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. 2021 Feb 15;22(4):1919.
doi: 10.3390/ijms22041919.

Early Covert Appearance of Marginal Zone B Cells in Salivary Glands of Sjögren's Syndrome-Susceptible Mice: Initiators of Subsequent Overt Clinical Disease

Affiliations

Early Covert Appearance of Marginal Zone B Cells in Salivary Glands of Sjögren's Syndrome-Susceptible Mice: Initiators of Subsequent Overt Clinical Disease

Ammon B Peck et al. Int J Mol Sci. .

Abstract

The C57BL/6.NOD-Aec1Aec2 mouse model has been extensively studied to define the underlying cellular and molecular bioprocesses critical in the onset of primary Sjögren's Syndrome (pSS), a human systemic autoimmune disease characterized clinically as the loss of lacrimal and salivary gland functions leading to dry eye and dry mouth pathologies. This mouse model, together with several gene knockout mouse models of SS, has indicated that B lymphocytes, especially marginal zone B (MZB) cells, are necessary for development and onset of clinical manifestations despite the fact that destruction of the lacrimal and salivary gland cells involves a classical T cell-mediated autoimmune response. Because migrations and functions of MZB cells are difficult to study in vivo, we have carried out ex vivo investigations that use temporal global RNA transcriptomic analyses to profile autoimmunity as it develops within the salivary glands of C57BL/6.NOD-Aec1Aec2 mice. Temporal profiles indicate the appearance of Notch2-positive cells within the salivary glands of these SS-susceptible mice concomitant with the early-phase appearance of lymphocytic foci (LF). Data presented here identify cellular bioprocesses occurring during early immune cell migrations into the salivary glands and suggest MZB cells are recruited to the exocrine glands by the upregulated Cxcl13 chemokine where they recognize complement (C')-decorated antigens via their sphingosine-1-phosphate (S1P) and B cell (BC) receptors. Based on known MZB cell behavior and mobility, we propose that MZB cells activated in the salivary glands migrate to splenic follicular zones to present antigens to follicular macrophages and dendritic cells that, in turn, promote a subsequent systemic cell-mediated and autoantibody-mediated autoimmune T cell response that targets exocrine gland cells and functions. Overall, this study uses the power of transcriptomic analyses to provide greater insight into several molecular events defining cellular bioprocesses underlying SS that can be modelled and more thoroughly studied at the cellular level.

Keywords: B cell receptor (BCR); C57BL/6.NOD-Aec1Aec2 mice; Notch2; RNA transcriptome microarrays; Sjögren’s syndrome; marginal zone B (MZB) cells; marginal zones (MZ); sphingosine-1-phosphate (S1P); sphingosine-1-phosphate receptor (S1PR).

