Characterization and functional analysis of cellular immunity in mice with biotinidase deficiency
Kirit Pindolia1, Hong Li2, Cisley Cardwell3
1Department of Medical Genetics, Henry Ford Hospital, Detroit, MI 48202, USA; Center for Molecular Medicine and Genetics, Wayne State University, Detroit, MI 48201, USA.
Insights
Biotinidase deficiency, a metabolic disorder, causes immune system dysfunction. This study used a mouse model to investigate these immunological changes, revealing altered T-cell populations and reduced lymphocyte proliferation.
Area of Science:
- Biochemistry
- Immunology
- Genetics
Background:
- Biotinidase deficiency is an inherited metabolic disorder.
- It can lead to neurological, cutaneous, and immunological issues, including candida infections.
- Understanding the immunological dysfunction is crucial for affected individuals.
Purpose of the Study:
- To investigate the immunological dysfunction in biotinidase deficiency.
- To utilize a genetically engineered biotinidase deficiency knock-out mouse model.
- To correlate mouse model findings with human symptoms.
Main Methods:
- Studied immunological function in biotinidase deficiency knock-out mice.
- Compared mice on biotin-restricted vs. biotin-replete diets.
- Analyzed thymus and spleen weights, histology, splenocyte subpopulations (CD4+ cells), and in vitro lymphocyte proliferation.
Main Results:
- Biotinidase deficient mice on restricted diets had smaller thymuses and spleens.
- Splenocyte analysis showed an increase in CD4+ T-cells.
- In vitro lymphocyte proliferation assays demonstrated diminished responses to stimuli.
Conclusions:
- Biotinidase deficiency in mice leads to significant alterations in cellular immunological function.
- These findings may explain cellular immunity abnormalities observed in human patients.
- The mouse model provides insights into the mechanisms of immune dysfunction in this disorder.
Abstract:
Biotinidase deficiency is an autosomal recessively inherited metabolic disorder that can be easily and effectively treated with pharmacological doses of the vitamin, biotin. Untreated children with profound biotinidase deficiency may exhibit neurological, cutaneous and cellular immunological abnormalities, specifically candida infections. To better understand the immunological dysfunction in some symptomatic individuals with biotinidase deficiency, we studied various aspects of immunological function in a genetically engineered knock-out mouse with biotinidase deficiency. The mouse has no detectable biotinidase activity and develops neurological and cutaneous symptoms similar to those seen in symptomatic children with the disorder. Mice with profound biotinidase deficiency on a biotin-restricted diet had smaller thymuses and spleens than identical mice fed a biotin-replete diet or wildtype mice on either diet; however, the organ to body weight ratios were not significantly different. Thymus histology was normal. Splenocyte subpopulation study showed a significant increase in CD4 positive cells. In addition, in vitro lymphocyte proliferation assays consistently showed diminished proliferation in response to various immunological stimuli. Not all symptomatic individuals with profound biotinidase deficiency develop immunological dysfunction; however, our results do show significant alterations in cellular immunological function that may contribute and/or provide a mechanism(s) for the cellular immunity abnormalities in individuals with biotinidase deficiency.
