PTPN22 1858C>T (R620W) functional polymorphism and human longevity

Valerio Napolioni, Annalia Natali, Patrizia Saccucci, Nazzareno Lucarini

Received: 25 June 2010 / Accepted: 17 November 2010 / Published online: 27 November 2010

Springer Science+Business Media B.V. 2010

Keywords: Association study, Genetic polymorphism, Human longevity, Italian population, Autoimmunity

1p13, which encodes lymphoid protein tyrosine phosphatase (LYP), plays a crucial role in the negative control of T lymphocyte activation. Since age-related changes in T-cell signal transduction may be one of the most important causes of cell-mediated immune response decline with aging, we performed a population-based association study to test whether the PTPN22 1858C>T (R620W) functional polymorphism affects the ability to survive to old age and reach exceptional life expectancy. We studied 892 unrelated healthy individuals (age range 8-106 years, 403 males and 489 females) from central Italy. For both genders, the frequency of PTPN22*T1858 carriers did not differ significantly in nona/centenarians and octogenarians compared to the young group. Allele and genotype frequencies of age groups were compared to those reported in previously published studies carried out on control individuals with Italian ancestry (N = 1393), further confirming results obtained from our sample population. Overall, our study suggests that the PTPN22*T1858 allele is not negatively selected at oldest ages, and we speculate that its increased ability to protect individuals against development of infectious diseases may counteract its deleterious effect on the immune system leading to autoimmunity.

Introduction

It is widely accepted that cell-mediated immune functions (cytotoxicity, delayed-type hypersensitivity, etc.) decline with age [1, 2]. These age-associated immunological changes render an individual more susceptible to infection and possibly cancer, as well as to age-associated autoimmune disorders. They may also contribute to atherosclerosis and Alzheimer's disease [3, 4]. Recent evidence suggests that T-cell hypo-responsiveness due to defects of signaling through the T Cell Receptor (TCR) from healthy elderly subjects or from individuals with autoimmune diseases such as rheumatoid arthritis or systemic lupus erythematosus results in an impaired ability to mount efficient immune responses and to maintain responsiveness to foreign antigens [5]. This implies that a high proportion of auto-reactive T cells might accumulate either intrathymically or in the periphery. T-cell anergy and differential TCR signaling could thus also be key players in the disruption of tolerance and the onset of autoimmune diseases.

The proliferation and clonal expansion of T lymphocytes are mostly controlled by interactions between the cytokine IL-2 and its cellular receptor [6] following TCR ligation [7]. It is now well accepted that the induction of IL-2 secretion decreases with age in mice, rats, and humans [8]. It seems that such defects occur in the transduction of mitogenic signals following TCR stimulation. Indeed, recent studies suggest that alterations in, for example, tyrosine kinase activity, intracellular free calcium, inositol phosphates, protein kinase C (PKC), and so on may all contribute to changes in signal transduction with aging [9-11]. Although the signaling machinery in T cells is extremely complicated and many steps remain to be clarified, the age-related change in T-cell signal transduction may be one of the most important causes of cell-mediated immune response decline with aging.