Cytokine production by bone marrow mononuclear cells in inherited bone marrow failure syndromes

Fanconi anaemia (FA), dyskeratosis congenita (DC), Diamond‐Blackfan anaemia (DBA), and Shwachman‐Diamond syndrome (SDS) are characterized by the progressive development of bone marrow failure. Overproduction of tumour necrosis factor‐α (TNF‐α) from activated bone marrow T‐cells has been proposed as a mechanism of FA‐related aplasia. Whether such overproduction occurs in the other syndromes is unknown. We conducted a comparative study on bone marrow mononuclear cells to examine the cellular subset composition and cytokine production. We found lower proportions of haematopoietic stem cells in FA, DC, and SDS, and a lower proportion of monocytes in FA, DC, and DBA compared with controls. The T‐ and B‐lymphocyte proportions were similar to controls, except for low B‐cells in DC. We did not observe overproduction of TNF‐α or IFN‐γ by T‐cells in any patients. Induction levels of TNF‐α, interleukin (IL)‐6, IL‐1β, IL‐10, granulocyte colony‐stimulating factor, and granulocyte‐macrophage colony‐stimulating factor in monocytes stimulated with high‐dose lipopolysaccharide (LPS) were similar at 4 h but lower at 24 h when compared to controls. Unexpectedly, patient samples showed a trend toward higher cytokine level in response to low‐dose (0·001 μg/ml) LPS. Increased sensitivity to LPS may have clinical implications and could contribute to the development of pancytopenia by creating a chronic subclinical inflammatory micro‐environment in the bone marrow.