Ageing, autoimmunity and arthritis: Perturbations of TCR signal transduction pathways with ageing – a biochemical paradigm for the ageing immune system

Abstract

290 APC = antigen-presenting cell; DRM = detergent-resistant microdomain; ERK = extracellular signal-regulated kinase; IFN = interferon; IL = interleukin; ITAM = immunoreceptor tyrosine-based activation motif; LAT = linker of activated T cells; mAb = monoclonal antibody; MAPK = mitogenactivated protein kinase; MHC = major histocompatibility complex; NF = nuclear factor; NFAT = nuclear factor of activated T cells; PKC = protein kinase C; pLAT, tyrosine-phosphorylated LAT; PTK = protein tyrosine kinase; RA = rheumatoid arthritis; SLE = systemic lupus erythematosus; TCR = T-cell receptor; Th cells = T helper cells; ZAP = zeta-associated protein. Arthritis Research & TherapyVol 5 No 6 Fülöp et al. IntroductionIt 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][5]. There is still no clear consensus as to why cell-mediated immunity declines with age. It is generally believed that age-related immune deficiency develops coincident with the gradual involution of the thymus gland and, consequently, that thymic-related (T-cell) functions are the most profoundly affected. It has recently been suggested that the alterations observed with ageing are a reflection of an accumulation of relatively inert memory T cells and a consequent AbstractIt is widely accepted that cell-mediated immune functions decline with age, rendering an individual more susceptible to infection and possibly cancer, as well as to age-associated autoimmune diseases. The exact causes of T-cell functional decline are not known. One possible cause could be the development of defects in the transduction of mitogenic signals following TCR stimulation. This T-cell hyporesponsiveness due to defects of signalling through the TCR either 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. This implies that a high proportion of autoreactive T cells might accumulate either intrathymically or in the periphery. T-cell anergy and differential TCR signalling could thus also be key players in the disruption of tolerance and the onset of autoimmune diseases. The increasing number of the elderly may lead to an increase of clinically important autoimmune diseases. We will review the signal transduction changes through the TCR-CD3 complex in T lymphocytes from healthy elderly subjects, which result in a modification of the activation of transcription factors involved in IL-2 gene expression leading to decreased IL-2 production. The putative contribution of altered T-cell signalling with ageing in the development of autoimmune diseases will be also discussed.

Cell Therapy: A Safe and Efficacious Therapeutic Treatment for Alzheimer’s Disease in APP+PS1 Mice

“…In other words, mice which initially have T-cell repertoires skewed towards Th1 T-cells, are likely to have lower blood (and presumably total) Aβ levels. It has been suggested that rheumatoid arthritis patients, those with chronic (Th1) inflammation, have a significantly lower risk of developing Alzheimer’s disease [67], [68]. Our results are consistent with the finding that an inclination towards a Th1 T-cell reaction may lower Aβ levels.…”

Altered naive and memory CD4+ T-cell homeostasis and immunosenescence characterize younger patients with myelodysplastic syndrome

“…24–27 As younger age in MDS represents an important characteristic related to IST response, the CD4+ and CD8+ naive and memory cell populations and the CD4:CD8 ratio were compared among eight IST responders and fifteen non-responders (ages ranged from 19 to 72 years old with a mean age of 46 and 62 years among responders and non-responders, respectively) to gain a better understanding of how altered T-cell homeostasis affects bone marrow suppression among the younger cases. To understand the relationship between T-cell turnover and IST response, we also determined the expression of Ki67, a nuclear proliferation-associated antigen, as an indicator of proliferation in both the CD4+ and CD8+ T cells.…”

Roles of calpain-calpastatin system (CCS) in human T cell activation

“…Calpain inhibition was reported to activate MAP kinases: Erk, p38, JNK, PI3K/Akt and others, but only in monocytes and not in lymphocytes [26]. Still, knowing that the kinases listed above are crucial for appropriate T cell activation [26, 46], it is conceivable that they would also be affected by calpain activity in these cells upon stimulation. On the other hand, proteolytic modulation of the same protein may result in its activation or inhibition depending of the extent and duration of calpain activity [16, 24, 47].…”