Lymphoma in rheumatoid arthritis: An immune system set up for failure

Weyand, Cornelia M.; Goronzy, Jörg J.; Kurtin, Paul J.

doi:10.1002/art.21674

Cited by 28 publications

(32 citation statements)

References 31 publications

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“…Premature senescence of the RA immune system is not limited to the memory T cell pool; it also involves naive T cells (43), the reserve pool of T cells that protect from infection and malignancy and enable tissue repair. Defects in naive T cells may well explain why RA patients are at increased risk of developing lymphoma and infection (4). The current study redirects the search for premature immunosenescence away from the peripheral immune system and toward the origins of all hematopoietic cells.…”

Section: Discussionmentioning

confidence: 82%

“…A reappraisal of RA disease manifestations over the last decade has emphasized the expanding spectrum of the rheumatoid syndrome, which now includes accelerated cardiovascular disease as well as increased susceptibility to lymphoma and infection (1)(2)(3). Although the broad use of immunosuppressants makes it difficult to distinguish between iatrogenic and disease-intrinsic pathogenic factors, it is clear that the overall immunocompetence of RA patients is compromised (4). Immune cells originate in the bone marrow (BM), raising the question of whether the BM itself plays a role in the impaired immunocompetence and in the disease process that defines RA (5).…”

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confidence: 99%

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

Colmegna

Díaz-Borjón

Fujii

et al. 2008

Arthritis & Rheumatism

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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.

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Section: Discussionmentioning

confidence: 82%

mentioning

confidence: 99%

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

Colmegna

Díaz-Borjón

Fujii

et al. 2008

Arthritis & Rheumatism

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“…Whereas T cell diversity is critical to normal host defense, T cell repertoire contraction is thought to underlie the immunocompromised phenotype of patients with RA (41), possibly leading to the increased risk of infection (42) and increase in other comorbidities including lymphoma and atherosclerotic heart disease (43,44). The degree to which clonal expansion of CD56ϩ T cells is associated with specific comorbid conditions in RA remains to be examined.…”

Section: Discussionmentioning

confidence: 99%

CD56‐expressing T cells that have features of senescence are expanded in rheumatoid arthritis

Michel

Turesson

Lemster

et al. 2007

Arthritis & Rheumatism

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Objective. T cells deficient in CD28 expression have been implicated in the pathogenesis of rheumatoid arthritis (RA). Given that CD28-null T cells are functionally heterogeneous, we undertook this study to screen for novel receptors on these cells.Methods. Seventy-two patients with RA (ages 35-84 years) and 53 healthy persons (32 young controls ages 19-34 years, 21 older controls ages 39-86 years) were recruited. Phenotypes and proliferative capacity of T cells from fresh leukocytes and of long-term cultures were monitored by flow cytometry. Lung biopsy specimens from patients with RA-associated interstitial pneumonitis (IP) were examined by immunohistochemistry. Receptor functionality was assessed by crosslinking bioassays.Results. Chronic stimulation of CD28؉ T cells in vitro yielded progenies that lacked CD28 but that gained CD56. Ex vivo analysis of leukocytes from patients with extraarticular RA showed a higher frequency of CD56؉,CD28-null T cells than in patients with disease confined to the joints or in healthy controls. CD56؉,CD28-null T cells had nil capacity for proliferation, consistent with cellular senescence. CD56؉ T cells had skewed T cell receptor (TCR) ␣/␤-chain usage and restricted TCR third complementarity-determining region spectra. Histologic studies showed that CD56؉ T cells were components of cellular infiltrates in RAassociated IP. CD56 crosslinking on T cells sufficiently induced cytokine production, although CD56/TCR coligation induced higher production levels.Conclusion. Chronic activation of T cells induces counterregulation of CD28 and CD56 expression. The loss of CD28 is accompanied by the gain of CD56 that confers TCR-independent and TCR-dependent activation pathways. We propose that accumulation of CD56؉ T cells in RA contributes to maladaptive immune responses and that CD56؉ T cells are potential targets for therapy.

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“…Patients with RA may lack immunocompetence, being more susceptible to lymphoma development, or immunosuppressive treatment may concur to weaken the patient's immune response. Therefore, lymphoma in RA could be due to a too strong or insufficient immunosuppressive therapy (Weyand et al, 2006). A matched case-control study on 378 consecutive Swedish RA patients in whom lymphoma occurred between 1964 and 1995 and 378 healthy controls showed that 48% of lymphoma cases were DLBCLs, and, within those, EBV infection was detected in 12% of lymphomas.…”

Section: Pathogenesismentioning

confidence: 99%