NFκB induces overexpression of bovine FcRn

Cervenak, Judit; Doleschall, Márton; Bender, Balázs; Mayer, Balázs; Schneider, Zita; Doleschall, Zoltán; Zhao, Yaofeng; Bösze, Zsuzsanna; Hammarström, Lennart; Oster, Wolfgang; Kacskovıcs, Imre

doi:10.4161/mabs.26507

Cited by 16 publications

(15 citation statements)

References 55 publications

(74 reference statements)

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“…This issue is important as the bFcRn expression is regulated by its own regulatory elements in these Tg mice ( 6 ) that are similar to its mouse and human counterparts with some differences. Notably, we found upregulation of the bFcRn by NFκB in the spleen and peritoneal MΦs ( 19 ) similarly to the human FcRn (hFcRn) ( 20 ), while this has not been reported for the mFcRn ( 21 ). Despite the difference of cytokine inducibility, mFcRn and hFcRn are considered to be expressed in the same cell types and thus mouse is a well-established model for analyzing the distribution and function of the hFcRn.…”

Section: Introductionmentioning

confidence: 51%

“…mFcRn localization was performed by using a mFcRn-specific hamster antiserum that had been developed and validated previously ( 14 ); as negative control, we used non-specific hamster serum with the same secondary reagent and found no specific staining. For bFcRn detection, we used the bFcRn-specific mAb (Z15_6D5/8) that we recently developed and showed that it does not cross-react with the endogenous mFcRn ( 19 ) (Figures 2 A–D). Staining of F4/80-positive red pulp MΦs revealed an expression pattern of bFcRn in Tg mice, which is similar to the mFcRn patterns in wt mice (Figures 2 E–H) and supporting previous studies that indicated mFcRn expression in these cells ( 14 ).…”

Section: Resultsmentioning

confidence: 99%

“…Dendritic cells were identified using hamster mAb against mouse CD11c (clone N418). Bovine FcRn-expressing cells were identified by Alexa Fluor 488- or Alexa Fluor 647-conjugated anti-bFcRn mAb (Z15_6D5/8) that was developed in our laboratory ( 19 ), while mFcRn expressing cells were stained by Armenian hamster anti-mFcRn serum provided by Dr. S. Akilesh (Washington University, St. Louis, MO, USA) ( 14 ) and FITC-labeled anti-hamster rabbit IgG (Southern Biotechnology Associates Inc., Birmingham, AL, USA). The pictures of fluorescence staining were edited with Adobe Photoshop, using adjustments for black level and hue for the entire images.…”

Section: Methodsmentioning

confidence: 99%

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Overexpression of Bovine FcRn in Mice Enhances T-Dependent Immune Responses by Amplifying T Helper Cell Frequency and Germinal Center Enlargement in the Spleen

et al. 2015

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The neonatal Fc receptor (FcRn) plays key roles in IgG and albumin homeostasis, maternal IgG transport, and antigen presentation of IgG-opsonized antigens. Previously, we reported that transgenic (Tg) mice that overexpress the bovine FcRn (bFcRn) have augmented T-dependent humoral immune response with increased IgG protection, higher level of antigen-specific antibodies, greater number of antigen-specific B cells, and effective immune response even against weakly immunogenic epitopes. In the current study, we analyzed the localization of the bFcRn in secondary lymphoid organs, and focused to demonstrate the in vivo impact of its overexpression in the spleen on the course of antibody production. bFcRn was highly expressed by red pulp macrophages and marginal zone macrophages in the spleen and by subcapsular sinus macrophages and macrophage-like cells in the interfollicular areas in the lymph node cortex. We also demonstrated that splenic dendritic cells of Tg mice express bFcRn and intraperitoneal immunization of these mice with T-dependent antigens led to more than threefold increase in the number of antigen-specific activated T helper cells with increased size and numbers of germinal centers compared to wild-type controls. bFcRn expression in splenic B cells was also detected and that may also contribute to the enhanced B cell activation. Finally, we demonstrated that these Tg mice developed efficient immune response against very low dose of antigen, reflecting another important practical benefit of these Tg mice.

