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Baylor Institute for Immunology Research
3434 Live Oak St.
Dallas, Texas 75204
PWSBIIR@baylorhealth.edu
Tel: (214) 820-7451
Fax: (214) 820-4813
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Center for Lupus Research
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We found that SLE blood monocytes display DC function, i.e. the capacity to induce mixed lymphocyte reaction. Furthermore, SLE patient serum induced normal monocytes to differentiate into DCs. The DC inducing properties were associated to the presence in SLE serum of IFN alpha/beta and other yet uncharacterized factors. Thus, we proposed that DC interplay takes place in SLE, whereby activated plasmacytoid DCs (pDCs) secrete IFN alpha/beta, which drives the differentiation of immature myeloid DCs into highly immunogenic mature cells able to induce the expansion of autoreactive lymphocytes. Although pDCs numbers are low in SLE blood, these cells accumulate at the sites of inflammation in the skin of SLE patients, where they locally secrete IFN-alpha.
Microarray analysis of PBMCs confirmed the universal activation of the IFN alpha/beta pathway in SLE. Furthermore, some of the most effective medications used to treat SLE patients extinguish the IFN alpha/beta signature, further supporting the role of this cytokine in disease pathogenesis. IFN alpha/beta also has a profound effect on B cells. It induces the expression of germinal center markers like CD38, which is upregulated in SLE blood B cells. IFN alpha/beta drives the differentiation of mature B cells into plasma cells, thereby possibly explaining the high frequency of plasma cell precursors in SLE blood.
Besides the IFN-signature, our microarray analysis revealed several other significant signatures. These included i) neutrophil-specific, ii) immunoglobulin (Ig), iii) lymphopenia and iv) ribosomal gene signatures. Genes within each of these signatures could be classified into modules of highly co-regulated transcripts. With the help of novel statistical approaches, these modules permitted us to generate a "genomic disease activity score". The genomic score highly correlates with classical disease activity scores (i.e., SLEDAI) but avoids the need for cumbersome clinical and serological parameters. Whether it might be applied to patients with more localized disease involvement, like cutaneous lupus, remains to be determined.
The differential expression of neutrophil-specific transcripts within SLE PBMCs correlates with the presence of low density neutrophils spanning different stages of granulopoiesis, from myeloblasts to polymorphonuclear cells. Furthermore, expression of these transcripts correlates with disease activity and with the presence of nephritis, one of the most severe forms of end-organ involvement in the pediatric SLE population. Although neutrophils are present in lupus nephritis (LN) biopsies and they represent markers of tissue activity, the role of these and other innate immunity cells has been long overlooked in SLE.
High titers of anti-nuclear antibodies are one of the hallmarks of SLE. The specific checkpoints where B cell tolerance to these antigens is broken in this disease are only starting to be elucidated. Indeed, recent studies have shown that the pre-B cell repertoire is enriched in self-reactivity, including polyreactive and anti-nuclear specificities. Most of the cells expressing these autoantibodies, however, are removed at two discrete checkpoints during B cell development, i) the immature B cell stage and ii) at the transition between new emigrants and mature B cells in the periphery. These two checkpoints have been found to be defective in SLE patients, allowing the differentiation of polyreactive antibody expressing B cells into the mature repertoire. Whether further downstream checkpoints, which have been shown to be important in murine SLE models, are relevant to human SLE remains to be elucidated.
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