Bone Marrow Clonogenic Capability, Cytokine Production, and Thymic Output in Patients with Common Variable Immunodeficiency

Abstract

In patients with primary Ab deficiencies, hematological and immunological abnormalities are frequently observed. A regenerative failure of hemopoietic stem/progenitor cells has been hypothesized. We evaluated in the bone marrow (BM) of 11 patients with common variable immunodeficiency, the phenotype of BM progenitors and their in vitro growth by colony-forming cell (CFC) and long-term culture (LTC) assays. A significant decrease in erythroid and mixed CFC and, to a greater extent, in primitive LTC-CFC progenitors was observed in patients compared with healthy controls. The frequency of BM pre-B and pro-B cells correlated directly with the absolute number of CD19+ lymphocytes. BM cells cultured in vitro produced spontaneously lower amounts of IL-2 and elevated levels of TNF-α compared with controls, indicating a skewing toward a proapoptotic cytokine pattern. In addition, stromal cells generated after BM LTC secreted less IL-7 and displayed by immunohistochemistry an altered phenotype. These findings were associated with a significant decrease in naive Th cells coexpressing CD31 in the peripheral blood. These results indicate an impaired growth and differentiation capacity of progenitor cells in patients with common variable immunodeficiency.

Life after the thymus: CD31+ and CD31− human naive CD4+ T-cell subsets

“…Furthermore, strong correlations of the TREC content in CD4 ϩ T cells and frequencies of CD31 ϩ thymic naive CD4 ϩ T cells have been described in common variable immunodeficiency patients 64 and in multiple sclerosis. 29 And, confirming its use as direct marker of thymic output, virtually all newly generated naive CD4 ϩ T cells after autologous stem cell transplantation express CD31.…”

T and B lymphocyte abnormalities in bone marrow biopsies of common variable immunodeficiency

“…The fact that CD4 ϩ CD45R0 ϩ T helper memory cells were significantly elevated together with sIL-2R levels (supplemental Table 1) suggests an activated state of the BMinfiltrating T cells. They may locally recognize putative (auto)antigens or influence by their altered cytokine signature the surrounding stromal cell milieu, as suggested by Isgro et al 13 Third, BM-dependent, early B-cell differentiation was severely disturbed in 9 of 25 patients, leading to an increase of pro-B and pre-B-I cells because of a bottleneck at the pre-B-I to pre-B-II differentiation stage. Accordingly, the number of immature, transitional, and mature B cells of these 9 patients was reduced.…”

“…The authors postulated a primary progenitor cell defect or a secondary influence of chronic recurrent infections leading to elevated TNF-␣ production by inflammatory cells in the BM. 13 In view of these intriguing findings, we felt that a systematic analysis of T and B lymphocytes in BM biopsies might provide new clues for an involvement of hematopoietic and lymphoid progenitor cells as well as BM-infiltrating T lymphocytes in the physiopathology of CVID. Our study embarked on 48 diagnostically indicated BM biopsies from clinically well-classified CVID patients.…”

“…Isgro et al 13 found in BM aspirates from 11 unclassified CVID patients significantly reduced numbers of hematopoietic lineage progenitors and a skewed cytokine production toward proapoptotic TNF-␣ at the expense of antiapoptotic IL-2 and reduced IL-7. The authors postulated a primary progenitor cell defect or a secondary influence of chronic recurrent infections leading to elevated TNF-␣ production by inflammatory cells in the BM.…”

“…3,[5][6][7][8] Despite important progress in immunopathology, molecular genetics, 9,10 diagnosis, and treatment, 11 very little is known in CVID about changes of T and B lymphocyte populations in the bone marrow (BM). 12,13 Here we report a retrospective analysis of BM biopsies from 48 well-classified CVID patients. Although the hematopoietic compartment showed no major abnormalities, we confirmed the absence of plasma cells 12 and observed a highly significant increase of diffuse and nodular CD3 ϩ T-cellular infiltrates in the majority of CVID BM biopsies.…”