Lazarus, MN; (2015) Changes in Leukocyte Subsets And Anti-dsDNA Antibody Levels After B Cell Depletion Therapy in Systemic Lupus Erythematosus. Doctoral thesis , UCL (University College London).

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Abstract

Clinical response to B cell depletion therapy (BCDT) is highly variable in patients with systemic lupus erythematosus (SLE). Reductions in anti-dsDNA antibody levels also vary. It has been shown that early relapse is more likely if anti-dsDNA antibody levels remain high after BCDT. The cellular factors that determine how anti-dsDNA antibodies are produced and whether they are likely to fall after BCDT have not been clarified. This thesis describes two different immunological processes that might explain why anti-dsDNA antibody levels either fall or remain high after BCDT. (1) In patients whose anti-dsDNA antibody levels fall, it was hypothesized that short-lived plasma cells arise from ectopic lymphoid tissue (ELT). They had higher percentages of CD4+ T cells expressing chemokine receptors CXCR3, CCR5 and the integrin CD49d, which are associated with migration into non-lymphoid tissue. Clinical relapse in this group starts with the expansion of B cells in the blood, in particular the IgD– CD27– subset, and is followed by a fall in circulating lymphocyte numbers before antidsDNA antibody levels rise. CD4+ T cell numbers are inversely related to HLA-DR expression by CD4+ T cells and CD4+CD49dhi T cells express HLA-DR, suggesting that HLA-DR induces T cell migration. Activated B cells can induce HLA-DR expression by T cells, suggesting that they initiate T cell migration. Taken together, the data suggest that B cells induce the formation of ELT. (2) Patients with anti-dsDNA antibody levels that do not fall after BCDT had higher percentages of CD4+ T cells that express CCR7 and CD62L, which are associated with migration to secondary lymphoid organs (SLO), supporting data that show long-lived plasma cells are produced in SLOs. In conclusion, T cell surface markers might be useful for predicting the clinical outcomes and serological changes following BCDT and designing therapeutic trials in SLE.

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