Testosterone is an endogenous regulator of BAFF and splenic B cell number

Wilhelmson, Anna S.; Rodriguez, Marta Lantero; Stubelius, Alexandra; Fogelstrand, Per; Johansson, Inger; Buechler, Matthew B.; Lianoglou, Steve; Kapoor, Varun; Johansson, Maria; Fagman, Johan Bourghardt; Duhlin, Amanda; Tripathi, Prabhanshu; Camponeschi, Alessandro; Porse, Bo T.; Rolink, Antonius; Nissbrandt, Hans; Turley, Shannon J.; Carlsten, Hans; Mårtensson, Inga‐Lill; Karlsson, Mikael C. I.; Tivesten, Åsa

doi:10.1038/s41467-018-04408-0

Cited by 79 publications

(60 citation statements)

References 62 publications

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“…Several observations suggest BAFF mediates the developmental effects of non-B cell ST6Gal-1. The bone marrow transplantation data showed a tendency toward male-specific in vivo differences in the IgD-/CD21- population upon loss of host ST6Gal-1, consistent with reported sex-associated variation in serum BAFF and the emerging role of sex hormones in the regulation of BAFF expression ( 46 , 70 , 71 ). ST6Gal-1-associated perturbations in early transitional B cells were observed in both bone marrow and splenic transitional compartments, consistent with the multi-stage significance of BAFF for immature B cells ( 72 , 73 ).…”

Section: Discussionsupporting

confidence: 85%

Systemic ST6Gal-1 Is a Pro-survival Factor for Murine Transitional B Cells

Irons

Lau

2018

Front. Immunol.

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Humoral immunity depends on intrinsic B cell developmental programs guided by systemic signals that convey physiologic needs. Aberrant cues or their improper interpretation can lead to immune insufficiency or a failure of tolerance and autoimmunity. The means by which such systemic signals are conveyed remain poorly understood. Hence, further insight is essential to understanding and treating autoimmune diseases and to the development of improved vaccines. ST6Gal-1 is a sialyltransferase that constructs the α2,6-sialyl linkage on cell surface and extracellular glycans. The requirement for functional ST6Gal-1 in the development of humoral immunity is well documented. Canonically, ST6Gal-1 resides within the intracellular ER-Golgi secretory apparatus and participates in cell-autonomous glycosylation. However, a significant pool of extracellular ST6Gal-1 exists in circulation. Here, we segregate the contributions of B cell intrinsic and extrinsic ST6Gal-1 to B cell development. We observed that B cell-intrinsic ST6Gal-1 is required for marginal zone B cell development, while B cell non-autonomous ST6Gal-1 modulates B cell development and survival at the early transitional stages of the marrow and spleen. Exposure to extracellular ST6Gal-1 ex vivo enhanced the formation of IgM-high B cells from immature precursors, and increased CD23 and IgM expression. Extrinsic sialylation by extracellular ST6Gal-1 augmented BAFF-mediated activation of the non-canonical NF-kB, p38 MAPK, and PI3K/AKT pathways, and accelerated tyrosine phosphorylation after B cell receptor stimulation. in vivo, systemic ST6Gal-1 did not influence homing of B cells to the spleen but was critical for their long-term survival and systemic IgG levels. Circulatory ST6Gal-1 levels respond to inflammation, infection, and malignancy in mammals, including humans. In turn, we have shown previously that systemic ST6Gal-1 regulates inflammatory cell production by modifying bone marrow myeloid progenitors. Our data here point to an additional role of systemic ST6Gal-1 in guiding B cell development, which supports the concept that circulating ST6Gal-1 is a conveyor of systemic cues to guide the development of multiple branches of immune cells.

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Section: Discussionsupporting

confidence: 85%

Systemic ST6Gal-1 Is a Pro-survival Factor for Murine Transitional B Cells

Irons

Lau

2018

Front. Immunol.

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“…4c). The enrichment of colocalizations in sex-specific tissues is consistent with established studies highlighting the strong sex bias and key role of sex hormones in autoimmunity [40][41][42] . Together, these results demonstrate that PICCOLO identifies genes that are likely specific to one trait category and in biologically relevant tissues.…”

supporting

confidence: 88%

Identification of putative effector genes across the GWAS Catalog using molecular quantitative trait loci from 68 tissues and cell types

Guo

Sieber²,

Esparza-Gordillo³

et al. 2019

Preprint

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Identifying the effector genes from genome-wide association studies (GWAS) is a crucial step towards understanding the biological mechanisms underlying complex traits and diseases. Colocalization of expression and protein quantitative trait loci (eQTL and pQTL, hereafter collectively called "xQTL") can be effective for mapping associations to genes in many loci. However, existing colocalization methods require full single-variant summary statistics which are often not readily available for many published GWAS or xQTL studies. Here, we present PICCOLO, a method that uses minimum SNP p-values within a locus to determine if pairs of genetic associations are colocalized. This method greatly expands the number of GWAS and xQTL datasets that can be tested for colocalization. We applied PICCOLO to 10,759 genomewide significant associations across the NHGRI-EBI GWAS Catalog with xQTLs from 28 studies. We identified at least one colocalized gene-xQTL in at least one tissue for 30% of associations, and we pursued multiple lines of evidence to demonstrate that these mappings are biologically meaningful. PICCOLO genes are significantly enriched for biologically relevant tissues, and 4.3-fold enriched for targets of approved drugs.

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“…With regard to androgens, they have previously found to regulate splenic B cells by suppressing their number both in male mice and men 27 . A more recent study also indicated, that androgens suppress the expression of BAFF cytokine in fibroblastic reticular cells (FRCs) in the spleen, and BAFF in turn, increases the number of the splenic B cells 28 .…”

Section: Discussionmentioning

confidence: 98%

Increased estrogen to androgen ratio enhances immunoglobulin levels and impairs B cell function in male mice

Aguilar-Pimentel

Cho

Gerlini

et al. 2020

Sci Rep

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Sex steroids, such as estrogens and androgens, are important regulators of the humoral immune response. Studies in female mice have demonstrated that alteration of circulating estrogen concentration regulates antibody-mediated immunity. As males have normally little endogenous estrogen, we hypothesized that in males high estrogens and low androgens affect the immune system and enhance the allergic inflammatory response. Here, we studied transgenic male mice expressing human aromatase (AROM+). These animals have a high circulating estrogen to androgen ratio (E/A), causing female traits such as gynecomastia. We found that AROM+ male mice had significantly higher plasma immunoglobulin levels, particularly IgE. Flow cytometry analyses of splenocytes revealed changes in mature/immature B cell ratio together with a transcriptional upregulation of the Igh locus. Furthermore, higher proliferation rate and increased IgE synthesis after IgE class-switching was found. Subsequently, we utilized an ovalbumin airway challenge model to test the allergic response in AROM+ male mice. In line with above observations, an increase in IgE levels was measured, albeit no impact on immune cell infiltration into the lungs was detected. Together, our findings suggest that high circulating E/A in males significantly alters B cell function without any significant enhancement in allergic inflammation.

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Testosterone is an endogenous regulator of BAFF and splenic B cell number

Cited by 79 publications

References 62 publications

Systemic ST6Gal-1 Is a Pro-survival Factor for Murine Transitional B Cells

Systemic ST6Gal-1 Is a Pro-survival Factor for Murine Transitional B Cells

Identification of putative effector genes across the GWAS Catalog using molecular quantitative trait loci from 68 tissues and cell types

Increased estrogen to androgen ratio enhances immunoglobulin levels and impairs B cell function in male mice

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