Allogeneic hematopoietic stem cell transplantation (alloHCT) is the definitive therapy for numerous otherwise incurable hematologic malignancies and non-malignant diseases. The genetic disparity between donor and recipient both underpins therapeutic effects and confers donor immune system-mediated damage in the recipient, called graft-versus-host disease (GVHD). Chronic GVHD (cGVHD) is a major cause of late post-transplant morbidity and mortality. B cells have a substantiated role in cGVHD pathogenesis, as first demonstrated by clinical response to the anti-CD20 monoclonal antibody, rituximab. Initiation of CD20 blockade is met at times with limited therapeutic success that has been associated with altered peripheral B cell homeostasis and excess B Cell Activating Factor of the TNF family (BAFF). Increased BAFF to B cell ratios are associated with the presence of circulating, constitutively activated B cells in patients with cGVHD. These cGVHD patient B cells have increased survival capacity and signal through both BAFF-associated and B Cell Receptor (BCR) signaling pathways. Proximal BCR signaling molecules, Syk and BTK, appear to be hyper-activated in cGVHD B cells and can be targeted with small molecule inhibitors. Murine studies have confirmed roles for Syk and BTK in development of cGVHD. Emerging evidence has prompted investigation of several small molecule inhibitors in an attempt to restore B cell homeostasis and potentially target rare, pathologic B cell populations.
B cells in chronic graft-versus-host disease.
W. McManigle,Ayman Youssef,S. Sarantopoulos
Published 2019 in Human Immunology
ABSTRACT
PUBLICATION RECORD
- Publication year
2019
- Venue
Human Immunology
- Publication date
2019-06-01
- Fields of study
Medicine
- Identifiers
- External record
- Source metadata
Semantic Scholar, PubMed
CITATION MAP
EXTRACTION MAP
CLAIMS
CONCEPTS
- b cell activating factor of the tnf family
A BAFF cytokine family member that supports B cell survival and homeostasis in the immune system.
Aliases: BAFF
- b cell receptor signaling
Signal transduction initiated by the B cell receptor on B cells.
Aliases: BCR signaling, BCR
- b cells
Antibody-producing lymphocytes discussed here as a key immune cell population involved in chronic graft-versus-host disease.
- btk
A Bruton's tyrosine kinase involved in proximal B cell receptor signaling and considered a therapeutic target here.
Aliases: Bruton's tyrosine kinase
- chronic graft-versus-host disease
A late post-transplant complication in which donor immune cells damage the recipient after allogeneic hematopoietic stem cell transplantation.
Aliases: cGVHD
- small molecule inhibitors
Low-molecular-weight compounds used to inhibit signaling targets implicated in B cell dysregulation.
- syk
A proximal B cell receptor signaling kinase discussed as a target in chronic graft-versus-host disease.
Aliases: spleen tyrosine kinase