Dysregulated Lymphoid Cell Populations in Mouse Models of Systemic Lupus Erythematosus

Abstract

Biases in the distribution and phenotype of T, B, and antigen-presenting cell populations are strongly connected to mechanisms of disease development in mouse models of systemic lupus erythematosus (SLE). Here, we describe longitudinal changes in lymphoid and antigen-presenting cell subsets in bone marrow, blood and spleen from two lupus-prone strains (MRL/lpr and B6.Sle1.Sle2.Sle3 tri-congenic mice), and how they integrate in our present understanding of the pathogenesis of the disease. In particular, we focus on (autoreactive) T cell activation patterns in lupus-prone mice. Break of T cell tolerance to chromatin constituents (histone peptides) is key to the development of the disease and is related to T cell intrinsic defects, contributed by genetic susceptibility factors and by extrinsic amplificatory mechanisms, in particular over-stimulation by antigen-presenting cells. We also describe shifts in B cell sub-populations, going from skewed immature B cell populations as an indication of disturbed central and peripheral tolerance checkpoints, to enriched long-lived plasma cells, which are key to persistent autoantibody production in the disease. B cell activation mechanisms in SLE are both T cell-dependent (break of tolerance and production of specific autoantibodies) and -independent (polyclonal B cell activation, production of autoantibodies by long-lived plasma cells). By providing a comprehensive evaluation of B and T cell surface markers in two major mouse models of SLE and a description of their changes before and after disease onset, this review illustrates how the study of lymphoid cell phenotype delivers key information regarding pathogenic pathways and supplies tools to assess the beneficial effects of novel therapeutic interventions.

IL1R8 Deficiency Drives Autoimmunity-Associated Lymphoma Development

“…2C and D, the pathologic score of lymphoid follicles (based on the presence of normal, reactive, atypical, or lymphomatous follicles) was significantly higher in 10-to 12-month-old Il1r8 À/À /lpr mice compared with 12-to 14month-old Il1r8 þ/þ /lpr mice (P ¼ 0.0001 in spleen and P ¼ 0.0022 in lymph nodes), and the diagnosis of lymphoma was mostly limited to Il1r8 À/À /lpr mice. Splenic and lymph nodal plasmacytosis occurred in the spleen and lymph nodes of both Il1r8 þ/þ /lpr and Il1r8 À/À /lpr mice, in agreement with the role of TLR ligands and autoantigens in inducing cellular differentiation into mature plasma cells and plasma cell expansion (37,38).…”

Gut microbiota promote the inflammatory response in the pathogenesis of systemic lupus erythematosus

“…Long-lived plasma cells which differentiated from germinal center B cells migrate to bone marrow and reside there for long-term antibody secretion. When self-reactive B cells differentiate into plasma cells, the secreted auto-antibodies, including anti-dsDNA antibodies impair tissue function and induce symptoms of SLE (De Groof et al 2017; Shapiro-Shelef and Calame 2005). The distribution of lymphocytes in spleen showed the different immune status when introduced with different fecal microbiota.…”

Selective Histone Deacetylase 6 Inhibition Normalizes B Cell Activation and Germinal Center Formation in a Model of Systemic Lupus Erythematosus

“…There are numerous signaling pathways, metabolic events, and transcription factors that regulate the differentiation of B cells into PC (41–45). Our rationale for continued investigations to define the molecular events in lupus immunopathogenesis mediated by HDAC6 is related to the uncertainty of the non-redundant roles of HDAC6 in immune function in general and lupus in particular.…”