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Original Article Gaucher Disease Is Associated with Lymph Node Reactive Follicular Hyperplasia with Tingible Body Macrophages of M2 Phenotype

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Original Article Gaucher Disease Is Associated with Lymph Node Reactive Follicular Hyperplasia with Tingible Body Macrophages of M2 Phenotype Int J Clin Exp Pathol 2017;10(2):2290-2297 www.ijcep.com /ISSN:1936-2625/IJCEP0037730 Original Article Gaucher disease is associated with lymph node reactive follicular hyperplasia with tingible body macrophages of M2 phenotype Margarita M Ivanova1,2, Renuka Pudi Limgala1,2, Erk Changsila1, Chidima Ioanou1,2, Ariel Badger1, Ozlem Goker-Alpan1,2 1Translational Medicine Unit, Lysosomal and Rare Disorders Research and Treatment Center, 11212 Waples Mill Rd. #103, Fairfax, VA, 22030 USA; 2O&O Alpan, LLC, 11212 Waples Mill Rd. #100, Fairfax, VA, 22030 USA Received August 11, 2016; Accepted August 24, 2016; Epub February 1, 2017; Published February 15, 2017 Abstract: In Gaucher disease (GD), deficiency of the lysosomal enzyme, acid β-glucocerebrosidase (GCase), and subsequent accumulation of its substrate in macrophages leads to inappropriate immune activation. GCase defi- ciency affects the differentiation of the mononuclear phagocyte lineage with the resultant dysfunction of reticulo- endothelial system organs including liver, spleen and lymph nodes. While lymphadenopathy is often observed in GD, the underlying mechanisms are unknown. We studied the pathophysiology of lymph node enlargement in a case with Gaucher disease (N370S/RecNciI) and monoclonal gammopathy of undetermined significance (MGUS). Reactive follicular hyperplasia with intrafollicular monotypic plasma cells (IgG kappa) was observed in lymph node biopsy with presence of variably sized follicles in polarized germinal centers and macrophage infiltration. Dual fluo- rescence labeling with macrophage (M2) marker and Ki67, a marker of proliferative activity, indicated that the le- sion was composed of active and proangiogenic macrophages. The immunophenotyping of peripheral blood showed clonal B-cell proliferation, and a reduced number of circulating marginal zone memory B-cells. M2 macrophages promote tumor formation through cell-to-cell interaction by differentiating into tumor-associated macrophages. M2 cells also promote vascularization and formation of lymphatic vessels. This data not only highlights the mechanisms of lymphadenopathy in GD, but also may bridge the gap between the cell types interplaying in the development of B cell related disorders. Keywords: Gaucher disease, lymphadenopathy, M2 macrophages Introduction with GD [2]. Patients with GD have an increased risk for the development of specific malignant Gaucher disease (GD), the most common lyso- disorders, commonly B-cell or plasma cell somal storage disorder, is caused by the defi- malignancies, multiple myeloma (MM) [3], and ciency of the enzyme b-glucocerebrosidase. less commonly, chronic lymphocytic leukemia, Accumulation of the substrate, glycosylce- acute myeloid leukemia, acute lymphoblastic ramide, most notably in macrophages, leads to leukemia, large B-cell lymphoma and Hodgkin the pathognomonic Gaucher cells with resul- lymphoma. Current data has shown that in GD, tant diverse immune phenotypic effects, includ- splenectomy is specifically associated with the ing dysregulation in differentiation of the mono- development of a malignancy [2]. It has been nuclear phagocytic cell lineage [1]. Gaucher hypothesized that loss of splenic function cells occur predominantly in liver, spleen and shifts the predominant site of hemolysis bone marrow, resulting in the most common from extravascular to intravascular tissues, clinical features: organomegaly, cytopenias, causing plasma hemoglobin levels to rise and and skeletal involvement with bone crisis, promote smooth muscle proliferation, and chronic pain and fractures. activation of platelets and endothelial cells [2]. Due to the success of enzyme replace- In addition to the classical symptoms, comor- ment therapy (ERT), splenectomy is now rarely bidities, especially cancer, occur in patients performed in GD. Gaucher disease and lymphadenopathy While lymphadenopathy is commonly reported PVDF membranes. Membranes were probed in patients with GD, the underlying mechanisms with antibody Ki67 (Abcam, Cambridge, MA). are not yet explored. This is the first report Immunoblots were scanned using Bio-Rad investigating the role of activated macrophages GelDoc (Bio-Rad, Hercules, CA). in the development of comorbidities including lymphadenopathy and tumor development in Flow cytometry immunophenotyping GD. This data not only highlights the mecha- nisms of lymphadenopathy in GD, but also may Direct immunofluorescence with specific anti- bridge the gap between the cell types interpl- bodies was performed on peripheral blood as aying in the development of B cell related previously described [6, 7]. Briefly, 100 μl of disorders. washed blood was used per tube, and samples were acquired on Accuri C6 flow cytometer (BD Material and methods Bioscience, San Jose, CA) and analyzed using FCS express software (De Novo software, Tissue samples and immunostaining Glendale, CA). The lymph node core biopsy and surgically- Ethical approval extracted right submandibular lymph node were fixed in 10% neutral formalin, embedded All research procedures have been perfo- in paraffin, and stained with hematoxylin-eosin rmed under the IRB approved protocol or antibodies CD20, CD3, immunoglobulin (Ig) NCT02000310, clinicaltrials.gov. light chains kappa & lambda, IgG, IgA, IgM, and IgD. Immunofluorescent staining (IFC) was per- Statistical analysis formed with antibodies against markers for cell proliferation (Ki67) and M2 macrophages Data are expresses as average ± standard (CD163, CD68). The marker indices for Ki-67, error of the mean. Statistical significance was CD163, and CD68 were defined as the percent- determined using Student’s t-test and statisti- age of positively stained cells in representative cal significance p value is <0.05. areas of the lymph nodes and were evaluated by counting using digital image analysis (ImageJ Results ITCN plugin). Clinical presentation Immunoglobulin PCR During annual evaluation, a 46-year old female DNA extraction was performed from paraffin with Type 1 GD presented with an enlarged embedded lymph node surgical tissue sec- right submandibular lymph node, measuring tions. To measure the immunoglobulin heavy 3 by 6 cm, not freely movable and medium in (IGH) locus, two separate reactions were per- consistency. The diagnosis of GD was at age formed using two primer sets. The first set of 19, followed by splenectomy. She was lost to primers covered framework region III and the follow up until she presented with thrombo- joining region of the immunoglobulin heavy cytopenia and transfusion dependent anemia chain gene (FRIII-IGH-PCR), while the second due to bone marrow failure, but was success- set of primers covered framework region II and fully treated with ERT for the past 2 years with the joining region of the immunoglobulin heavy normalization of hematological parameters. chain gene (FRII-IGH-PCR) [4]. For both reac- The current work-up showed increased IgG, tions, the joining region primers were covalently 1792 (700-1,600 mg/dl), decreased IgM, 25 linked to fluorescent dye FAM for fluorescence (26-217 mg/dl), and an observed serum M detection following the protocol [5]. Testing for spike. The immunofixation showed monoclonal the IGκ locus was performed at laboratory of pathology, National Cancer Institute (NCI), NIH protein with light chain specificity. Urine free as described previously [5]. kappa light chains and lambda light chains were elevated, 41.37 (3.30-19.40 mg/L) and Western blot 27.65 (5.71 and 26.3 mg/L) respectively (Figure 1A). She was diagnosed with monoclo- Whole cell extracts of PBMCs (30 μg) were nal gammopathy of undetermined signific- separated on NuPAGE 4-12% gel and blotted to ance (MGUS) and lymphadenopathy. For a 2291 Int J Clin Exp Pathol 2017;10(2):2290-2297 Gaucher disease and lymphadenopathy Figure 1. A: Hematoxylin-eosin (H&E) and IFC showing biopsy of lymph node with areas of Ki67 positive cells. Green fluorescence indicates cells positively stained for proliferative marker, Ki67; Blue represents nuclear staining (DAPI). B: 40× magnification of area with high prolif- erative activity highlighting markers: Ki67, tubulin, and DAPI. Top left panel: 40× magnification of area with high Ki67+ cells proliferative activ- ity (Ki67) (green, left top panel). Top middle and right panels: cells with sizable cytoplasmic volume as determined by tubulin staining (red) in the area with Ki67 positive cells. Image of DAPI-nuclear staining (left bottom panel). suspected hematologic malignancy, a core Molecular studies biopsy of the lymph node was performed fol- lowed by the surgical removal of the lymph Lymph node enlargement with large, foamy node. macrophages is frequently observed in GD patients. To determine the contribution of the Histopathological analysis macrophages to tumor formation and lymph- adenopathy in GD, we performed IFC staining The histopathological analysis of the core biop- with CD68 and CD163 antibodies [8], both sy specimen showed areas with high prolifera- markers for M2 type macrophages [9]. The tive activity (87% of Ki67 positive cells) (Figure results showed CD68 and CD163 positive mac- rophages were present in follicular centers and 1A). Unlike the surrounding cells, Ki67+ cells interfollicular zones, confirming the H&E histo- had sizeable cytoplasmic volume (tubulin stain- pathology analysis (Figure 2B). Scoring, on the ing), suggesting a predominant population of basis of the percentage of positively stained large cells (Figure 1B). The analysis of the cells, demonstrated a significantly increased remaining
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