Chronic graft-versus-host disease: focusing on the B cells

2021 ◽  
Vol 15 (5) ◽  
pp. 1582-1588
Author(s):  
S. Parkhideh ◽  
A. Hajifathali ◽  
E. Roshandel ◽  
Bentolhoda . ◽  
K. Dehaghi ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Graft Versus Host Disease ◽  
Peripheral Tolerance ◽  
Cell Homeostasis ◽  
Host Disease ◽  
Allogeneic Hsct ◽  
Graft Versus Host ◽  
B Cell Homeostasis

Graft-versus-host disease (GVHD) has posed many challenges in allogeneic HSCT. Thanks to the development of immunomodulating approaches, the mortality of acute GVHD (aGVHD) is drastically decreased. Nevertheless, chronic GVHD (cGVHD) is became the leading causes of death in patients who survived of aGVHD. Various studies have demonstrated the essential role of B cells in the development of cGVHD. B cells are directly involved in allogeneic reactions through a variety of mechanisms such as alloantibody production, triggering complement system, promoting antibody-dependent cellular cytotoxicity (ADCC), and cross-presentation of immune complexes. It has been known that the pathways involved in the B-cell homeostasis and survival, such as BAFF, BCR, and Notch2 signaling pathways are abnormal in cGVHD. Post-HSCT lymphopenia triggers the continuous release of BAFF, leading to abnormalities in B cell homeostasis, and increasing the survival of alloreactive/autoreactive B cells, leading to production of allo/auto-antibodies. On the other hand, reduction of regulatory B cells following HSCT, causes loss of T cell peripheral tolerance, leading to cGVHD incidence. Therefore, B cells deserve special consideration in allogeneic HSCT, and targeting alloreactive B cells might be a promising approach in cGVHD management. In this article, we discussed the role of B cells in pathophysiology of cGVHD. Keywords: Chronic graft-versus-host disease, Hematopoietic stem cell transplantation, B cell, BAFF

scholarly journals Altered B-cell homeostasis and excess BAFF in human chronic graft-versus-host disease

Blood ◽  
2009 ◽  
Vol 113 (16) ◽  
pp. 3865-3874 ◽  
Author(s):  
Stefanie Sarantopoulos ◽  
Kristen E. Stevenson ◽  
Haesook T. Kim ◽  
Corey S. Cutler ◽  
Nazmim S. Bhuiya ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Graft Versus Host Disease ◽  
High Plasma ◽  
Cell Homeostasis ◽  
Hematopoietic Stem ◽  
Host Disease ◽  
Graft Versus Host ◽  
B Cell Homeostasis

Abstract Chronic graft-versus-host disease (cGVHD) causes significant morbidity and mortality in patients otherwise cured of malignancy after hematopoietic stem cell transplantation (HSCT). The presence of alloantibodies and high plasma B cell–activating factor (BAFF) levels in patients with cGVHD suggest that B cells play a role in disease pathogenesis. We performed detailed phenotypic and functional analyses of peripheral B cells in 82 patients after HSCT. Patients with cGVHD had significantly higher BAFF/B-cell ratios compared with patients without cGVHD or healthy donors. In cGVHD, increasing BAFF concentrations correlated with increased numbers of circulating pre–germinal center (GC) B cells and post-GC “plasmablast-like” cells, suggesting in vivo BAFF dependence of these 2 CD27+ B-cell subsets. Circulating CD27+ B cells in cGVHD comprised in vivo activated B cells capable of IgG production without requiring additional antigen stimulation. Serial studies revealed that patients who subsequently developed cGVHD had delayed reconstitution of naive B cells despite persistent BAFF elevation as well as proportional increase in CD27+ B cells in the first year after HSCT. These studies delineate specific abnormalities of B-cell homeostasis in patients with cGVHD and suggest that BAFF targeting agents may be useful in this disease.

scholarly journals Recovery of B-cell homeostasis after rituximab in chronic graft-versus-host disease

