Context Severe sepsis is typically characterized by initial cytokine-mediated hyper-inflammation. Whether this hyperinflammatory phase is followed by immunosuppression is controversial. Animal studies suggest that multiple immune defects occur in sepsis, but data from humans remain conflicting. Objectives To determine the association of sepsis with changes in host innate and adaptive immunity and to examine potential mechanisms for putative immunosuppression. Design, Setting, and Participants Rapid postmortem spleen and lung tissue harvest was performed at the bedsides of 40 patients who died in intensive care units (ICUs) of academic medical centers with active severe sepsis to characterize their immune status at the time of death (2009–2011). Control spleens (n=29) were obtained from patients who were declared brain-dead or had emergent splenectomy due to trauma; control lungs (n=20) were obtained from transplant donors or from lung cancer resections. Main Outcome Measures Cytokine secretion assays and immunophenotyping of cell surface receptor-ligand expression profiles were performed to identify potential mechanisms of immune dysfunction. Immunohistochemical staining was performed to evaluate the loss of immune effector cells. Results The mean ages of patients with sepsis and controls were 71.7 (SD, 15.9) and 52.7 (SD, 15.0) years, respectively. The median number of ICU days for patients with sepsis was 8 (range, 1–195 days), while control patients were in ICUs for 4 or fewer days. The median duration of sepsis was 4 days (range, 1–40 days). Compared with controls, anti-CD3/anti-CD28–stimulated splenocytes from sepsis patients had significant reductions in cytokine secretion at 5 hours: tumor necrosis factor, 5361 (95% CI, 3327–7485) pg/mL vs 418 (95% CI, 98–738) pg/mL; interferon γ, 1374 (95% CI, 550–2197) pg/mL vs 37.5 (95% CI, −5 to 80) pg/mL; interleukin 6, 3691 (95% CI, 2313–5070) vs 365 (95% CI, 87–642) pg/mL; and interleukin 10, 633 (95% CI, −269 to 1534) vs 58 (95% CI, −39 to 156) pg/mL; (P<.001 for all). There were similar reductions in 5-hour lipopolysaccharide-stimulated cytokine secretion. Cytokine secretion in sepsis patients was generally less than 10% that in controls, independent of age, duration of sepsis, corticosteroid use, and nutritional status. Although differences existed between spleen and lung, flow cytometric analysis showed increased expression of selected inhibitory receptors and ligands and expansion of suppressor cell populations in both organs. Unique differences in cellular inhibitory molecule expression existed in immune cells isolated from lungs of sepsis patients vs cancer patients and vs transplant donors. Immunohistochemical staining showed extensive depletion of splenic CD4, CD8, and HLA-DR cells and expression of ligands for inhibitory receptors on lung epithelial cells. Conclusions Patients who die in the ICU following sepsis compared with patients who die of nonsepsis etiologies have biochemical, flow cytometric, and immunohistochemical findings consistent ...

Rationale: The mechanistic basis for cardiac and renal dysfunction in sepsis is unknown. In particular, the degree and type of cell death is undefined. Objectives: To evaluate the degree of sepsis-induced cardiomyocyte and renal tubular cell injury and death. Methods: Light and electron microscopy and immunohistochemical staining for markers of cellular injury and stress, including connexin-43 and kidney-injury-molecule-1 (Kim-1), were used in this study. Measurements and Main Results: Rapid postmortem cardiac and renal harvest was performed in 44 septic patients. Control hearts were obtained from 12 transplant and 13 brain-dead patients. Control kidneys were obtained from 20 trauma patients and eight patients with cancer. Immunohistochemistry demonstrated low levels of apoptotic cardiomyocytes (,1-2 cells per thousand) in septic and control subjects and revealed redistribution of connexin-43 to lateral membranes in sepsis (P , 0.020). Electron microscopy showed hydropic mitochondria only in septic specimens, whereas mitochondrial membrane injury and autophagolysosomes were present equally in control and septic specimens. Control kidneys appeared relatively normal by light microscopy; 3 of 20 specimens showed focal injury in approximately 1% of renal cortical tubules. Conversely, focal acute tubular injury was present in 78% of septic kidneys, occurring in 10.3 6 9.5% and 32.3 6 17.8% of corticomedullary-junction tubules by conventional light microscopy and Kim-1 immunostains, respectively (P , 0.01). Electron microscopy revealed increased tubular injury in sepsis, including hydropic mitochondria and increased autophagosomes. Conclusions: Cell death is rare in sepsis-induced cardiac dysfunction, but cardiomyocyte injury occurs. Renal tubular injury is common in sepsis but presents focally; most renal tubular cells appear normal. The degree of cell injury and death does not account for severity of sepsis-induced organ dysfunction.Keywords: sepsis; apoptosis; necrosis; autophagy; kidney Sepsis causes profound myocardial depression, and echocardiography frequently reveals severe biventricular dysfunction (1-5). Sepsis also induces renal insufficiency in 30 to 60% of patients, up to half of whom require dialysis (6-10). The mechanistic basis for cardiac and renal dysfunction occurring in sepsis is controversial (1,5,7,9,(11)(12)(13)(14)(15)(16). The degree to which apoptosis, necrosis, or autophagy contribute to cardiac and renal dysfunction in sepsis is unresolved (2,3,(16)(17)(18)(19).Although a few well controlled studies have been performed, extensive cell death in hearts or kidneys in patients dying of sepsis has not been described, leading investigators to postulate that cellular "hibernation" or metabolic suppression and not cell death is the basis of sepsis-induced organ failure (11,13,14,16,18,(20)(21)(22). Cardiac dysfunction in sepsis is reversible, and the majority of renal failure patients who survive sepsis recover baseline renal function; these observations are consistent with organ "hibernation" (1, ...

