Risk of pulmonary embolism and deep vein thrombosis in systemic lupus erythematosus: a population-based cohort study

Abstract

Background: CD4 T cells help B cells produce antibodies following antigen challenge. This response classically occurs in germinal centers (GC) located in B-cell follicles of secondary lymphoid organs (SLO), a site of immunoglobulin isotype switching and affinity maturation. GC formation requires specialized CD4 T cells, T-follicular helper (Tfh) cells, which localize to follicles and provide B cells with survival and differentiation signals that are essential for B-cell maturation into memory and long-lived plasma cells. Pathogenic autoantibodies in human and murine lupus arise in a like manner. Although Tfh cells are critical for GC development, their genesis in humans, role in promotion of autoimmunity, and potential as therapeutic targets in SLE are incompletely understood. To address these issues, we dissected Tfh cell development and function, defining their transcriptional regulation, migration, and function in vivo in normal and lupus-prone mice and ex vivo in normal humans and patients with SLE. Methods: We used a combination of approaches-flow cytometry, confocal microscopy, microarrays, quantitative chromatin immunoprecipitation and DNA sequencing (ChIP-seq), retroviral overexpression, and T-cell-B-cell helper assays-to characterize Tfh cells in normal mice and in lupus-prone strains, and from the tonsils of normal humans and the blood of patients with SLE. Results: We found that the transcription factor Bcl6 (B-cell CLL/lymphoma 6) is necessary and sufficient for Tfh development and function, via genetic control of Tfh proteins that are essential for their migration to B-cell follicles and GC and subsequent B-cell maturation. We dissected steps in Tfh development within SLO, beginning with their genesis in the T-cell zone followed by emigration to sites of B-cell interaction outside the B-cell follicle, where we have shown that B cells serve to provide signals for continued Tfh expansion and follicular migration. We have now begun to tease apart the factors that mediate T-cell-B-cell collaboration in the follicle; these represent therapeutic targets in SLE. Finally, we have shown that patients with SLE have expansion of Tfh cells in the blood, a finding that highlights their potential role in the pathogenesis of SLE and as likely therapeutic targets. Conclusion: These studies help define the developmental pathways for Tfh cells, and the steps that enable these cells to function in the B-cell follicle to promote immunoglobulin and autoantibody production. They have also helped define markers of Tfh cells in normals and autoimmune individuals, and suggest that they are a promising therapeutic target in patients.

Risk of deep venous thrombosis and pulmonary embolism in individuals with polymyositis and dermatomyositis: a general population-based study

“…Several studies evaluating risk of VTE in other inflammatory conditions, including RA, SLE and scleroderma, have reported similar trends, supporting the proposed role of chronic inflammation in the pathogenesis of VTE 9 10 19 20 44…”

Systemic lupus erythematosus increases the risks of deep vein thrombosis and pulmonary embolism: a nationwide cohort study

“…Our results show that the SLE patients had a 12.8-fold higher adjusted HR for DVT and a 19.7-fold higher adjusted HR for PE than the general population in Taiwan. Aviña-Zubieta et al [20] reported that, in Canada, SLE patients had relative risks of 4.1 for DVT and 4.6 for PE, as compared with the general population, after adjustment for covariates. Although the underlying cause of the risk disparities remains unclear, it might be associated with racial differences and environmental factors [26,27].…”

“…Aviña‐Zubieta et al . demonstrated increased risks of DVT and PE in a population‐based SLE cohort in Canada. Therefore, we investigated whether the risks of DVT and PE are higher among SLE patients in a nationwide, population‐based cohort in Taiwan.…”

“…However, the generalizability of these findings of Mok et al and Weng et al is limited, because of the relatively small samples used in their studies. Aviña-Zubieta et al [20] demonstrated increased risks of DVT and PE in a population-based SLE cohort in Canada. Therefore, we investigated whether the risks of DVT and PE are higher among SLE patients in a nationwide, population-based cohort in Taiwan.…”

Rowell syndrome secondary to anti-tubercular therapy: A case report and literature review

“…There was no evidence of frothing from her mouth on inspection and no abnormalities detected on auscultation of her chest. Based on these findings and inherent increased risk of pulmonary embolism in lupus erythematosus [10,11], her cause of death was suspected to be a pulmonary embolism.…”