The development of autoimmune features in aging mice is closely associated with alterations of the peripheral CD4⁺ T‐cell compartment

Abstract

Some signs of potential autoimmunity, such as the appearance of antinuclear antibodies (ANAs) become prevalent with age. In most cases, elderly people with ANAs remain healthy. Here, we investigated whether the same holds true for inbred strains of mice. Indeed, we show that most mice of the C57BL/6 (B6) strain spontaneously produced IgG ANA at 8-12 months of age, showed IgM deposition in kidneys and lymphocyte infiltrates in submandibular salivary glands. Despite all of this, the mice remained healthy. ANA production is likely CD4 + T-cell dependent, since old (40-50 weeks of age) B6 mice deficient for MHC class II do not produce IgG ANAs. BM chimeras showed that ANA production was not determined by age-related changes in radiosensitive, hematopoietic progenitor cells, and that the CD4 + T cells that promote ANA production were radioresistant.Thymectomy of B6 mice at 5 weeks of age led to premature alterations in T-cell homeostasis and ANA production, by 15 weeks of age, similar to that in old mice. Our findings suggest that a disturbed T-cell homeostasis may drive the onset of some autoimmune features.Keywords: Antinuclear antibody r Autoimmunity r Sjögren's syndrome r T-cell homeostasis See accompanying Commentary by Winkler and WaismanAdditional supporting information may be found in the online version of this article at the publisher's web-site IntroductionIt is well established that the functional activity of the immune system declines with age. The fact that mortality and morbidity during annual influenza epidemics increases in the elderly population is a clear example of this [1]. Moreover, influenza vaccinations are only marginally protective for the elderly [2][3][4]. Yet another example of immune activity decline with age is the reactivation of the Varicella zoster virus in the elderly. The frequency of this reactivation increases in individuals after the fiftieth year [5] and is thought to be due to a generalized decreased memory response to Correspondence: Prof. Antonius Rolink e-mail: antonius.rolink@unibas.ch chronic infections. In addition, some malignancies are more often found among the elderly [6]. For multiple myeloma, the median age of diagnosis is 66 years and only 2% of all patients are younger than 40 years of age. The increased incidence of this plasma cell tumor and of certain other malignancies with age might suggest that, in these cases, immune surveillance is effective in young individuals, but declines with age. The decline in immune competence is thought to be due to an age-related decrease in production of both B cells and T cells. We and others have shown that in both mouse and man, B-cell production decreases with age [7][8][9]. Thus, the frequency of mouse BM derived pro-B cells, which can be grown on stromal cells in the presence of IL-7, decreases with age: from a frequency of around 1 in 50 at 2 weeks of age, whereas this frequency drops to 1 in C 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim www.eji-journal.eu 2894 Anja Nusser et al. Eur. J. Immunol. 2014. 44: 2893-2902...

Human neonatal thymectomy induces altered B‐cell responses and autoreactivity

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