The frequency of B cells secreting antibodies against donor MHC antigens in rats rejecting renal allografts

Highly purified, small dense splenic B cells from unstimulated mice showed increased expression of class II major histocompatibility complex (MHC) antigens and enhanced viability when cultured with affinity-purified recombinant interleukin 10 (rIL-10), compared with B cells cultured in medium alone. These responses were blocked by a monoclonal antibody (mAb) specific for IL-10, but not by an isotype-matched control antibody. IL-10 did not upregulate the expression of Fc epsilon receptors (CD23) or class I MHC antigens on small dense B cells or induce their replication as monitored by [3H]thymidine incorporation. While these B cell-stimulatory properties of IL-10 are also mediated by IL-4, the two cytokines appear to act independently in these assays; anti-IL-10 antibodies blocked IL-10 but not IL-4-mediated B cell viability enhancement, and vice versa. Similarly, since IL-4 upregulates CD23 on small dense B cells, the inability of IL-10 to do so argues against its acting via endogenously generated IL-4. Finally, IL-10 did not upregulate class II MHC antigens on B cells from X chromosome-linked immunodeficiency (XID) mice, while the same cells showed normal upregulation of class II antigens in response to IL-4. This report also extends our understanding of the relationship between IL-10 and the highly homologous Epstein-Barr virus (EBV)-encoded Bam HI fragment C rightward reading frame no. 1 (BCRFI) protein. It has previously been shown that BCRFI protein exhibits the cytokine synthesis inhibitory activity of IL-10. This report indicates that BCRFI protein also enhances in vitro B cell viability, but does not upregulate class II MHC antigens on B cells. One explanation for these data is that IL-10 contains at least two functional epitopes, only one of which has been conserved by EBV.

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Innate-like self-reactive B cells infiltrate human renal allografts during transplant rejection

Nature Communications ◽

10.1038/s41467-021-24615-6 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Yuta Asano ◽

Joe Daccache ◽

Dharmendra Jain ◽

Kichul Ko ◽

Andrew Kinloch ◽

...

Keyword(s):

B Cells ◽

Plasma Cells ◽

Transplant Rejection ◽

Transplant Recipients ◽

Tissue Destruction ◽

Renal Allografts ◽

Cell Proliferation And Differentiation ◽

Proliferation And Differentiation ◽

Specific Antigens ◽

Transcriptional State

AbstractIntrarenal B cells in human renal allografts indicate transplant recipients with a poor prognosis, but how these cells contribute to rejection is unclear. Here we show using single-cell RNA sequencing that intrarenal class-switched B cells have an innate cell transcriptional state resembling mouse peritoneal B1 or B-innate (Bin) cells. Antibodies generated by Bin cells do not bind donor-specific antigens nor are they enriched for reactivity to ubiquitously expressed self-antigens. Rather, Bin cells frequently express antibodies reactive with either renal-specific or inflammation-associated antigens. Furthermore, local antigens can drive Bin cell proliferation and differentiation into plasma cells expressing self-reactive antibodies. These data show a mechanism of human inflammation in which a breach in organ-restricted tolerance by infiltrating innate-like B cells drives local tissue destruction.

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Tolerance induction to self-MHC antigens in fetal and neonatal mouse B cells

International Immunology ◽

10.1093/intimm/dxm116 ◽

2007 ◽

Vol 20 (1) ◽

pp. 11-20 ◽

Cited By ~ 4

Author(s):

S. M. Caucheteux ◽

C. Vernochet ◽

J. Wantyghem ◽

M.-C. Gendron ◽

C. Kanellopoulos-Langevin

Keyword(s):

B Cells ◽

Tolerance Induction ◽

Neonatal Mouse ◽

Mhc Antigens

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Comparative expression of major histocompatibility complex (MHC) antigens on CD5+ and CD5− B cells in patients with chronic lymphocytic leukaemia (CLL)

European Journal of Cancer ◽

10.1016/s0959-8049(98)00158-0 ◽

1998 ◽

Vol 34 (10) ◽

pp. 1618-1622 ◽

Cited By ~ 10

Author(s):

A.M.E Nouri ◽

S Smith ◽

A.C Newland ◽

M.G Macey

Keyword(s):

Major Histocompatibility Complex ◽

B Cells ◽

Chronic Lymphocytic Leukaemia ◽

Lymphocytic Leukaemia ◽

Major Histocompatibility ◽

Mhc Antigens ◽

Histocompatibility Complex

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Prolonged survival of actively enhanced rat renal allografts despite accelerated cellular infiltration and rapid induction of both class I and class II MHC antigens.

