Abstract
Splenic long-lived plasma cells are abnormally numerous and deleterious in systemic autoimmune diseases, yet how they accumulate remains poorly understood. We demonstrate here that a pathological role of spleen-derived CD11b+Gr-1+ myeloid cells (SDMCs) underpins the accumulation of splenic long-lived plasma cells in a lupus-prone model named sanroque. We found that SDMCs were progressively accumulated in sanroque mice from the early clinical phase. Transcriptome profiles revealed that SDMCs have a predominant shift toward an inflammatory phenotype relative to the bone marrow-derived counterparts and are distinct from neutrophils and monocytes. SDMCs were expanded in situ via splenic extramedullary myelopoiesis under the proinflammatory cytokine milieu during lupus progression. SDMCs promoted the development of IFN-γ-secreting Th1 and follicular helper T cells, thereby licensing CD4+ T cells to be pathologic activators of SDMCs and plasma cells. SDMCs also directly promoted the survival of plasma cells by providing B-cell activating factor of the TNF family. The frequency of SDMCs correlated with that of splenic long-lived plasma cells. Selective depletion of CD11b+Gr-1+ cells reduced autoantibody production in sanroque mice. Thus, our findings suggest that SDMCs expanded in situ establish a positive feedback loop with CD4+ T cells, leading to accumulation of long-lived plasma cells which exacerbates lupus autoimmunity.
Highlights
Systemic lupus erythematosus (SLE) is a prototypic systemic autoimmune disease characterized by an abundance of Ig class-switched autoantibodies against nuclear components [1]
We have shown above that spleen-derived CD11b+Gr-1+ myeloid cell (SDMC) expand in situ during the progression of autoimmune disease and exacerbate autoimmunity
SDMCs are a mixture of GMDSCs and M-myeloid-derived suppressor cell (MDSC) in which proinflammatory signals are more strongly activated than in their bone marrow (BM) counterparts
Summary
Systemic lupus erythematosus (SLE) is a prototypic systemic autoimmune disease characterized by an abundance of Ig class-switched autoantibodies against nuclear components [1]. Contradictory to conventional PCs [8, 9], we and others have shown that autoimmune long-lived PCs abnormally accumulate in the spleen rather than homing to the bone marrow (BM), as evidenced in murine models, such as the (NZBxNZW)F1, NZM2410, and K/BxNsf mice [10,11,12] This phenomenon is recapitulated in patients with autoimmune disease, such as primary warm autoimmune hemolytic anemia and primary immune thrombocytopenia [13, 14]. Splenic long-lived PCs govern their own fate via a cell-autonomous mechanism and a positive feedback with Tfh cells, according to our previous studies [11, 15, 16] They can transfer the disease to RAG knockout mice, indicating their pathogenic role [17], and are refractory to treatment with cytostatic drugs, leading to disease being incurable [9, 11, 12, 18]. The role of splenic long-lived PCs appears to be central to the exacerbation of autoantibody-mediated diseases, yet the mechanisms underlying their development and maintenance are poorly understood
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