Dataset Information

Dissecting Integrin Expression and Function on Memory B Cells in Mice and Humans in Autoimmunity.

ABSTRACT: Immunological memory ensures life-long protection against previously encountered pathogens, and in mice and humans the spleen is an important reservoir for long-lived memory B cells (MBCs). It is well-established that integrins play several crucial roles in lymphocyte survival and trafficking, but their involvement in the retention of MBCs in secondary lymphoid organs, and differences between B cell subsets in their adhesion capacity to ICAM-1 and/or VCAM-1 have not yet been confirmed. Here, we use an autoimmune mouse model, where MBCs are abundant, to show that the highest levels of LFA-1 and VLA-4 amongst B cells are found on MBCs. In vivo blockade of VLA-4 alone or in combination with LFA-1, but not LFA-1 alone, causes a release of MBCs from the spleen into the blood stream. In humans, we find that in peripheral blood, spleens, and tonsils from healthy donors the highest expression levels of the integrins LFA-1 and VLA-4 are also found on MBCs. Consistent with this, we found MBCs to have a higher capacity to adhere to ICAM-1 and VCAM-1 than naïve B cells. In patients with the autoimmune disease rheumatoid arthritis, it is the MBCs that have the highest levels of LFA-1 and VLA-4; moreover, compared with healthy donors, naïve B and MBCs of patients receiving anti-TNF medication have enhanced levels of the active form of LFA-1. Commensurate levels of the active ?L subunit can be induced on B cells from healthy donors by exposure to the integrin ligands. Thus, our findings establish the selective use of the integrins LFA-1 and VLA-4 in the localization and adhesion of MBCs in both mice and humans.

SUBMITTER: Camponeschi A

PROVIDER: S-EPMC6437070 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Dissecting Integrin Expression and Function on Memory B Cells in Mice and Humans in Autoimmunity.

Camponeschi Alessandro A Gerasimcik Natalija N Wang Ying Y Fredriksson Timothy T Chen Dongfeng D Farroni Chiara C Thorarinsdottir Katrin K Sjökvist Ottsjö Louise L Aranburu Alaitz A Cardell Susanna S Carsetti Rita R Gjertsson Inger I Mårtensson Inga-Lill IL Grimsholm Ola O

Frontiers in immunology 20190321

Immunological memory ensures life-long protection against previously encountered pathogens, and in mice and humans the spleen is an important reservoir for long-lived memory B cells (MBCs). It is well-established that integrins play several crucial roles in lymphocyte survival and trafficking, but their involvement in the retention of MBCs in secondary lymphoid organs, and differences between B cell subsets in their adhesion capacity to ICAM-1 and/or VCAM-1 have not yet been confirmed. Here, we ...[more]

PMID: 30949178

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Project description:BackgroundExperiments were designed to identify the developmental expression and function of the Dickkopf-Like1 (DKKL1/Dkkl1) gene in humans and mice.MethodsMouse testes cDNA samples were collected at multiple postnatal times (days 4, 9, 18, 35, and 54, as well as at 6 months) and hybridized to Affymetrix mouse whole genome Genechips. To further characterize the homologous gene DKKL1 in human beings, the expression profiles between human adult testis and foetal testis were compared using Affymetrix human Genechips. The characteristics of DKKL1/Dkkl1 were analysed using various cellular and molecular biotechnologies.ResultsThe expression of Dkkl1 was not detected in mouse testes on days 4 or 9, but was present on days 18, 35, and 54, as well as at 6 months, which was confirmed by RT-PCR and Western blot results. Examination of the tissue distribution of Dkkl1 demonstrated that while Dkkl1 mRNA was abundantly expressed in testes, little to no expression of Dkkl1 was observed in the epididymis or other tissues. In an in vitro fertilization assay, a Dkkl1 antibody was found to significantly reduce fertilization. Human Genechips results showed that the hybridization signal intensity of DKKL1 was 405.56-fold higher in adult testis than in foetal testis. RT-PCR analysis of multiple human tissues indicated that DKKL1 mRNA was exclusively expressed in the testis. Western blot analysis also demonstrated that DKKL1 was mainly expressed in human testis with a molecular weight of approximately 34 kDa. Additionally, immunohistochemical staining showed that the DKKL1 protein was predominantly located in spermatocytes and round spermatids in human testes. An examination of the expression levels of DKKL1 in infertile male patients revealed that while no DKKL1 appeared in the testes of patients with Sertoli cell only syndrome (SCOS) or cryptorchidism, DKKL1 was observed with variable expression in patients with spermatogenic arrest.ConclusionsThese results, together with previous studies, suggest that DKKL1/Dkkl1 may play an important role in testicular development and spermatogenesis and may be an important factor in male infertility.

