Translational Mini-Review Series on B cell subsets in disease. Reconstitution after haematopoietic stem cell transplantation - revelation of B cell developmental pathways and lineage phenotypes

Abstract

Haematopoietic stem cell transplantation (HSCT) is an immunological treatment that has been used for more than 40 years to cure a variety of diseases. The procedure is associated with serious side effects, due to the severe impairment of the immune system induced by the treatment. After a conditioning regimen with high-dose chemotherapy, sometimes in combination with total body irradiation, haematopoietic stem cells are transferred from a donor, allowing a donor-derived blood system to form. Here, we discuss the current knowledge of humoral problems and B cell development after HSCT, and relate these to the current understanding of human peripheral B cell development. We describe how these studies have aided the identification of subsets of transitional B cells and also a robust memory B cell phenotype.

Fig. 1

Human B cell development. (a) When immature B cells leave the bone marrow, they go through distinct differentiation stages. Transitional (T1, T2 and T3), naive and memory B cells as well as plasmablasts are found in blood. Black arrows indicate differentiation pathways well supported by experimental data, grey arrows pathways less well-defined or only proposed pathways. Recent data suggest that immunoglobulin (Ig)M⁺CD27⁺ cells may not be memory cells, but rather the human counterpart to marginal zone B or B1 lineages. T3′ cells lack CD27^- but express CD45RB^MEM55 and may be upstream cells in these lineages or cells downstream from T3 cells. (b) The different B cell stages can be distinguished from each other based on expression of cell surface markers. The subtypes express or lack expression, as indicated. Blank spaces indicate that the expression of this marker has not, to our knowledge, been described in the literature.

Fig. 2

Identification of peripheral blood B differentiation stages based on expression of surface markers. In (a) peripheral blood cells were stained with antibodies against CD19, CD27, immunoglobulin (Ig)M, CD24, CD38 and CD10. To the left, CD19⁺ B cells were gated into IgM⁺CD27⁺, class-switched memory B cells and CD27^- cells. The CD27^- cells were divided further into T1, T2 and T3/naive cells based on expression of CD24 and CD38 (middle panels) or CD10 and CD38 (right panels). Typical results obtained using peripheral blood from five adults and four children are shown. In (b), peripheral blood cells were preincubated with the dye Rhodamine 123 followed by antibodies against CD19, CD27, CD5, CD10 and CD45RB^MEM55. CD19⁺ B cells were divided into naive, memory and transitional cells based on expression of CD27 and extrusion of the dye (upper panel). The transitional cells could be divided further into T1/T2 cells expressing CD5 and CD10, and two distinct populations (T3 and T3′) that lacked these based on expression of CD45RB^MEM55 (lower panels). The data represent typical data from three different healthy donors tested.

Fig. 3

Subtyping of B cells in children who have undergone haematopoietic stem cell transplantation (HSCT). (a) In healthy adults, the CD19⁺ B cells can be divided into immunoglobulin (Ig)M^highIgD^lowCD27⁺ and IgM^-IgD^-CD27⁺ memory cells and IgM^lowIgD^highCD27^- naive cells, with few cells being IgM^highCD27^-. In paediatric patients who have undergone HSCT, IgM^highIgD^highCD27^- B cells is a major population even 1 year after transplantation when normal numbers of B cells has been reached in blood. In (b) are shown the mean frequency of CD27⁺ B cells and IgM^highCD27⁺ B cells in healthy children (n = 9), healthy adults (n = 3) or children who have undergone HSCT 1 year prior to the analysis (n = 10). (c) Few of the IgM^highCD27⁺ B cells express markers typical for transitional cells in healthy controls (n = 4) or paediatric HSCT patients (n = 4).