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Histological photomicrographs depicting lymphocytic infiltrations (lymphocytic foci (LF)) present within the salivary glands of both C57BL/6J (a) and C57BL/6.NOD-Aec1Aec2 mice (b) at 7 months of age. While the infiltrations within the salivary glands of both mouse strains contain both T cells (green fluorescence) and B cells (red fluorescence), both the transcriptomes and immunological activities are very different from each other. During the early disease stages, LF of our SSS mice contain higher numbers of B cells; however, at later stages, the T lymphocyte population(s) tend to overtake the number of B lymphocytes. In addition, the LF of the SSS mice are strongly periductal.
Figure 2
Figure 2
Prolonged upregulated activation of the Notch2 signal transduction pathway in the salivary glands prior to onset of the adaptive response. Notch2 is a transmembrane protein receptor whose extracellular portion is post-translationally modified in the Golgi bodies by furin and fringe molecules (i.e., Lfng, Mfng or Rfng) prior to insertion into the cellular membrane, enhancing subsequent MZB cell functions. On activation by a Notch2 ligand (i.e., Jagged or Delta), the Notch2 molecule undergoes sequential cleavage first by Adam10 and then by γ-secretase, thereby releasing the cytoplasmic protein Dtx (an E3 ubiquitin ligase), as well as the Notch intracellular domain (NICD) that gets transported to the nucleus. In the nucleus, NICD displaces corepressors, including HDAC (histone deacetylase complex), permitting direct interaction with Rbpk to activate Hes, thus driving Notch2-regulated gene transcription. Downregulation of the Notch2 pathway occurs through phosphorylation of NCID by Cdk8 that initiates polyubiquitination and proteasome degradation. In this model, however, while the Notch2 pathway remains activated, Cdk8 exhibits, at best, minimum upregulated expression, suggesting the MZB cells may persist and over time differentiate from their effector function to their APC function for invoking the adaptive response. Gene symbols and gene descriptions are: Notch (notch gene homolog (Drosophila)); Furin (paired basic amino acid-cleaving enzyme); Lfng (LFNG O-fucosylpeptide 3-beta-acetylglucosaminyltransferase); Mfgn (MFNG O-fucosylpeptide 3-beta-n-acetylglucosaminyltransferase); Rfng (RFNG O-fucosylpeptide 3-beta-acetylglucosaminyltransferase); Jag1 (jagged 1); Jag2 (jagged 2); Dll1 (delta-canonical Notch ligand/delta-like 1 homolog); Dll2 (delta-canonical Notch ligand/delta-like 2 homolog); Dll3 (delta-canonical Notch ligand/delta-like 3 homolog); Dll4 (delta-canonical Notch ligand/delta-like 4 homolog); Adam10 (a disintegrin and metallopeptidase domain 10); Adam15 (a disintegrin and metallopeptidase domain 15); Psen1 (Presenilin 1); Ncstn (nicastrin); Aph1b (aph-1 homolog B, gamma-secretase); Dtx4 (deltex 4 homolog (Drosophila)); Hdac1 (histone deacetylase 1); Hdac5 (histone deacetylase 5); Hdac6 (histone deacetylase 6); Hdac11 (histone deacetylase 11); Rbpk (recombination signal binding protein for the IgK J region); Cba2t2 (partner transcriptional co-repressor 2); Hes6 (hairy and enhancer of split 6 (Drosophila)); Cdk8 (cyclin dependent kinase 8).
Figure 3
Figure 3
Prolonged upregulated activation of the type 1 IFN response correlates with downregulated Dtx expression. Regulation of type 1 IFN is, in part, dependent on activation of deltex family protein Dtx4 (deltex E3 ubiquitin ligase 4) via Nlrp4 (NLR family, pyrin domain-containing 4). The Nlrp4 complex regulates IFN synthesis by targeting Tbk1 (Tank-binding kinase 1) for degradation by Dtx4. Tbk1 is a critical component in the activation pathway involving Tmem173 (Sting), Tbk1 and Irf3 (interferon regulatory factor 3). As neither Dtx4 nor any one of the possible Nlrp4 genes expressed in mice (i.e., Nlrp4a, b, c, e and f) exhibit temporal upregulated expression, it is predicted that a strong prolonged IFN response would occur in the SS-susceptible C57BL/6.NOD-Aec1Aec2 mice during the disease state giving rise to the IFN signature characteristic of SS.
Figure 4
Figure 4
Differential expression profiles for genes encoding various receptors associated with the MZB cell function. Comparative transcriptome data showing the temporal expression of MZB cell-associated receptor genes (Cd21, S1pr4, Tnfrsf13b and Cd40), receptor ligands (Tnfsf13b, Tnfsf13 and Cd40lg) and macrophage receptors (Marco, Cd209b, Clec4a4 and Siglec1) in salivary glands of SSS C57BL/6.NOD-Aec1Aec2 mice (left) versus SSNS C57BL/6J mice (right).
Figure 5
Figure 5
Differential expression profiles for genes encoding chemokine and chemokine receptors associated with MZB cell activity. Comparative transcriptome data showing the temporal expression of MZB cell-associated chemokine receptor (chemokine (CXC motif) receptor) genes (Cxcr3, Cxcr4, Cxcr5, Cxcr6 and Cxcr7) and their respective chemokine ligand (chemokine (CXC motif) ligand) genes (Cxcl9, Cxcl10, Cxcl12, Cxcl13, Ccl20, Cxcl19 and Cxcl21) in salivary glands of SSS C57BL/6.NOD-Aec1Aec2 mice (left) versus SSNS C57BL/6J mice (right).
Figure 6
Figure 6
Differential expression profiles for genes encoding various factors involved in the regulation of MZB cell signal transductions. Comparative transcriptome data showing the temporal expression of genes encoding factors critical in controlling the Notch2 signal transduction pathway of MZB cells, i.e., Taok3 (TAO kinase 3), Adam10, Ncstn (nicastrin), Btk (Bruton’s tyrosine kinase), Prp38 (proline rich protein 38) and Mapk14a (mitogen-activated protein kinase 14a) in salivary glands of SSS C57BL/6.NOD-Aec1Aec2 mice (left) versus SSNS C57BL/6J mice (right).

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