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. 2023 Nov 6;24(21):16012.
doi: 10.3390/ijms242116012.

Persistent Hypogammaglobulinemia after Receiving Rituximab Post-HSCT Is Not Caused by an Intrinsic B Cell Defect

Lisa M Ott de Bruin  1   2 , Ingrid Pico-Knijnenburg  1 , Monique M van Ostaijen-Ten Dam  1 , Thomas J Weitering  1 , Dagmar Berghuis  2 , Robbert G M Bredius  2 , Arjan C Lankester  2 , Mirjam van der Burg  1
Affiliations

Persistent Hypogammaglobulinemia after Receiving Rituximab Post-HSCT Is Not Caused by an Intrinsic B Cell Defect

Lisa M Ott de Bruin et al. Int J Mol Sci. .

Abstract

In the setting of hematopoietic stem cell transplantation (HSCT), Rituximab (RTX) is used for the treatment and prevention of EBV-associated post-transplantation lymphoproliferative disease or autoimmune phenomena such as autoimmune hemolytic anemia (AIHA). Persistent hypogammaglobulinemia and immunoglobulin substitution dependence has been observed in several patients after RTX treatment despite the normalization of total B cell numbers. We aimed to study whether this is a B cell intrinsic phenomenon. We analyzed four patients with different primary diseases who were treated with myeloablative conditioning and matched unrelated donor HSCT who developed persistent hypogammaglobulinemia after receiving RTX treatment. They all received RTX early after HSCT to treat EBV infection or AIHA post-HSCT. All patients showed normalized total B cell numbers but absent to very low IgG positive memory B cells, and three lacked IgA positive memory B cells. All of the patients had full donor chimerism, and none had encountered graft-versus-host disease. Sorted peripheral blood naïve B cells from these patients, when stimulated with CD40L, IL21, IL10 and anti-IgM, demonstrated intact B cell differentiation including the formation of class-switched memory B cells and IgA and IgG production. Peripheral blood T cell numbers including CD4 follicular T-helper (Tfh) cells were all within the normal reference range. In conclusion, in these four HSCT patients, the persistent hypogammaglobulinemia observed after RTX cannot be attributed to an acquired intrinsic B cell problem nor to a reduction in Tfh cell numbers.

Keywords: HSCT; RTX; class switch recombination; hematopoietic stem cell transplantation; memory B cells; rituximab.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
(a) A schematic overview of the procedure. Cryopreserved PBMCs were taken from a biobank. Part of the sample was used for the flow cytometry of T and B cell subsets. The rest of the sample was used to FACS sort naïve B cells (CD20+CD27−IgA−IgG−) to stimulate in vitro. On day 6, part of the cells were counted, RNA was isolated for AID expression, and IgA and IgG memory B cells were measured via flow cytometry. The rest of the cells were cultured until day 10 when the supernatant was collected for ELISA in order to measure IgA and IgG production; (b) Absolute cell counts on day 6 after stimulation compared to unstimulated wells; (c) AID expression was normalized to the housekeeping gene GUSB.
Figure 2
Figure 2
(a) Flow cytometry gating strategy on day 6. (b) Percentage of IgA positive memory B cells and (c) percentage of IgG positive memory B cells. Stimulated (+) versus unstimulated (−) wells.
Figure 3
Figure 3
ELISA on collected supernatant on day 10. (a) IgA in ng/mL; (b) IgG in ng/mL.
See this image and copyright information in PMC

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