The large B-cell infiltrates in granulomatous tissue and increased molecular signs of antibody maturation are indicative of direct involvement of B cells in local inflammatory processes in patients with sarcoidosis. Moreover, CD27(-)IgA(+) B cells could be a marker for treatment with TNF-α blockers. These findings of B cells as emerging key players provide a rationale for a systematic study on B-cell ablative therapy in patients with sarcoidosis.
Granulomas in sarcoidosis express high levels of 1a-hydroxylase, an enzyme that catalyzes the hydroxylation of 25-OH vitamin D to its active form, 1,25(OH) 2 vitamin D. Overproduction of 1a-hydroxylase is held responsible for the development of hypercalcemia in sarcoidosis patients. Corticosteroids are used as first-line treatment in organ-threatening sarcoidosis. In this light, osteoporosis prevention with calcium and vitamin D (CAD) supplementation is often warranted. However, sarcoidosis patients are at risk for hypercalcemia, and CAD supplementation affects the calcium metabolism. We studied calcium and vitamin D disorders in a large cohort of sarcoidosis patients and investigated if CAD supplementation is safe. Retrospectively, data of 301 sarcoidosis patients from July 1986 to June 2009 were analyzed for serum calcium, 25-hydroxy vitamin D (25-(OH)D), 1,25-dihydroxy vitamin D (1,25(OH) 2 D), and use of CAD supplementation. Disease activity of sarcoidosis was compared with serum levels of vitamin D. Hypercalcemia occurred in 8%. A significant negative correlation was found between 25-(OH)D and disease activity of sarcoidosis measured by somatostatin receptor scintigraphy. In our study, 5 of the 104 CAD-supplemented patients developed hypercalcemia, but CAD supplementation was not the cause of hypercalcemia. Patients without CAD supplementation were at higher risk for developing hypercalcemia. During CAD supplementation, no hypercalcemia developed as a result of supplementation. Hypovitaminosis D seems to be related with more disease activity of sarcoidosis and, therefore, could be a potential risk factor for disease activity of sarcoidosis. Thus, vitamin D-deficient sarcoidosis patients should be supplemented.
BackgroundB-cell depletion can improve a variety of chronic inflammatory diseases, but does not appear beneficial for patients with Crohn’s disease.ObjectiveTo elucidate the involvement of B cells in Crohn’s disease, we here performed an ‘in depth’ analysis of intestinal and blood B-cells in this chronic inflammatory disease.MethodsPatients with Crohn’s disease were recruited to study B-cell infiltrates in intestinal biopsies (n = 5), serum immunoglobulin levels and the phenotype and molecular characteristics of blood B-cell subsets (n = 21). The effects of infliximab treatment were studied in 9 patients.ResultsGranulomatous tissue showed infiltrates of B lymphocytes rather than Ig-secreting plasma cells. Circulating transitional B cells and CD21low B cells were elevated. IgM memory B cells were reduced and natural effector cells showed decreased replication histories and somatic hypermutation (SHM) levels. In contrast, IgG and IgA memory B cells were normally present and their Ig gene transcripts carried increased SHM levels. The numbers of transitional and natural effector cells were normal in patients who responded clinically well to infliximab.ConclusionsB cells in patients with Crohn’s disease showed signs of chronic stimulation with localization to granulomatous tissue and increased molecular maturation of IgA and IgG. Therapy with TNFα-blockers restored the defect in IgM memory B-cell generation and normalized transitional B-cell levels, making these subsets candidate markers for treatment monitoring. Together, these results suggest a chronic, aberrant B-cell response in patients with Crohn’s disease, which could be targeted with new therapeutics that specifically regulate B-cell function.
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