Research paper
Abnormalities of B cell subsets in patients with systemic lupus erythematosus

https://doi.org/10.1016/j.jim.2010.06.009Get rights and content

Abstract

The prototypic autoimmune disease, SLE, is known to be associated with polyclonal B cell hyperreactivity. Developing an understanding of the complex nature of human B cell differentiation, largely through the application of multiparameter flow cytometry to an analysis of circulating B cells has permitted an assessment of whether specific stages of B cell maturation are affected by the tendency for polyclonal B cell activation. Moreover, the analysis of perturbations of the specific stages of B cell maturation has generated new information on whether abnormalities in B cell differentiation are primarily involved in autoimmune disease immunopathology or, rather, are secondary to the inflammatory environment characteristic of subjects with this autoimmune disease. Multivariant analysis has begun to document abnormalities in B cell maturation that are primarily associated with lupus, or, alternatively related to disease duration, disease activity and concomitant medication. Together, these analyses have provided new insights on the role of B cell over-reactivity in SLE.

Introduction

Increasing knowledge of the distinct roles of B cells under normal conditions, including their differentiation into memory cells and antibody secreting plasma cells, has generated substantial insight into the roles of these cells in autoimmunity, and has already stimulated the introduction of B cell-directed therapies. The subtle differentiation processes of naïve and memory B cells in healthy individuals and subjects with autoimmune diseases have been reviewed in detail (Dorner et al., 2009), but the characteristic abnormalities detected by multiparameter flow cytometry largely of peripheral blood populations have not been thoroughly reviewed. Systemic lupus erythematosus (SLE) is the prototypic systemic autoimmune disease, and is associated with a wide variety of polyclonal B cell abnormalities, diffuse B cell hyperreactivity and the production of a plethora of autoantibodies.

Section snippets

The cellular and humoral context of enhanced B cell activation in SLE

A central set of findings in SLE is the expansion of immature transitional B cells, memory B cells and plasma cells in the peripheral blood, associated with a decline in the number of naïve B cells. In humans as in mice, B cells follow a tightly regulated life cycle with a number of checkpoints to cull immature B cells in the bone marrow and subsequently mature B cells in the spleen and during antigen-specific selection of autoreactivity and, therefore, to prevent the development of

Disturbances of pre-naïve B cells in SLE

Pre-immune B cells in the periphery can be separated into 2 maturational subsets, transitional B cells and naïve B cells. In mice, transitional B cells can be subdivided into several developmental subsets. Initially, murine transitional B cells were separated into two subsets, T1 and T2, based on expression of CD21 and IgD. CD24hiCD21loIgDlo T1 and CD24hiCD21hiIgDhi T2 cells appear to have different population dynamics, and require different maturation signals (Loder et al., 1999). Others have

Abnormalities of the memory B cell compartment in SLE

An initial finding in phenotyping peripheral blood B cells in adult SLE was the substantial increase of antigen-experienced CD27+ memory B cells in proportion to other B cell subsets (Odendahl et al., 2000). Notably, these memory cells are the B cell subset less susceptible to immunosuppressive therapy because their numbers in the peripheral blood do not change with various classic immunosuppressive treatments (Dorner et al., 2009, Odendahl et al., 2000). This resistance likely relates to the

Disturbances of plasmablasts/plasma cells in SLE

One hallmark in adult and juvenile SLE is the significant increase of CD27++ expressing plasmablasts/plasma cells in active SLE. These cells were CD38+++, surface Ig(low) and lacked expression of CD20, but were positive for intracellular Ig, indicating that they were, indeed plasma cells. Interestingly, not all of the peripheral blood icIg+CD27++/CD19+ cells expressed CD138, is typical of bone marrow plasma cells (Odendahl et al., 2000, Odendahl et al., 2003, Medina et al., 2002). These data

Conclusion

In conclusion, characterization of peripheral blood B cell subsets in patients with SLE has provided unique opportunities to identify abnormalities among pre-naïve, transitional, pre-naïve memory B cells and in particular plasmablast/plasma cells including indications for defects in negative selection of autoreactive B cells at certain stages. The pathogenic impact of all these individual disturbances remains less clear, although the findings have served to identify SLE as associated with

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