Altered toll‐like receptor responsiveness underlies a dominant heritable defect in B cell tolerance in autoimmune New Zealand Black mice

Clark, Amy G.; Buckley, Elizabeth; Foster, Mary H.

doi:10.1002/eji.201747287

Cited by 3 publications

(6 citation statements)

References 39 publications

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“…CXorf21 is a binding partner of another SLE-risk gene— Slc15a4 . As noted above SLC15A4 is involved in transport of oligopeptides and hydrogen ions out of the lysosome, and knockout of Slc15a4 results in abrogation of TLR7 signaling as well as amelioration of murine lupus (17, 18, 20, 21). We have shown that CXorf21 protein is expressed exclusively in monocytes, B cells, and dendritic cells, and the protein levels are two–three-fold higher in female cells compared to male cells.…”

Section: Discussionmentioning

confidence: 84%

“…There is increased expression of interferon-regulated genes in peripheral blood mononuclear cells from patients with either disease (7–10). Evidence from both human disease (11–13) and murine models (14–17) suggests that signaling through lysosomal, nucleic acid-binding toll-like receptors (TLR) 7 and 9 is in part responsible for the pathogenicity, including increased interferon activity in these diseases.…”

Section: Introductionmentioning

confidence: 99%

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Lysosomal pH Is Regulated in a Sex Dependent Manner in Immune Cells Expressing CXorf21

et al. 2019

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Background: CXorf21 and SLC15a4 both contain risk alleles for systemic lupus erythematosus (SLE) and Sjögren's syndrome (pSS). The former escapes X inactivation. Our group predicts specific endolysosomal-dependent immune responses are driven by the protein products of these genes, which form a complex at the endolysosomal surface. Our previous studies have shown that knocking out CXorf21 increases lysosomal pH in female monocytes, and the present study assesses whether the lysosomal pH in 46,XX women, who overexpress CXorf21 in monocytes, B cells, and dendritic cells (DCs), differs from 46,XY men. Methods: To determine endolysosome compartment pH we used both LysoSensor™ Yellow/Blue DND-160 and pHrodo ® Red AM Intracellular pH Indicator in primary monocyte, B cells, DCs, NK cells, and T cells from healthy men and women volunteers. Results: Compared to male samples, female monocytes, B cells, and DCs had lower endolysosomal pH (female/male pH value: monocytes 4.9/5.6 p < 0.0001; DCs 4.9/5.7 p = 0.044; B cells 5.0/5.6 p < 0.05). Interestingly, T cells and NK cells, which both express low levels of CXorf21, showed no differential pH levels between men and women. Conclusion: We have previously shown that subjects with two or more X-chromosomes have increased CXorf21 expression in specific primary immune cells. Moreover, knockdown of CXorf21 increases lysosomal pH in female monocytes. The present data show that female monocytes, DC, B cells, where CXorf21 is robustly expressed, have lower lysosomal pH compared to the same immune cell populations from males. The lower pH levels observed in specific female immune cells provide a function to these SLE/SS-associated genes and a mechanism for the reported inflated endolysosomal-dependent immune response observed in women compared to men (i.e., TLR7/type I Interferon activity).

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Section: Discussionmentioning

confidence: 84%

Section: Introductionmentioning

confidence: 99%

Lysosomal pH Is Regulated in a Sex Dependent Manner in Immune Cells Expressing CXorf21

et al. 2019

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“…Isolated lung cells from exposed B6, MRL and NZB mice were cultured with or without ligands to TLRs to assess silica-related responsivity, with and without the additional environmental (TLR) stimulus. Ligand to TLR4 or a mixture of ligands to TLR7 and TLR9 were used, based on our prior experience demonstrating additive effect of TLR7 and 9 ligands in unmasking reversible anergy in NZB lupus (20). Both TLR solutions induced anti-DNA IgM, including from lung cells of both silica- and vehicle-exposed mice; the highest levels of anti-DNA IgM were induced by TLR7/9 ligand combination (not shown).…”

Section: Resultsmentioning

confidence: 99%

“…For flow cytometry, freshly isolated red blood cell-depleted lung or spleen cell suspensions were Fcgamma Receptor blocked and stained using fluorescence (FL)-labeled Ig, and isotype controls, for CD45 (leukocytes), CD19 (B cells), CD3 (T cells), IgMa (Ig Tg), and IgMb (endogenous Ig) as previously described (19, 20). Data were acquired using FACScalibur or FACSCanto machines (BD Biosciences, San Jose, CA), and data were analyzed using FlowJo software (Ashland, OR).…”

