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Open Access Research article

Reduced proportions of natural killer T cells are present in the relatives of lupus patients and are associated with autoimmunity

Joan Wither1*, Yong-chun Cai2, Sooyeol Lim3, Tamara McKenzie2, Nicole Roslin3, Jaime O Claudio2, Glinda S Cooper4, Thomas J Hudson5, Andrew D Paterson3, Celia MT Greenwood3, Dafna Gladman6, Janet Pope7, Christian A Pineau8, C Douglas Smith9, John G Hanly10, Christine Peschken11, Gilles Boire12, CaNIOS Investigators13 and Paul R Fortin146

Author Affiliations

1 Arthritis Centre of Excellence; Division of Genetics and Development, Toronto Western Hospital Research Institute, University Health Network; Departments of Medicine and Immunology, University of Toronto, Bathurst Street, Toronto, Ontario, M5T 2S8, Canada

2 Toronto Western Hospital Research Institute, University Health Network, Bathurst Street, Toronto, Ontario, M5T 2S8, Canada

3 Program in Genetics and Genome Biology, The Hospital for Sick Children Research Institute, College Street, Toronto, Ontario, M5G 1L7, Canada

4 United States Environmental Protection Agency, Pennsylvania Avenue NW, Washington, District of Columbia 20460, USA

5 McGill University and Genome Quebec Innovation Centre, Penfield Avenue, Montreal, Quebec, H3A 1A4, Canada; and Ontario Institute for Cancer Research, College Street, Toronto, Ontario, M5G 1L7, Canada

6 University of Toronto Lupus Clinic, Centre for Prognosis Studies in the Rheumatic Diseases, Toronto Western Hospital, University Health Network; Department of Medicine, University of Toronto, Bathurst Street, Toronto, Ontario, M5T 2S8, Canada

7 Division of Rheumatology, St Joseph's Health Centre, Grosvenor Street, London, Ontario, N6A 4V2, Canada

8 Division of Rheumatology, McGill University Health Center, Cedar Avenue, Montreal, Quebec, H3G 1A4, Canada

9 Division of Rheumatology, Ottawa Hospital, Riverside Drive, Ottawa, Ontario, K1H 829, Canada

10 Division of Rheumatology, Department of Medicine, Queen Elizabeth II Health Sciences Centre and Dalhousie University, Summer Street, Halifax, Nova Scotia, B3H 4K4, Canada

11 Division of Rheumatology, Department of Medicine, Faculty of Medicine, University of Manitoba, Sherbrook Street, Winnipeg, Manitoba, R3A 1M4, Canada

12 Division of Rheumatology, Department of Medicine, Faculty of Medicine and Health Sciences, Université de Sherbrooke, 12th Avenue N, Sherbrooke, Quebec, J1H 5N4, Canada

13 CaNIOS Investigators are listed in the Acknowledgments section

14 Arthritis Centre of Excellence; Division of Health Care and Outcomes Research, Toronto Western Hospital Research Institute, University Health Network; Department of Medicine, University of Toronto, Bathurst Street, Toronto, Ontario, M5T 2S8, Canada

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Arthritis Research & Therapy 2008, 10:R108  doi:10.1186/ar2505

Published: 10 September 2008

Abstract

Introduction

Systemic lupus erythematosus is a genetically complex disease. Currently, the precise allelic polymorphisms associated with this condition remain largely unidentified. In part this reflects the fact that multiple genes, each having a relatively minor effect, act in concert to produce disease. Given this complexity, analysis of subclinical phenotypes may aid in the identification of susceptibility alleles. Here, we used flow cytometry to investigate whether some of the immune abnormalities that are seen in the peripheral blood lymphocyte population of lupus patients are seen in their first-degree relatives.

Methods

Peripheral blood mononuclear cells were isolated from the subjects, stained with fluorochrome-conjugated monoclonal antibodies to identify various cellular subsets, and analyzed by flow cytometry.

Results

We found reduced proportions of natural killer (NK)T cells among 367 first-degree relatives of lupus patients as compared with 102 control individuals. There were also slightly increased proportions of memory B and T cells, suggesting increased chronic low-grade activation of the immune system in first-degree relatives. However, only the deficiency of NKT cells was associated with a positive anti-nuclear antibody test and clinical autoimmune disease in family members. There was a significant association between mean parental, sibling, and proband values for the proportion of NKT cells, suggesting that this is a heritable trait.

Conclusions

The findings suggest that analysis of cellular phenotypes may enhance the ability to detect subclinical lupus and that genetically determined altered immunoregulation by NKT cells predisposes first-degree relatives of lupus patients to the development of autoimmunity.