Defective proliferative capacity and accelerated telomeric loss of hematopoietic progenitor cells in rheumatoid arthritis

Abstract

Objective. In rheumatoid arthritis (RA), telomeres of lymphoid and myeloid cells are ageinappropriately shortened, suggesting excessive turnover of hematopoietic precursor cells (HPCs). The purpose of this study was to examine the functional competence (proliferative capacity, maintenance of telomeric reserve) of CD34؉ HPCs in RA.Methods. Frequencies of peripheral blood CD34؉,CD45؉ HPCs from 63 rheumatoid factorpositive RA patients and 48 controls matched for age, sex, and ethnicity were measured by flow cytometry. Proliferative burst, cell cycle dynamics, and induction of lineage-restricted receptors were tested in purified CD34؉ HPCs after stimulation with early hematopoietins. Telomere sequences were quantified by real-time polymerase chain reaction. HPC functions were correlated with the duration, activity, and severity of RA as well as its treatment.Results. In healthy donors, CD34؉ HPCs accounted for 0.05% of nucleated cells; their numbers were strictly age dependent and declined at a rate of 1.3% per year. In RA patients, CD34؉ HPC frequencies were age-independently reduced to 0.03%. Upon growth factor stimulation, control HPCs passed through 5 replication cycles over 4 days. In contrast, RA-derived HPCs completed only 3 generations. Telomeres of RA CD34؉ HPCs were age-inappropriately shortened by 1,600 bp.

Aging of the Immune System. Mechanisms and Therapeutic Targets

“…Loss of the costimulatory molecule CD28 is now recognized as a reliable aging marker on T cells (14). Subsequent studies revealed that RA T cells have shortening of telomeric sequences and that the telomeric loss affects naive, unprimed T cells as well as bone marrow precursor cells (15)(16)(17)(18)(19). Remarkably, healthy individuals typing HLA-DR4, a MHC class II haplotype associated with RA, share with patients the faster erosion of telomeres, already beginning during the second to third decades of life (16).…”

The dynamics of macrophage lineage populations in inflammatory and autoimmune diseases

“…The potential significance of these subsets is detailed below. Of possible relevance to the reported differences in monocyte numbers and subpopulations in the blood of patients with RA, previous reports have described bone marrow abnormalities in RA patients, such as abnormal myeloid cells (48)(49)(50), enhanced promonocyte DNA synthesis activity (51), increased numbers of HLA-DR and CD14-positive mononuclear cells (52), high myeloid precursor numbers and CSF activity in bone marrow next to affected joints (53,54), and a defective proliferative capacity of hematopoietic progenitor cells (55).…”

“…Based on such observations in clinical and animal studies, it has been proposed but not yet proven that bone marrow abnormalities may even initiate and drive RA pathogenesis (48,49,55,63). In this context, the potential benefits of hematopoietic stem cell transplantation in RA have been debated (64,65), and appropriate clinical trials are needed to clarify this issue.…”

Lymphocyte Reproductive Activity Normalized to Numbers of Hematopoietic Stem Cells in Blood and Rate of Death in Fatal Diseases

“…Hayflick's limit characterizes the maximum number of divisions that a single cell is able to undergo, despite telomerase activity, International Journal of Genetics and Genomics 2017; 5(5): 54-62 55 until its death. The ability of an organism to reproduce cells becomes weaker with age and with some diseases [6,7], especially those with life-threatening pathologies [8,9]. The decrease in human life span (LS) with age is accompanied by a reduction in lymphocytopoietic activity in organisms, a marked decline in the production of naïve T cells, and an increase in granulocyte numbers [7,10].…”