Apoptosis Susceptibility Prolongs the Lack of Memory B Cells in Acute Leukemic Patients After Allogeneic Hematopoietic Stem Cell Transplantation

Abstract

Long-term survival after allogeneic hematopoietic stem cell transplantation requires intact immunosurveillance, which is hampered by lymphoid organ damage associated with conditioning therapy, graft-versus-host disease, and immunosuppression. Our study aimed to identify the mechanisms contributing to sustained low memory B cell numbers after transplantation. Peripheral B and T cell subset recovery and functional marker expression were investigated in 35 acute leukemic patients up to 1 year after transplantation. Apoptosis of B cells after CD40/TLR-9, CD40/BCR, and CD40/BCR/TLR-9-dependent stimulation and drug efflux capacity were analyzed. One half of the patients suffered from infections after day 180. All patients had strongly diminished CD27(+) memory B cells despite already normalized total B cell numbers and fully recovered CD27(-)IgD(-) memory B cells, putatively of extra-follicular origin. Circulating memory follicular helper T cells were reduced in the majority of patients as well. Naïve B cells exhibited a decreased expression of CXCR5, which mediates follicular B cell entry. Additionally, a lower HLA-DR expression was found on naïve B cells, impairing antigen presentation. Upon CD40/TLR-9-dependent activation, B cells underwent significantly increased apoptosis paralleled by an aberrant up-regulation of Fas-L on activated T cells and Fas on resting B cells. Significantly increased B cell apoptosis was also observed after CD40/BCR and CD40/BCR/TLR-9-dependent activation. Drug efflux capacity of naïve B cells was diminished in cyclosporin A-treated patients, additionally contributing to an apoptosis-prone phenotype. We conclude that B cell survival and migration and T cell communication defects are contributing candidates for an impaired germinal center formation of memory B cells after allogeneic hematopoietic stem cell transplantation. Follow-up studies should evaluate effectiveness of revaccinations on the cellular level and should address the long-term sequelae of B cell defects after transplantation.

A Multi-Factorial Observational Study on Sequential Fecal Microbiota Transplant in Patients with Medically Refractory Clostridioides difficile Infection

“…These antigen-specific memory B cells may no longer be required in the context of presumed C. difficile clearance and may have transited into the lymphoid organs. Alternatively, these observations may reflect memory B cell apoptosis, which has been reported to contribute to impaired germinal center formation of memory B cells after allogeneic hematopoietic stem cell transplantation [70]. In contrast, peripheral toxin A-and B-expressing memory B cells seemed to peak in frequency two weeks post-FMT for the non-responder.…”

Spike-Specific Memory B Cell Response in Hematopoietic Cell Transplantation Recipients following Multiple mRNA-1273 Vaccinations: A Longitudinal Observational Study

“…This is in contrast to solid-organ transplantation recipients, where immunosuppressive treatment continues throughout life. These treatments could impact the immune response to vaccinations and may have an impact on the generation of neutralizing antibodies, potentially hindering the germinal center reaction and B cell maturation [32], as proposed by Yi-Chou Hou and colleagues in their discussion of the effectiveness of COVID-19 vaccines in kidneytransplanted patients [33]. In our cohort, those individuals exhibiting a lower immune response and a lack of neutralizing antibody activity were precisely the patients who, due to post-transplant complications such as graft-versus-host disease, had to prolong their immunosuppressive treatment.…”

C59T mutation in exon 2 of monocytic leukemia-associated antigen-34 gene indicates a high risk of recurrence of acute myeloid leukemia

“…AML is a genetically heterogeneous disease which results from the over-proliferation of hematopoietic stem cells and their failure to differentiate, resulting in an uncontrolled accumulation of myeloblasts accumulated in the bone marrow as well as the blood (2,3). Allogeneic hematopoietic stem cell transplantation has been demonstrated to be the most effective therapeutic method for acute leukemia and has been integrated into the standard of care (4). However, its application has so far been limited, offering only incomplete prevention of AML clinical relapse (5,6).…”