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Section: Introductionmentioning

confidence: 51%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Overexpression of Bovine FcRn in Mice Enhances T-Dependent Immune Responses by Amplifying T Helper Cell Frequency and Germinal Center Enlargement in the Spleen

et al. 2015

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“… 21 – 24 Immunization protocols that include a strong adjuvant, such as the Freund’s adjuvant used in our study, are highly immunostimulatory to this organ system, with a substantial expansion of myeloid derivatives, their activation state, and upregulated levels of FCGRT expression. 25 – 27 We thus posit that the relatively anemic half-life reductions of HuLys11 and trastuzumab in immunized Tg32-hFc mice occurred because immunization increased the overall capacity of hFCGRT to recycle IgG.…”

Section: Discussionmentioning

confidence: 99%

Functional humanization of immunoglobulin heavy constant gamma 1 Fc domain human FCGRT transgenic mice

Low

Christianson

Lowell

et al. 2020

mAbs

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A major asset of many monoclonal antibody (mAb)-based biologics is their persistence in circulation. The MHC class I family Fc receptor, FCGRT, is primarily responsible for this extended pharmacokinetic behavior. Engagement of FCGRT with the crystallizable fragment (Fc) domain protects IgG from catabolic elimination, thereby extending the persistence and bioavailability of IgG and related Fc-based biologics. There is a need for reliable in vivo models to facilitate the preclinical development of novel IgG-based biologics. FcRn-humanized mice have been widely accepted as translationally relevant surrogates for IgG-based biologics evaluations. Although such FCGRT-humanized mice, especially the mouse strain, B6.Cg-Fcgrt tm1Dcr Tg(FCGRT)32Dcr (abbreviated Tg32), have been substantially validated for modeling humanized IgG-based biologics, there is a recognized caveat – they lack an endogenous source of human IgG that typifies the human competitive condition. Here, we used CRISPR/Cas9-mediated homology-directed repair to equip the hFCGRT Tg32 strain with a human IGHG1 Fc domain. This replacement now results in mice that produce human IgG1 Fc-mouse IgG Fab 2 chimeric antibodies at physiologically relevant levels, which can be further heightened by immunization. This endogenous chimeric IgG1 significantly dampens the serum half-life of administered humanized mAbs in an hFCGRT-dependent manner. Thus, such IgG1-Fc humanized mice may provide a more physiologically relevant competitive hFCGRT-humanized mouse model for the preclinical development of human IgG-based biologics.

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“…Serum NE binds with β2AR on B cells and activates PKA–p38 MAPK pathways, which subsequently leads to the release of bound p-p38 MAPK to bind with enhancer in the promoter region of pIgR , and pIgR increase followed ( 62 ). When inflammation occurs, lymphocyte homing induced antibodies production in lamina propria; subsequently, microbes bind with epithelial TLRs with MAMPs and activate NFκB; cytokines released in the vicinity of lymphocytes bind to cytokine receptors and activate IRF-1/NFκB-dependent pathways ( 58 ); IRF-1/NFκB proteins get into nucleus and trigger the transcription of Igs receptors ( 63 ). As a consequence, concentrations of Ig transporting receptors increase.…”

Section: Current Understanding About the Regulations Of Fcrn And Pigrmentioning

confidence: 99%

Immunoglobulin Transporting Receptors Are Potential Targets for the Immunity Enhancement and Generation of Mammary Gland Bioreactor

Jiang

Diraviyam

et al. 2016

Front. Immunol.

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The functions of immunoglobulin transporting receptors (Ig transporting receptors) in immune system encompass from passive immunity to adaptive immunity by transporting immunoglobulins (Igs) and prolonging their half-life as well as enhancing immunosurveillance. Prior to the weaning, Ig transportations from mother to offspring confer the immediate passive immunity for neonates. After the weaning, FcRn and polymeric immunoglobulin receptor on infant intestinal epithelial cells retrieve Ig in intestinal lamina propria into the gut lumen for preventing pathogen invasion. This is not only improving the pathological consequences of infection but also helping the neonates for developing their own immune response; besides it would be the guidance for designing novel vaccines. Moreover, the investigations on Ig transporting receptors over-expressed transgenic animals have been carried out to improve Ig concentrations in serum and milk; thus, it would be a sustainable method to produce antibody-enriched milk-derived colostrum replacer for neonates. In order to generate mammary gland bioreactor, a series of methods have been developed for enhanced regulation of Ig transporting receptors expression and Ig transportation.

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NFκB induces overexpression of bovine FcRn

Cited by 16 publications

References 55 publications

Overexpression of Bovine FcRn in Mice Enhances T-Dependent Immune Responses by Amplifying T Helper Cell Frequency and Germinal Center Enlargement in the Spleen

Overexpression of Bovine FcRn in Mice Enhances T-Dependent Immune Responses by Amplifying T Helper Cell Frequency and Germinal Center Enlargement in the Spleen

Functional humanization of immunoglobulin heavy constant gamma 1 Fc domain human FCGRT transgenic mice

Immunoglobulin Transporting Receptors Are Potential Targets for the Immunity Enhancement and Generation of Mammary Gland Bioreactor

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