Tumor-activated lymph node fibroblasts suppress T cell function in diffuse large B cell lymphoma.

Recent transcriptomic-based analysis of diffuse large B cell lymphoma (DLBCL) has highlighted the clinical relevance of LN fibroblast and tumor-infiltrating lymphocyte (TIL) signatures within the tumor microenvironment (TME). However, the immunomodulatory role of fibroblasts in lymphoma remains unclear. Here, by studying human and mouse DLBCL-LNs, we identified the presence of an aberrantly remodeled fibroblastic reticular cell (FRC) network expressing elevated fibroblast-activated protein (FAP). RNA-Seq analyses revealed that exposure to DLBCL reprogrammed key immunoregulatory pathways in FRCs, including a switch from homeostatic to inflammatory chemokine expression and elevated antigen-presentation molecules. Functional assays showed that DLBCL-activated FRCs (DLBCL-FRCs) hindered optimal TIL and chimeric antigen receptor (CAR) T cell migration. Moreover, DLBCL-FRCs inhibited CD8+ TIL cytotoxicity in an antigen-specific manner. Notably, the interrogation of patient LNs with imaging mass cytometry identified distinct environments differing in their CD8+ TIL-FRC composition and spatial organization that associated with survival outcomes. We further demonstrated the potential to target inhibitory FRCs to rejuvenate interacting TILs. Cotreating organotypic cultures with FAP-targeted immunostimulatory drugs and a bispecific antibody (glofitamab) augmented antilymphoma TIL cytotoxicity. Our study reveals an immunosuppressive role of FRCs in DLBCL, with implications for immune evasion, disease pathogenesis, and optimizing immunotherapy for patients.

A rare case of nephrotic syndrome and Tangier disease.

Rarely, disorders of lipid metabolism cause nephrotic syndrome with progressive kidney disease. Tangier disease is a rare condition belonging to this family of lipid disorders; however, it is not associated with kidney disease. We report a patient presenting with nephrotic syndrome, leading to the unmasking of Tangier disease. A 34-year-old man presented with ankle oedema, nephrotic-range proteinuria and hypoalbuminaemia. Kidney biopsy demonstrated membranous nephropathy with features of immunoperoxidase staining, suggesting a secondary aetiology. Acute serology was negative. Imaging showed lymphadenopathy with splenomegaly suggestive of lymphoproliferative disorder. Bone marrow biopsy revealed foamy macrophages with widespread lipid deposition. Genomic sequencing revealed a pathological homozygous variant for ATP-binding cassette subfamily A member 1 (ABCA1) c.1510-1G > A, consistent with Tangier disease. Review of the ultrastructural kidney biopsy features demonstrated, in addition to membranous subepithelial and intramembranous usual-type electron-dense deposits, intramembranous osmiophilic lipid deposits similar to those in LCAT deficiency. The patient's renal function gradually declined (serum creatinine 133 µmol/L); therefore, he was started on rituximab. Metabolic disorders causing nephrotic syndrome are rare and even more so their association with membranous nephropathy. These should be considered in cases with unexplained persistent nephrotic syndrome with progressive kidney disease and lipid deposits on renal biopsy.

A rapidly expanding cutaneous tumour in the context of a Janus kinase inhibitor agent following allogeneic stem cell transplant.

Ruxolitinib is a selective, Janus kinase (JAK)1 and JAK2 inhibitor, which is effective in management of chronic graft-versus-host disease (cGvHD). However, the ensuing immunosuppressive effects can give rise to aggressive cutaneous tumours, including Merkel cell carcinoma. We present this case to highlight the development of cutaneous tumours with ruxolitinib, an increasingly used therapy, and the challenge of managing such tumours in the context of refractory cGvHD. Click here for the corresponding questions to this CME article.

A rare cause of lymphadenopathy - Rosai-Dorfman disease in a HIV-positive Ugandan woman.

This case illustrates a rare cause of lymphadenopathy as a presenting feature of HIV and highlights the importance HIV testing in all patients who present with lymphadenopathy.

Bone marrow transplantation modulates tissue macrophage phenotype and enhances cardiac recovery after subsequent acute myocardial infarction.