Blood ◽  
2011 ◽  
Vol 117 (7) ◽  
pp. 2275-2283 ◽  
Author(s):  
Stefanie Sarantopoulos ◽  
Kristen E. Stevenson ◽  
Haesook T. Kim ◽  
Whitney S. Washel ◽  
Nazmim S. Bhuiya ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Graft Versus Host Disease ◽  
Cell Number ◽  
Cell Recovery ◽  
Cell Homeostasis ◽  
Host Disease ◽  
Graft Versus Host ◽  
Cell Numbers ◽  
B Cell Homeostasis

Abstract Investigation of the effects of rituximab (anti-CD20) on B-cell-activating factor of the tumor necrosis factor family (BAFF) and B cells would better define the significance of B-cell homeostasis in chronic graft-versus-host disease (cGVHD) pathophysiology. We studied 20 cGVHD patients at a median of 25 months after rituximab treatment when most patients had recovered total B-cell numbers. A total of 55% of patients had stable/improved cGVHD, and total B-cell numbers in these patients were significantly higher compared with rituximab-unresponsive patients. Although total B-cell number did not differ significantly between cGVHD groups before rituximab, there was a proportional increase in B-cell precursors in patients who later had stable/improved cGVHD. After rituximab, BAFF levels increased in all patients. Coincident with B-cell recovery in the stable/improved group, BAFF/B-cell ratios and CD27+ B-cell frequencies decreased significantly. The peripheral B-cell pool in stable/improved cGVHD patients was largely composed of naive IgD+ B cells. By contrast, rituximab-unresponsive cGVHD patients had persistent elevation of BAFF and a predominance of circulating B cells possessing an activated BAFF-RLoCD20Lo cell surface phenotype. Thus, naive B-cell reconstitution and decreased BAFF/B-cell ratios were associated with clinical response after rituximab in cGVHD. Our findings begin to delineate B-cell homeostatic mechanisms important for human immune tolerance.

scholarly journals Aberrant B-cell homeostasis in chronic GVHD

Blood ◽  
2015 ◽  
Vol 125 (11) ◽  
pp. 1703-1707 ◽  
Author(s):  
Stefanie Sarantopoulos ◽  
Jerome Ritz
Keyword(s):  
B Cells ◽  
B Cell ◽  
Chronic Gvhd ◽  
Cell Receptor ◽  
Cell Homeostasis ◽  
Graft Versus Host ◽  
B Cell Homeostasis ◽  
Immune Pathology ◽  
New Strategies

Abstract Recent studies have compelled further interest in the potential pathological role of B cells in chronic graft-versus-host disease (cGVHD). In patients with cGVHD, B cells are activated and primed for survival via B-cell activating factor and B-cell receptor–associated pathways. Understanding the signaling pathways that drive immune pathology in cGVHD will facilitate the development of new strategies to selectively target aberrantly activated B cells and restore normal B-cell homeostasis after allogeneic stem cell transplantation.

scholarly journals Absence of surface IgD does not impair naive B cell homeostasis and memory B cell formation in humans

2018 ◽  
Author(s):  
J. Nechvatalova ◽  
S.J.W. Bartol ◽  
Z. Chovancova ◽  
L. Boon ◽  
M. Vlkova ◽  
...  
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Activation ◽  
Genetic Defect ◽  
Memory B Cells ◽  
Cell Homeostasis ◽  
Human B Cells ◽  
B Cell Homeostasis

One Sentence SummaryHuman B cells with a genetic defect in IGHD develop normally in vivo, and do not have a competitive disadvantage to IgD-expressing B cells for developing into memory B cells.AbstractSurface immunoglobulin D (IgD) is co-expressed with IgM on naive mature B cells. Still, the role of surface IgD remains enigmatic even 50 years after its initial discovery. We here examined the in vivo role of surface IgD in human B-cell homeostasis and antibody responses in four individuals with heterozygous nonsense mutations in IGHD. All IGHD heterozygous individuals had normal numbers of B cells and serum immunoglobulins, and did not show signs of immunodeficiency or immune dysregulation. IgD+ and IgD– naive mature B cells were present in equal numbers and showed similar immunophenotypes, except for decreased expression of CD79b in the IgD– subset. Furthermore, both IgD+ and IgD– naive mature B cells had normal replication histories, similar capacities to differentiate into plasma cells upon in vitro stimulation, and Ig switched memory B cells showed similar levels of somatic hypermutations. Thus human B cells lacking IgD expression develop normally and generate immunological memory in vivo, suggesting that surface IgD might function more restricted in regulating of B-cell activation to specific antigenic structures.

