B cells play a crucial pathologic role in SLE.7
Abnormal B cell proliferation, maturation, prolonged life-span of auto reactive clones, and autoantibody production are documented along with immune deregulation and tolerance breakdown.8
Some SLE patients have abnormal selection at the immature to early transitional stage due to intrinsic B cell defects.10
Auto reactive B cells in SLE differentiate into memory and plasma cells. In immature bone marrow, diminished auto reactive B cell deletion is associated with polymorphisms in gene encoding modulators of BCR signaling, such as PTPN22 and BLK.11
In antigen activated mature B cells, differentiation to effector cells is stimulated by T cell help and costimulation, enhanced BCR signals via CD19 upregulation, increased TLR signals, or impaired negative signals mediated trough FcγRIIB and CD22.13
Abnormal B cell function is characterized by the production of autoantibodies – a serologic hallmark of SLE. Another abnormal B cell function is cytokine secretion. B cells have been shown to produce interleukin-4, 6, 10, interferon gamma, transforming growth factor beta, and limphotoxin alfa. The overproduction of cytokines in SLE can lead to amplification of autoimmune response.8
B cells are also antigen presenting cells; B cells activate T cells by surface expression of peptide-MHC complex that interact with T cell receptors.14
In summary B cells play a crucial role in SLE pathogenesis through the presentation of self-antigens, T cell activation, and through the production of autoantibodies and cytokines. All of the above have provided the rationale for the use of B cell directed therapy in SLE treatment.
Rituximab is the first chimeric, mouse-human monoclonal antibody which is directed against CD20. CD20 is a B lymphocyte restricted surface molecule that is expressed from pre-B to memory B cells. Despite intensive studies, the precise function of rituximab remains puzzling. CD20-knockout mice do not present with specific phenotype abnormalities and seem to preserve normal immunologic response, and in addition, CD20 has no known natural ligand.15
It is a phosphoprotein with a structure of four transmembrane regions and an amino-acid extracellular loop. According to structural homologies, it is supposed that CD20 may have a calcium channel function. Administration of the CD20-specific antibody results in the death of B cells, which is achieved by antibody-dependent cell-mediated cytotoxicity, complement-mediated lyses, or apoptosis.
Rituximab does not target pre-B cells, plasmablasts, or plasma cells producing disease-specific autoantibodies (double-stranded deoxyribonucleic acid or anti-Smith antigens), which can lead to diminished efficacy of the drug in patients with B cell depletion who demonstrate poor serologic response. On the other hand, the decline of autoantibodies is not always associated with a good clinical response. It seems reasonable that different symptoms of SLE result from different mechanisms and are not always autoantibody-dependent.
Rituximab influences homeostasis and improves the disturbances found in peripheral B cells that are characteristic of active SLE, and it affects both the cellular and the humoral arm of the immune system.16
After effective B cell depletion during a reconstitution period, naive B cell lymphopenia, expansion of a CD27-, IgD- (double negative) population, and expansion of circulating plasmablasts are significantly decreased. In addition, the frequency of auto reactive memory B cells was found to be decreased 1 year post-treatment.16
However, the magnitude, duration, and consequences of depletion therapy in SLE have not yet been completely elucidated. Long-term follow-up (mean duration 41 months) has shown a delayed recovery of memory CD27+ B cells in peripheral blood and lymphoid tissue after rituximab administration.18
B cell levels after rituximab administration have been measured in clinical trials, but their importance in clinical practice has not been proven. The grade of B cell depletion by routine measures was not predictive for a clinical response. It was suggested that the timing of retreatment for patients with rheumatoid arthritis and vasculitis should be based mainly on clinical activity. However, measurement by highly sensitive flow cytometry, which can define B cell numbers 50–100 times lower than conventional techniques, predicts the overall effectiveness of rituximab. In a recent study of 39 patients with active SLE treated with rituximab, clinical outcomes correlated with the level of B cell depletion. Moreover, plasmablast repopulation was significantly faster in patients with earlier relapse when compared to patients with later relapse.19
In clinical practice, the regimen and tools for B cell depletion assessment in SLE patients have yet to be determined.