Section: Methodsmentioning

confidence: 99%

“…This unique mouse reporter system was previously generated to study gene-environment interactions in SLE. For this purpose, a lupus autoAb was expressed as a transgene (Tg) in the non-autoimmune C57BL/6 (B6) strain as well as in multiple classic lupus strains (MRL, NZB, BXSB) (17–20). Each lupus strain carries a different constellation of lupus susceptibility genes, such that they collectively mirror the genetic complexity of human lupus.…”

Section: Introductionmentioning

confidence: 99%

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Silica Exposure Differentially Modulates Autoimmunity in Lupus Strains and Autoantibody Transgenic Mice

et al. 2019

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Inhalational exposure to crystalline silica is linked to several debilitating systemic autoimmune diseases characterized by a prominent humoral immune component, but the mechanisms by which silica induces autoantibodies is poorly understood. To better understand how silica lung exposure breaks B cell tolerance and unleashes autoreactive B cells, we exposed both wildtype mice of healthy C57BL/6 and lupus-prone BXSB, MRL, and NZB strains and mice carrying an autoantibody transgene on each of these backgrounds to instilled silica or vehicle and monitored lung injury, autoimmunity, and B cell fate. Silica exposure induced lung damage and pulmonary lymphoid aggregates in all strains, including in genetically diverse backgrounds and in autoantibody transgenic models. In wildtype mice strain differences were observed in specificity of autoantibodies and site of enhanced autoantibody production, consistent with genetic modulation of the autoimmune response to silica. The unique autoantibody transgene reporter system permitted the in vivo fate of autoreactive B cells and tolerance mechanisms to be tracked directly, and demonstrated the presence of transgenic B cells and antibody in pulmonary lymphoid aggregates and bronchoalveolar lavage fluid, respectively, as well as in spleen and serum. Nonetheless, B cell enumeration and transgenic antibody quantitation indicated that B cell deletion and anergy were intact in the different genetic backgrounds. Thus, silica exposure sufficient to induce substantial lung immunopathology did not overtly disrupt central B cell tolerance, even when superimposed on autoimmune genetic susceptibility. This suggests that silica exposure subverts tolerance at alternative checkpoints, such as regulatory cells or follicle entry, or requires additional interactions or co-exposures to induce loss of tolerance. This possibility is supported by results of differentiation assays that demonstrated transgenic autoantibodies in supernatants of Toll-like receptor (TLR)7/TLR9-stimulated splenocytes harvested from silica-exposed, but not vehicle-exposed, C57BL/6 mice. This suggests that lung injury induced by silica exposure has systemic effects that subtly alter autoreactive B cell regulation, possibly modulating B cell anergy, and that can be unmasked by superimposed exposure to TLR ligands or other immunostimulants.

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Postactivated B cells in systemic lupus erythematosus: update on translational aspects and therapeutic considerations

Schrezenmeier

Weißenberg

Stefanski

et al. 2019

Current Opinion in Rheumatology

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Purpose of review This review summarizes recent insights and current understanding of the role of postactivated B cells in SLE and related pathogenic and potential therapeutic implications. Recent finding B cells are considered key players in SLE and experience from various B-cell-targeted therapies underlines their clinical relevance. In the last years, new insights have been obtained on B-cell abnormalities within the complex pathophysiology of SLE. These insights involve a revised understanding of BCR signaling, that has been reported to be hyperresponsive in the past, but newer studies suggest a postactivation functiotype in terms of reduced BCR and TLR signaling. Despite comprehensive efforts to delineate B-cell abnormalities on assessing large-scale genomic, epigenomic and proteomic data, understanding functional impairments of cellular interactions and subcellular functions remains crucial. A recently identified enhanced protein tyrosine phosphatase (PTP) activity was found in relation to diminished BCR responses in SLE. This finding together with reduced cytokine production upon TLR9 activation appears to mark postactivated lupus B cells. Other studies identified increased PTP activity in line with a gain-of-function mutation of phosphatase PTPN22, one of the strongest SLE risk alleles. Improved understanding of these B cell abnormalities in SLE holds promise to gain further insights in mechanisms of autoimmunity and pave the way for selective therapies targeting key principles of chronic autoimmunity. Summary SLE B cells (similar as previously described for lupus T cells) are characterized by a postactivation (exhausted) functiotype mandating consideration for innovative therapies.

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Altered toll‐like receptor responsiveness underlies a dominant heritable defect in B cell tolerance in autoimmune New Zealand Black mice

Cited by 3 publications

References 39 publications

Lysosomal pH Is Regulated in a Sex Dependent Manner in Immune Cells Expressing CXorf21

Lysosomal pH Is Regulated in a Sex Dependent Manner in Immune Cells Expressing CXorf21

Silica Exposure Differentially Modulates Autoimmunity in Lupus Strains and Autoantibody Transgenic Mice

Postactivated B cells in systemic lupus erythematosus: update on translational aspects and therapeutic considerations

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