Induction of Xenogeneic Graft-Versus-Host Disease through Administration of HuPBMC to Immune Deficient RAG2−/−γc−/− Mice: A Model for B Cell-Involvement in Chronic Graft-Versus-Host Disease.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3099-3099
Author(s):  
Marijke C. Canninga-van Dijk ◽  
Rozemarijn S. van Rijn ◽  
Elles R. Simonetti ◽  
Marieke C. Hogenes ◽  
Saskia Smulders ◽  
...  
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
Graft Versus Host Disease ◽  
Plasma Cells ◽  
Lymphocytic Infiltrate ◽  
Small Scale ◽  
Host Disease ◽  
Graft Versus Host ◽  
Lymphocytic Infiltrates

Abstract Graft-versus-host disease (GVHD) is the most important determinant for long-term morbidity and mortality in allogeneic stem cell transplantation, affecting approximately 50% of patients. Acute (a)GVHD is a distinctive syndrome of dermatitis, hepatitis and enteritis, while the term chronic (c)GVHD describes a more pleiotropic syndrome. Many clinical manifestations of cGVHD are very similar to those of autoimmune diseases such as lupus erythematosus and scleroderma. In addition, in cGVHD autoantibody formation is a common feature. To investigate the pathogenesis of cGVHD and to study the effect of new treatment modalities, clinically relevant models are of great importance. Recently, we were able to develop a model for GVHD by intravenous transfer of huPBMC in RAG2−/− γc−/− mice (van Rijn et al., Blood102: 2522, 2003). In this study we report on the whole spectrum of histological and immunohistochemical findings in the skin, bowel, tongue, liver, kidney, spleen, bone marrow and lung of 3 mice with acute and 7 with chronic X-GVHD and compare them with those seen in patients with GVHD. All mice showed a ruffled fur and 3 acute and 2 chronic mice had an erythematous skin with loss of hair. Lymphocytic infiltrates and tissue damage were observed in all organs. These lymphocytic infiltrates consisted of T lymphocytes with a surprising predominance of CD4+ cells (75–85%) that was not reflected in the peripheral blood. The kidneys contained variable numbers of lymphocytes, mainly localized in the interstitium. The lungs contained a mild to severe lymphoplasmacellular infiltrate. In three mice there was damage of the bronchial epithelium. 5/7 of the chronic mice showed peribronchial fibrosis. All mice showed a mild to moderate fibrosis in the bone marrow. The bowels contained a very mild lymphocytic infiltrate, but there were no signs of epithelial damage or diarrhoea. Chronic mice demonstrated less lymphocytic infiltrate, more plasma cells and more fibrosis than acute mice. Fibrosis was found in the skin, liver, lungs, spleen and bone marrow. One mouse had severe fibrosis of the liver, spleen, skin and lungs. In later experiments, five more mice sacrificed with chronic GVHD showed a similar histology. Importantly, the livers of the chronic mice showed an auto-immune hepatitis with large amounts of plasma cells. In 5/7 chronic mice even a deposition of human IgA and/or IgG was observed in liver and/or skin. A honeycomb-like pattern was present in the IgA staining, with an IgA-positive surface of the periportal hepatocytes in the liver of 5/7 chronic mice. Ig deposits were also observed in the skin of 4/7 mice. The presence of Ig- and complement-deposits were confirmed in the skin of 3/30 patients cGVHD patients without and 3/3 with blistering diseases. These data provide evidence for a participating role of B cells in the pathogenesis of cGVHD. The beneficial effect of anti-CD20 Ab in cGVHD reported in small scale clinical studies is also consistent with a critical role of B cells in cGVHD-pathology. In summary, the histopathological findings in chronic mice are very similar to the findings in cGVHD. As a consequence, the huPBMC/RAG2−/− γc−/− mouse model provides the unique opportunity to study the contribution of B cells to the pathogenesis of cGVHD.

Sign in / Sign up

Export Citation Format

Share Document