Project description:BackgroundInnate monocytes can adopt dynamic "memory" states ranging from low-grade inflammation to pathogenic exhaustion, dependent upon signal strength and history of challenges. Low-grade inflammatory monocytes facilitate the pathogenesis of chronic inflammatory diseases, while exhausted monocytes drive the pathogenesis of severe sepsis. Although clinical and basic studies suggest the conservation of key features of exhausted monocytes from human and murine sepsis, systems analyses of monocyte exhaustion among human and murine monocytes are lacking.MethodsWe performed cross examination of septic monocytes scRNAseq data recently collected from human sepsis patients as well as experimental septic mice, in reference to monocytes experimentally exhausted in vitro. Furthermore, we performed pseudo-time analyses of in vitro programmed monocytes following prolonged challenges causing either low-grade inflammation or exhaustion. Additional comparative analyses of low-grade inflammatory monocytes were performed with scRNAseq data from selected human patients with chronic low-grade inflammatory diseases.ResultsOur systems analyses reveal key features of monocyte exhaustion including reduced differentiation, pathogenic inflammation and immune suppression that are highly conserved in human and murine septic monocytes, and captured by in vitro experimental exhaustion. Pseudo-time analyses reveal that monocytes initially transition into a less-differentiated state with proliferative potential. The expansion of proliferative monocytes can be observed not only in experimentally challenged monocytes, but also in tissues of murine sepsis and human septic blood. We observed that monocytes similarly transition into the less-differentiated state when challenged with a subclinical dose endotoxin under chronic inflammatory conditions. Instead of being exhausted, monocytes with prolonged challenges with super-low dose endotoxin bifurcate into the low-grade inflammatory immune-enhancing or the chemotactic/adhesive state, often see in atherosclerosis or auto-immune diseases.ConclusionsKey features of monocyte memory dynamics are identified and conserved in human and murine monocytes, which can be captured by prolonged challenges of innate signals with varying signal strength.

Project description:Alport disease in humans, which usually results in proteinuria and kidney failure, is caused by mutations to the COL4A3, COL4A4, or COL4A5 genes, and absence of collagen ?3?4?5(IV) networks found in mature kidney glomerular basement membrane (GBM). The Alport mouse harbors a deletion of the Col4a3 gene, which also results in the lack of GBM collagen ?3?4?5(IV). This animal model shares many features with human Alport patients, including the retention of collagen ?1?2?1(IV) in GBMs, effacement of podocyte foot processes, gradual loss of glomerular barrier properties, and progression to renal failure. To learn more about the pathogenesis of Alport disease, we undertook a discovery proteomics approach to identify proteins that were differentially expressed in glomeruli purified from Alport and wild-type mouse kidneys. Pairs of cy3- and cy5-labeled extracts from 5-week old Alport and wild-type glomeruli, respectively, underwent 2-dimensional difference gel electrophoresis. Differentially expressed proteins were digested with trypsin and prepared for mass spectrometry, peptide ion mapping/fingerprinting, and protein identification through database searching. The intermediate filament protein, vimentin, was upregulated ?2.5 fold in Alport glomeruli compared to wild-type. Upregulation was confirmed by quantitative real time RT-PCR of isolated Alport glomeruli (5.4 fold over wild-type), and quantitative confocal immunofluorescence microscopy localized over-expressed vimentin specifically to Alport podocytes. We next hypothesized that increases in vimentin abundance might affect the basement membrane protein receptors, integrins, and screened Alport and wild-type glomeruli for expression of integrins likely to be the main receptors for GBM type IV collagen and laminin. Quantitative immunofluorescence showed an increase in integrin ?1 expression in Alport mesangial cells and an increase in integrin ?3 in Alport podocytes. We conclude that overexpression of mesangial integrin ?1 and podocyte vimentin and integrin ?3 may be important features of glomerular Alport disease, possibly affecting cell-signaling, cell shape and cellular adhesion to the GBM.

Dataset Information

Dissecting Integrin Expression and Function on Memory B Cells in Mice and Humans in Autoimmunity.

Publications

Dissecting Integrin Expression and Function on Memory B Cells in Mice and Humans in Autoimmunity.

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