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J Inherit Metab Dis. 2012 Jan;35(1):159-68. doi: 10.1007/s10545-011-9349-x. Epub 2011 May 24.

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

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

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.

PMID:
21607759
[PubMed - indexed for MEDLINE]
PMCID:
PMC3654530
Free PMC Article
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