IMMUNOMODULATORY EFFECTS of SARS-COV-2 VACCINATION: INCREASE of REGULATORY T CELLS after MRNA VACCINE

Background: Besides the ability to induce antigen-specifc responses, vaccines can be endowed with immunomodulatory properties including the capacity to induce or downregulate regulatory T cells (Treg) that suppress adaptative and autoreactive immune responses (1). Objectives: We asked if an anti-SARS-CoV-2 mRNA vaccine could also induce an accumulation of Treg cells in patients with mixed cryoglobulinemia vasculitis (MCV), who have a defciency of Treg cells (2) and in healthy individuals. We also investigated immunologic variables possibly associated with a low immunogenic-ity of SARS-CoV-2 mRNA vaccine in patients with MCV (3). Methods: We analyzed peripheral blood lymphocyte subpopulations and anti-SARS-CoV-2 serological response in 24 patients with MCV and 9 Healthy donors (HD) before and after 2 weeks after the second dose of the Pfzer/BioNTech vaccine. Results: Among MCV patients we found 15 serological responders and 9 non-responders. All 5 seronegative patients treated recently with rituximab had <5 B cells/μ L, whereas the absolute B cell count was increased in 2 of 4 untreated patients due to monoclonal B cell lymphocytosis, with monoclonal cells representing more than 90% of B cells, associated with non-Hodgkin lymphoma. The percentage of pathologic CD21low B cells was signifcantly increased in seronegative patients. Before receiving the Pfzer/BioNTech vaccine, patients with MCV had a signifcantly reduced frequency of Treg cells among CD4+ T cells compared to HD. After the second dose of the vaccine, there was in MCV patients a signifcant increase in the percent and absolute count of Treg among CD4+ T cells Concerning the pre-vaccination distribution of T cells subpopulations, including the percentages and absolute counts of total CD3+, CD4+, CD8+, HLA-DR+ activated, Treg or CD56+ natural killer T cells, we could not reveal any pattern signifcantly associated with lack of serological response to vaccine. Conclusion: Our fndings show that lack of immunoreactivity in patients with MCV may be associated with expansion of pathologic B cells and that anti-SARS-CoV2 mRNA vaccine may induce an increase of Treg cells.

Monoclonal B-cell Lymphocytosis - a review of diagnostic criteria, biology, natural history, and clinical management.

Since first described almost two decades ago, there has been significant evolution in our definition and understanding of the biology and implications of monoclonal B-cell lymphocytosis (MBL). This review provides an overview of the definition, classification, biology, and natural history of MBL, mainly focused on the dominant CLL-like phenotype form of MBL. The increasingly recognized implications of MBL with respect to immune dysfunction are discussed, particularly in view of the COVID-19 pandemic, along with management recommendations for MBL in the clinic.

POS-126 PROLIFERATIVE GLOMERULONEPHRITIS WITH MONOCLONAL IgG DEPOSITS;A NOVEL PATHOLOGIC PRESENTATION

Introduction: Proliferative glomerulonephritis with monoclonal IgG deposits (PGNMID) is a rare form of PGN that mimics immune-complex (IC) GN by light microscopy (LM), but shows monoclonal IgG deposits by immunofluorescence (IF). PGNMID often presents with membranoproliferative (MPGN) pattern or endocapillary hypercellularity. Focal crescents are not uncommon in PGNMID, but diffuse crescentic involvement is very rare. Methods: 78-year-old man with a history of hypertension and multiple cardiovascular comorbidities presented with weakness, dizziness, and anorexia, and was found to have severe hypertension and acute kidney injury with serum creatinine of 12 mg/dl (baseline 1 mg/dl). He was a chronic smoker and alcoholic. He reported productive cough with scanty whitish sputum, but denied hemoptysis. Urine analysis showed marked proteinuria, hematuria, and leukocyturia. Renal ultrasound revealed bilateral decrease corticomedullary differentiation without obstruction. Hemodialysis was initiated. Imaging showed bilateral upper lobe pneumonia with concerns for alveolar hemorrhages. Serology for complements, ANA, dsDNA, ANCA, Hepatitis B and C, Covid19 was negative. Kappa/lambda free light chain ratio was normal. SPEP, UPEP and immunofixation were negative for paraproteinemia. Renal biopsy showed diffuse crescentic and endocapillary PGN with MPGN features, and linear monoclonal IgG3-kappa immune deposits. Given the lack of clinical evidence of cryoglobulinemia and presence of immune-type electron dense deposits without organized substructures by EM, the findings were most consistent with PGNMID. However, the unusual biopsy presentation raised concerns for possible concurrent anti-GBM disease. Subsequently, Solu-Medrol was started followed by prednisone 1 mg/kg. He received 2 sessions of plasmapheresis before anti-GBM serology returned negative. Bone marrow biopsy revealed monoclonal B-cell lymphocytosis with CLL phenotype. Unfortunately, the patient developed Covid19 infection, and passed away before receiving further treatment. [Formula presented] Results: PGNMID is a rare form of renal involvement by monoclonal immunoglobulin deposition that mimics ICGN on renal biopsy. Nephrotic range proteinuria, hematuria and renal insufficiency are usual presentation. Cases of PGNMID classically show IgG3k, in a granular glomerular capillary wall, mesangial, and occasionally subepithelial distribution. By EM, these deposits appear granular typical of ICGN which lack organized substructure. The predominant LM patterns are MPGN and endocapillary hypercellularity. Less frequently focal crescents may be present, but diffuse crescentic involvement is especially rare (~5%). In our case, the diffuse cellular crescents and semilinear to linear GBM staining was unusual. Together with the clinical presentation, the findings prompted concerns for a concomitant Goodpasture syndrome, but anti-GBM antibody returned negative. The pathogenesis is still unclear, but some authors suggest infection as a possible trigger for crescentic transformation in PGNMID. The presence of crescents seem to confer a poorer prognosis and associated with progression to ESRD. Conclusions: Our case is a unique presentation of PGNMID in a patient who presented with clinical and pathologic features concerning for Goodpasture syndrome. PGNMID can rarely present with diffuse crescents and IF findings similar to anti-GBM nephritis in a patient with RPGN. No conflict of interest

The Pivotal Role of Viruses in the Pathogeny of Chronic Lymphocytic Leukemia: Monoclonal (Type 1) IgG K Cryoglobulinemia and Chronic Lymphocytic Leukemia Diagnosis in the Course of a Human Metapneumovirus Infection.

BACKGROUND: Type-1 cryoglobulinemia (CG) is a rare disease associated with B-cell lymphoproliferative disorder. Some viral infections, such as Epstein-Barr Virus infections, are known to cause malignant lymphoproliferation, like certain B-cell lymphomas. However, their role in the pathogenesis of chronic lymphocytic leukemia (CLL) is still debatable. Here, we report a unique case of Type-1 CG associated to a CLL transformation diagnosed in the course of a human metapneumovirus (hMPV) infection. CASE PRESENTATION: A 91-year-old man was initially hospitalized for delirium. In a context of febrile rhinorrhea, the diagnosis of hMPV infection was made by molecular assay (RT-PCR) on nasopharyngeal swab. Owing to hyperlymphocytosis that developed during the course of the infection and unexplained peripheral neuropathy, a type-1 IgG Kappa CG secondary to a CLL was diagnosed. The patient was not treated for the CLL because of Binet A stage classification and his poor physical condition. CONCLUSIONS: We report the unique observation in the literature of CLL transformation and hMPV infection. We provide a mini review on the pivotal role of viruses in CLL pathophysiology.