BACKGROUND: Bone marrow transplantation (BMT) is commonly used in experimental studies to investigate the contribution of BM-derived circulating cells to different disease processes. During studies investigating the cardiac response to acute myocardial infarction (MI) induced by permanent coronary ligation in mice that had previously undergone BMT, we found that BMT itself affects the remodelling response. METHODS AND RESULTS: Compared to matched naive mice, animals that had previously undergone BMT developed significantly less post-MI adverse remodelling, infarct thinning and contractile dysfunction as assessed by serial magnetic resonance imaging. Cardiac rupture in male mice was prevented. Histological analysis showed that the infarcts of mice that had undergone BMT had a significantly higher number of inflammatory cells, surviving cardiomyocytes and neovessels than control mice, as well as evidence of significant haemosiderin deposition. Flow cytometric and histological analyses demonstrated a higher number of alternatively activated (M2) macrophages in myocardium of the BMT group compared to control animals even before MI, and this increased further in the infarcts of the BMT mice after MI. CONCLUSIONS: The process of BMT itself substantially alters tissue macrophage phenotype and the subsequent response to acute MI. An increase in alternatively activated macrophages in this setting appears to enhance cardiac recovery after MI.

Transscleral albumin diffusion and suprachoroidal albumin concentration in uveal effusion syndrome.

PURPOSE: To test the hypothesis that uveal effusion syndrome is caused by reduced transscleral albumin permeability. METHODS: Surgical scleral specimens were obtained from a 55-year-old patient with nanophthalmic uveal effusion syndrome. Specimens were clamped in a modified Ussing chamber, and the rate of transscleral diffusion of fluorescein isothiocyanate-albumin was measured over 12 hours, using a spectrophotometer and predetermined standard curves. The diffusion coefficient was determined at 20°C, and then adjusted to body temperature using Einstein's equation. Results in 3 scleral samples were compared with 10 age-matched controls. Albumin and total protein concentration were measured in choroidal fluid and serum. RESULTS: Histologic staining with Alcian blue showed interfibrillary acid mucin deposits. Transmission electron microscopy showed deposits measuring 1 µm to 10 µm and collections of expanded, degenerate collagen fibrils. The mean (±SD) albumin diffusion coefficient was 12% of that in controls (1.22 ± 0.67(-8) × 10 vs. 10.3 ± 7.0 × 10(-8) cm2/second) and below the lower 95% confidence limit of the control group. The diffusion coefficient was calculated to increase 53% to 1.87 ± 1.03 × 10(-8) cm2/second at 37°C. Choroidal albumin concentration was much higher than physiologic levels, measuring 200 g/L (total protein 321 g/L), 5 times the serum albumin concentration of 42 g/L (total protein 70 g/L). CONCLUSION: Nanophthalmic uveal effusion syndrome can be associated with reduced scleral permeability to albumin, and a very high concentration of retained suprachoroidal albumin. This will lead to an osmotic gradient that retains fluid and may partly explain the pathogenesis of uveal effusion syndrome in some patients.

Skin disease among human immunodeficiency virus-infected adolescents in Zimbabwe: a strong indicator of underlying HIV infection.

BACKGROUND: Southern Africa is witnessing the emergence of an epidemic of long-term survivors of vertically acquired human immunodeficiency virus (HIV) infection presenting with untreated HIV as adolescents. Dermatologic conditions, common in both HIV-infected adults and children, have not been described in this age-group. We investigated the prevalence and spectrum of skin conditions in adolescents admitted to hospitals in Zimbabwe. METHODS: A total of 301 consecutive adolescents admitted to 2 central Harare hospitals, underwent a dermatologic examination. Clinical history, HIV serology, and CD4 lymphocyte counts were obtained. Herpes simplex virus-2 serology was used as a surrogate marker for sexual activity. RESULTS: : A total of 139 (46%) patients were HIV-1 antibody positive, of whom only 2 (1.4%) were herpes simplex virus-2 antibody positive. The prevalence of any skin complaint among HIV-infected and uninfected participants was 88% and 14%, respectively (odds ratio: 37.7, 95% confidence interval: 19.4-72). The most common HIV-related conditions were pruritic papular eruptions (42%) and plane warts >5% of body area (24%). Having 3 or more skin conditions, a history of recurrent skin rashes and angular cheilitis were each associated with CD4 counts <200 cells/microL (P < 0.03, P < 0.01, and P < 0.05, respectively). CONCLUSIONS: Skin disease was a common and striking feature of underlying HIV-infection in hospitalized HIV-infected adolescents in Zimbabwe. In resource-poor settings with maturing epidemics, the presence of skin disease should be regarded as a strong indication for HIV testing and especially as it may reflect advanced immunosuppression. The high frequency of multiple plane warts has not previously been described, and may be a feature that distinguishes vertically-infected from horizontally-infected adolescents.

