Case report: Persistent hypogammaglobulinemia and mixed chimerism after HLA class-II disparate-hematopoietic stem cell transplant.

ABSTRACT

Allogeneic hematopoietic stem cell transplantation (HSCT) is a curative treatment for various hematological, immunological and metabolic diseases, replacing the patient's hematopoietic system with donor-derived healthy hematopoietic stem cells. HSCT can be complicated by early and late events related to impaired immunological recovery such as prolonged hypogammaglobulinemia post-HSCT. We present a 16-year-old female patient with sickle-cell disease who underwent HSCT with stem cells from a human leukocyte antigen (HLA) class-II mismatched family donor. While cellular recovery was good post-HSCT, the patient developed mixed chimerism and suffered from cervical lymphadenopathy, recurrent airway infections and cutaneous SLE. She presented with hypogammaglobulinemia and was started on immunoglobulin substitution therapy and antibiotic prophylaxis. B-cell phenotyping showed that she had increased transitional and naïve mature B cells, reduced memory B cells, and diminished marginal zone/natural effector cells. In-depth immunophenotyping and B-cell receptor repertoire sequencing ruled out an intrinsic B-cell defect by expression of activation-induced cytidine deaminase (AID), presence of somatic hypermutations and differentiation into IgG- and IgA-producing plasma cells in vitro. Immunohistochemistry and flow cytometry of lymph node tissue showed a clear block in terminal B-cell differentiation. Chimerism analysis of sorted lymph node populations showed that exclusively patient-derived B cells populated germinal centers, while only a minor fraction of follicular helper T cells was patient-derived. Given this discrepancy, we deduced that the HLA class-II disparity between patient and donor likely hinders terminal B-cell differentiation in the lymph node. This case highlights that studying disturbed cognate T-B interactions in the secondary lymphoid organs can provide unique insights when deciphering prolonged hypogammaglobulinemia post-HSCT.