Immunotactoid glomerulopathy - an enigmatic case in the setting of nodal marginal zone lymphoma and systemic sclerosis sine scleroderma.

BACKGROUND: Immunotactoid Glomerulopathy (ITG) is an exceedingly rare type of glomerulopathy characterised by distinctive electron microscopic features. ITG has been linked to lymphoproliferative or autoimmune disorders. The clinical manifestations are diverse including nephrotic syndrome (NS), haematuria, acute kidney injury and end stage renal failure (ESRD). We present a case with a stage 3 Nodal Marginal Zone Lymphoma (NMZL) and systemic sclerosis sine scleroderma (SSSS), where the evolution of ITG was documented in 2 renal biopsies 19 months apart. To the best of our knowledge, no cases have been reported linking ITG to NMZL. Furthermore, there is only one non-peer reviewed report linking ITG to scleroderma. We discuss the implications of our findings and highlight the satisfactory management of the case. CASE PRESENTATION: A 79-year-old female with history of systemic sclerosis sine scleroderma and stage 3 NMZL presented with acute kidney injury and NS on a background of chronic kidney disease. Her first kidney biopsy showed a diffuse proliferative glomerulonephritis and her serum protein electrophoresis showed no abnormalities. She was managed satisfactorily with conservative measures. She returned 19 months later with features of fluid overload, increasing proteinuria and rising serum creatinine. A repeat serum protein electrophoresis showed excess free kappa light chains and ITG was detected in the repeat kidney biopsy. Her kidney function and proteinuria showed a good and sustained response to rituximab administered after the second biopsy. CONCLUSION: ITG is a rare type of glomerulopathy, associated with underlying haematological malignancies and autoimmune disorders that may result in ESRD. Rituximab is one of the effective agents used in the management of ITG with haematological malignancies.

Membrane microdomain sphingolipids are required for anti-CD20-induced death of chronic lymphocytic leukemia B cells.

BACKGROUND: Chronic lymphocytic leukemia remains incurable, despite the addition of rituximab to chemotherapy as an available means of treatment. The resistance of certain patients to this monoclonal antibody prompted us to set up in vitro studies of another CD20-specific monoclonal antibody, B1 (later termed tositumomab). We hypothesized that the membrane lipid organization of leukemic B cells might be instrumental in the cells' sensitivity to the B1 monoclonal antibody. DESIGN AND METHODS: B lymphocytes from 36 patients with chronic lymphocytic leukemia and 13 patients with non-Hodgkin's lymphoma were investigated for B1-triggered cell death. Membrane components, such as sphingomyelin and ganglioside M1, were investigated by flow cytometry, immunofluorescence and co-immunoprecipitation, together with the Csk-binding protein. RESULTS: Chronic lymphocytic leukemia patients segregated into two groups: B cells from one group were sensitive to B1, whereas those from the second group were not. Further results ascribed the resistance of these latter cases to a defective recruitment of Csk-binding protein, resulting in a lack of sphingomyelin and ganglioside M1 at the outer leaflet of the plasma membrane of their malignant B cells. Sphingolipids were indeed retained in the cytoplasm, because of lowered activity of P-glycoprotein. Supporting this mechanism, rifampicin, an inducer of P-glycoprotein, improved the activity of this transmembrane efflux pump, normalized the quantity of sphingomyelin within the membrane, and thereby restored the efficacy of the B1 monoclonal antibody in the formerly B1-resistant cases of chronic lymphocytic leukemia. CONCLUSIONS: The lipid organization of membranes of B cells from patients with chronic lymphocytic leukemia differs from one patient to another. In practice, given the relevance of the membrane lipid distribution to the efficacy of biotherapies, this observation is of potential importance.

A new approach to comparing anti-CD20 antibodies: importance of the lipid rafts in their lytic efficiency.

The view that B lymphocytes are pathogenic in diverse pathological settings is supported by the efficacy of B-cell-ablative therapy in lymphoproliferative disorders, autoimmune diseases and graft rejection. Anti-B-cell antibodies (Abs) directed against CD20 have therefore been generated, and of these, rituximab was the first anti-CD20 monoclonal Ab (mAb) to be applied. Rituximab-mediated apoptosis, complement-dependent cytotoxicity and Ab-dependent cellular cytotoxicity differ from one disease to another, and, for the same disease, from one patient to another. This knowledge has prompted the development of new anti-CD20 mAbs in the hope of improving B-cell depletion. The inclusion of CD20/anti-CD20 complexes in large lipid rafts (LRs) enhances the results of some, but not all, anti-CD20 mAbs, and it may be possible to include smaller LRs. Lipid contents of membrane may be abnormal in malignant B-cells, and could explain resistance to treatment. The function of these mAbs and the importance of LRs warrant further investigation. A detailed understanding of them will increase results for B-cell depletion in lymphoproliferative diseases.

Improvement of rituximab efficiency in chronic lymphocytic leukemia by CpG-mediated upregulation of CD20 expression independently of PU.1.

Lipopolysaccharide (LPS), CpG-containing phosphothioate oligonucleotides (CpG) and various cytokines impact chronic lymphocytic leukemia (CLL) B cells. For example, they influence cell cycle entry, expression of co-receptors, and CD20. Rituximab (RTX), for which CD20 molecule is the target, proved to be less efficient in CLL than in lymphoma. This is accounted for by a lower CD20 level in the former than in the latter B lymphocytes. CD20 transcription is mediated by four transcription factors, of which only purine-rich box-1 (PU.1) is reduced in CLL. We thus examined the effects of LPS, CpG, tumor necrosis factor-alpha, interferon-alpha, interleukin (IL)-3, IL-4, IL-21, granulocyte macrophage-colony stimulating factor (CSF), and granulocyte-CSF on the transcription of PU.1, and the subsequent expression of CD20. It appeared that CpG was unique in that it raised the membrane expression of CD20 on malignant B cells, owing to a PU.1 independent increase in its gene transcription. Moreover, RTX-induced complement-mediated lysis was also ameliorated. Thus, CpG accelerates the transcription of CD20 independently of PU.1, and thereby improves the efficacy of RTX in CLL.