Abstract
IntroductionSystemic 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.MethodsPeripheral blood mononuclear cells were isolated from the subjects, stained with fluorochrome-conjugated monoclonal antibodies to identify various cellular subsets, and analyzed by flow cytometry.ResultsWe 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.ConclusionsThe 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.
Highlights
Systemic lupus erythematosus is a genetically complex disease
Arthritis Research & Therapy Vol 10 No 5 Wither et al 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
Despite the recent success of genome-wide association studies, the precise informative allelic polymorphisms contained within many of these regions remain unidentified [4,5]. This lack of knowledge reflects the facts that most linkage and association studies have investigated the association with the global phenotype of lupus, which is clinically heterogeneous, and that multiple genes act in concert to produce lupus, each having a relatively minor effect
Summary
Systemic lupus erythematosus is a genetically complex disease. Currently, the precise allelic polymorphisms associated with this condition remain largely unidentified. Despite the recent success of genome-wide association studies, the precise informative allelic polymorphisms contained within many of these regions remain unidentified [4,5] This lack of knowledge reflects the facts that most linkage and association studies have investigated the association with the global phenotype of lupus, which is clinically heterogeneous, and that multiple genes act in concert to produce lupus, each having a relatively minor effect. In murine lupus study of allelic polymorphisms has been greatly aided by the ability to create congenic mice in which a single susceptibility allele, or small cluster of alleles, are back-crossed onto a normal genetic background These congenic mice frequently exhibit subclinical phenotypes that are characterized by production of anti-nuclear antibodies (ANAs) and/or cellular changes indicative of increased B-cell or T-cell activation [7,8,9]. This concept is supported by the well documented observation that first-degree relatives of lupus patients have an increased prevalence of ANAs and other lupus-associated autoantibodies as compared with the general population [10,11], and these phenotypes have successfully been used to map genetic loci that promote production of autoantibodies in lupus patients and their family members [12,13]
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