Journal of Experimental Medicine ◽

10.1084/jem.165.3.891 ◽

1987 ◽

Vol 165 (3) ◽

pp. 891-907 ◽

Cited By ~ 63

Author(s):

H E Armstrong ◽

E M Bolton ◽

I McMillan ◽

S C Spencer ◽

J A Bradley

Keyword(s):

Class Ii ◽

Suppressive Effect ◽

Class I ◽

Target Antigen ◽

Effector Cells ◽

Renal Allografts ◽

Mhc Antigens ◽

Class Ii Mhc ◽

Class Ii Mhc Antigens ◽

Nonspecific Cytotoxicity

Administration of 1 ml of donor whole blood 7 d before renal transplantation produces long-term (greater than 100 d) graft survival in the DA (RT1a) into PVG (RT1c) rat strain combination. Using this model, the pattern and phenotype of infiltrating leukocytes were examined in rejecting and enhanced renal allografts, at days 1, 3, 5, and 7 after transplantation, by immunohistologic techniques. Paradoxically, enhanced grafts showed a more rapid and substantial leukocyte infiltrate, the phenotype of which was similar to that in rejecting grafts except for a reduced number of MRC OX-8+ cells and MRC OX-39+ cells. Graft infiltrating cells and splenocytes from transfused animals showed similar, although modest, levels of both nonspecific cytotoxicity and alloantigen-specific cytotoxicity. Immunohistologic analysis of MHC antigen distribution within the allograft revealed, unexpectedly, that enhanced grafts underwent an accelerated and extensive induction of both donor class I and class II MHC antigens. These findings were confirmed by allospecific quantitative absorption analysis, which showed severalfold increases in class I and class II MHC antigens by day 3 in enhanced grafts but not until day 5 in rejecting grafts. An additional observation was the more rapid disappearance of donor interstitial cells from enhanced grafts. These findings emphasize the overwhelming suppressive effect induced by an organ allograft after preoperative blood transfusion despite the associated induction of large numbers of potential effector cells and increased target antigen density within the graft.

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Graft-derived extracellular vesicles transported across subcapsular sinus macrophages elicit B cell alloimmunity after transplantation

Science Translational Medicine ◽

10.1126/scitranslmed.abb0122 ◽

2021 ◽

Vol 13 (585) ◽

pp. eabb0122

Author(s):

Furong Zeng ◽

Zhizhao Chen ◽

Rao Chen ◽

William J. Shufesky ◽

Mohna Bandyopadhyay ◽

...

Keyword(s):

B Cells ◽

B Cell ◽

Extracellular Vesicles ◽

Cell Activation ◽

Transplant Rejection ◽

Mouse Skin ◽

Lymphoid Tissues ◽

Mhc Antigens ◽

Mhc Molecules ◽

Subcapsular Sinus

Despite the role of donor-specific antibodies (DSAs) in recognizing major histocompatibility complex (MHC) antigens and mediating transplant rejection, how and where recipient B cells in lymphoid tissues encounter donor MHC antigens remains unclear. Contrary to the dogma, we demonstrated here that migration of donor leukocytes out of skin or heart allografts is not necessary for B or T cell allosensitization in mice. We found that mouse skin and cardiac allografts and human skin grafts release cell-free donor MHC antigens via extracellular vesicles (EVs) that are captured by subcapsular sinus (SCS) macrophages in lymph nodes or analog macrophages in the spleen. Donor EVs were transported across the SCS macrophages, and donor MHC molecules on the EVs were recognized by alloreactive B cells. This triggered B cell activation and DSA production, which were both prevented by SCS macrophage depletion. These results reveal an unexpected role for graft-derived EVs and open venues to interfere with EV biogenesis, trafficking, or function to restrain priming or reactivation of alloreactive B cells.

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B cells are going innate in human renal allografts

American Journal of Transplantation ◽

10.1111/ajt.16048 ◽

2021 ◽

Vol 21 (10) ◽

pp. 3213-3213

Author(s):

Xian C. Li

Keyword(s):

B Cells ◽

Renal Allografts

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