of costimulatory molecules in splenocytes of the mevalonate kinase-deficient mouse model of human hyper-IgD syndrome (HIDS). J Inherit Metab Dis 35, 159–168 (2012). https://doi.org/10.1007/s10545-011-9349-x

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  • DOI: https://doi.org/10.1007/s10545-011-9349-x

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