Investigation of the relationship with tissue immunoglobulin-G positive plasma cell profile and serum donor specific antibody levels in repeat antibody-mediated rejection of cardiac transplantations

Antibody-mediated rejection (AMR) of cardiac allograft is an insidious process associated with chronic graft damage, graft loss, and difficulty in treatment. It remains a challenging diagnosis for the pathologist, immunologist, and clinician; its boundaries are unclear. Accurate and rapid diagnosis of immunological and histopathological features of AMR are indispensable for timely treatment. Monitoring them properly is essential to prevent undesirable outcomes and avoid unnecessary immunosuppression and costs. In transplant heart follow-up, detailed immunological tests and histopathological examinations of endomyocardial biopsies guide appropriate treatment approaches. In this thesis study, our primary goal was to understand the role of plasma cells and their products, immunoglobulins (Ig), in the pathogenesis of AMR and to find potential helpful markers in histopathological and immunological examinations. We planned a retrospective multidisciplinary study with 91 endomyocardial biopsy (EMB) samples taken from 19 allograft heart transplant patients and synchronous serum samples taken for immunological examinations, for which there is sufficient material and patient records in the Pathology and Immunology archives of our center. The study group consisted of patients with a chronic course with recurrent AMR attacks. All tissue samples were re-evaluated with immunohistochemical stainings with CD138, IgG, IgG1, and IgG3, in addition to the immune markers (C4d, CD68) in our diagnostic pathology routine. Taking into account all inflammatory cells in the myocardial interstitium, subendocardial area, or capillary lumens, positive mononuclear cells were counted in a high magnification field by selecting the areas with the most positive cells, and the ratio of all inflammatory cells to all inflammatory cells in the field was calculated, based on a 10% threshold value. Positivity rates in endothelial cells were also recorded using the same method. Only one CD138-positive plasma cell or IgG, IgG1, or IgG3-positive mononuclear cell in the tissue was associated with C4d positivity and DSA positivity. Positivity rates in endothelial cells were also parallel to positive mononuclear cell rates, and their distribution among diagnostic groups showed significant differences. In patient-based analyses, taking into account acute rejection and treatment times, the presence of IgG1 and IgG3 positive cells in the tissue and the increase in their numbers showed a close correlation with the DSA MFI levels in the patient's synchronous serum. Each of them stood out as a potentially helpful marker, especially in AMR-1 cases with borderline histomorphological and immunohistochemical C4d and CD68 findings in the pathology routine and unknown DSA status.