Low grade cerebellar T-cell lymphoma: a novel response to treatment; a case report.

Low-grade primary T-cell lymphoma of the central nervous system is extremely rare. We present a case developing in a previously fit young woman presenting with symptoms of raised intracranial pressure and found on CT to have a cerebellar mass. Biopsy of this lesion revealed features of non-Hodgkin's lymphoma with histochemical analysis confirming T-cell phenotype and a Ki67 proliferation index of only 1%. Contrary to the prevailing view in the literature, the patient's clinical condition deteriorated following high-dose intravenous methotrexate and improved after a short course of whole-brain radiotherapy.

CD38 expression in chronic lymphocytic leukemia is regulated by the tumor microenvironment.

Chronic lymphocytic leukemia (CLL) is a lymphoproliferative disease with a highly variable outcome. The prognosis of patients with CLL may be predicted using a number of biomarkers, including the level of CD38 expression at the leukemic cell surface. This study investigates the hypothesis that CD38 expression by CLL cells reflects interactions with nonmalignant cells within pseudofollicles in secondary lymphoid tissue where tumor cell proliferation is thought to occur. CD38 expression is higher in tissues that contain pseudofollicles compared with those that do not. In addition, we show that CD38 expression in CLL is dynamic, changes in response to contact with activated CD4(+) T cells, and identifies cells that are primed to proliferate. Finally, we demonstrate close contact between activated CD4(+) T cells and proliferating tumor in primary patient tissue. Proliferating tumor cells in lymph nodes express CD38, which is in turn associated with an increased number of CD31(+) vascular endothelial cells. Although the factors resulting in colocalization of tumor, T cells, and endothelium remain unclear, the existence of these cellular clusters may provide an explanation for the association between CD38 expression and adverse outcome in CLL and suggests novel therapeutic targets.

Eczematoid graft-vs-host disease: a novel form of chronic cutaneous graft-vs-host disease and its response to psoralen UV-A therapy.

BACKGROUND: Chronic cutaneous graft-vs-host disease (GVHD) is generally classified by whether lesions have a lichenoid or sclerodermatous morphology. Other unusual clinical forms have been reported that exhibit the features of dermatomyositis and lupus erythematosus. Within a large population of individuals who underwent allogeneic stem cell transplantation because of hematologic malignancy, a group of patients was identified in whom severe and persistent eczema developed. OBSERVATIONS: We prospectively evaluated 10 adult patients with unexplained eczematous dermatosis after allogeneic hematopoietic stem cell transplantation. The dermatosis developed between 2 and 18 months (mean, 7.5 months) after receipt of the transplant, exhibited the typical clinical features of dermatitis, and became erythrodermic in each case. The patient group had strong risk factors for chronic cutaneous GVHD: 8 had received a transplant from an unrelated donor, 7 had evidence of extracutaneous GVHD, and 7 had a history of acute cutaneous GVHD. Sampling of lesional skin revealed the histologic features of GVHD coexisting with the changes of dermatitis. The patients were treated with topical corticosteroid and systemic immunosuppressive agents. Six patients also received psoralen-UV-A. Four patients achieved prolonged remission. Six patients died, 5 of infective complications and 1 of relapsed leukemia. CONCLUSIONS: The eczematous dermatosis observed represents a novel form of chronic cutaneous GVHD that we named eczematoid GVHD. Eczematoid GVHD is an aggressive, chronic dermatosis that requires substantial immunosuppression therapy to achieve control. It is associated with a poor prognosis. Although atopy can be transmitted to an individual from a hematopoietic stem cell transplant, none of the donors in this series gave a history of an atopic disorder. Therefore, other factors must be implicated in provoking the expression of an eczematous phenotype in individuals with underlying chronic graft-vs-host activity.