CD10 and MUM1 are representative B cell differentiation markers. Follicular lymphoma (FL) is usually positive for CD10 and negative for MUM1. In this study, however, we compared 22 FLs with peculiar phenotype CD10 ؊ MUM1 ؉ with 119 typical CD10 ؉ MUM1 ؊ FLs. All CD10 ؊ MUM1 ؉ FL patients exhibited follicular structure with follicular dendritic meshwork, and a high rate of somatic hypermutation and ongoing mutation, similar to typical FL. However, CD10 ؊ MUM1 ؉ FLs were encountered frequently in the elderly compared with CD10 ؉ MUM1 ؊ typical FLs (67.0 versus 58.7 years, P < .01), showed high grade (grade 3A or 3B) morphology (91% versus 17%, P < .001), diffuse proliferation (59% vs 19%, P < .001), and lacked BCL2/IGH translocation (5% versus 92.5%, P < .001), which is the most characteristic aberration in FL, and 88% showed BCL6 gene abnormalities (translocation or amplification IntroductionFollicular lymphoma (FL) is the most prevalent form of low-grade B-cell lymphoma in adults. 1 Typically, FL cells express CD10, BCL2, and BCL6. CD10 is a marker for germinal center (GC) B cells, and thus its expression suggests that GC B cells are a normal counterpart of FL. 2 However, some reports, including our previous study, described the existence of CD10 Ϫ FL, especially in high-grade (grade 3) FL. [3][4][5][6] However, it is not clear whether CD10 negativity is just aberrant loss or whether it is meaningful, reflecting a specific differentiation stage and affecting clinical features. MUM1 (multiple myeloma oncogene 1)/IRF4 (interferon regulatory factor 4) is a lymphoid-specific member of the interferon regulatory factor family of transcription factors, 7-9 and it is a reliable marker of "late-stage GC" or "post-GC" B cells. 8 In this study, we clinicopathologically compared CD10 Ϫ MUM ϩ and "classical" CD10 ϩ MUM1 Ϫ FLs. Materials and methods Biologic materialTissue specimens were obtained from human lymph nodes filed at the Department of Pathology at Fukuoka University and Kurume University. The 147 FL patients have already been reported in our previous publication. 5 Paraffin-embedded tissues were available in almost all patients, while frozen tissues and cell suspensions were available in some patients. Histopathological diagnoses and grading were based on the new WHO classification and carried out by 4 pathologists (Y.G., K.K., M.K., and K.O.). 1 Clinical information was obtained by reviewing the tumor registry records and/or patients' medical charts. This study was approved by the Kurume University institutional review board (Kurume, Japan), and patients provided informed consent in accordance with the Declaration of Helsinki. ImmunohistochemistryParaffin sections from each sample were immunostained with monoclonal antibodies against CD10 (Novocastra, Newcastle, United Kingdom), Bcl2 (DAKO, Glostrup, Denmark), MUM1 (DAKO), CD21 (DAKO), CD138 (Novocastra), and Bcl6 (Novocastra) following the method described previously. 5 The following 2 categories were defined: negative (Ͻ 30% positively-stained tumor cells) and ...

Context-Severe sepsis is typically characterized by initial cytokine-mediated hyperinflammation. Whether this hyperinflammatory phase is followed by immunosuppression is controversial. Animal studies suggest that multiple immune defects occur in sepsis, but data from humans remain conflicting.Objectives-To determine the association of sepsis with changes in host innate and adaptive immunity and to examine potential mechanisms for putative immunosuppression.Design, Setting, and Participants-Rapid postmortem spleen and lung tissue harvest was performed at the bedsides of 40 patients who died in intensive care units (ICUs) of academic medical centers with active severe sepsis to characterize their immune status at the time of death (2009)(2010)(2011). Control spleens (n=29) were obtained from patients who were declared brain-dead or had emergent splenectomy due to trauma; control lungs (n=20) were obtained from transplant donors or from lung cancer resections.Main Outcome Measures-Cytokine secretion assays and immunophenotyping of cell surface receptor-ligand expression profiles were performed to identify potential mechanisms of immune dysfunction. Immunohistochemical staining was performed to evaluate the loss of immune effector cells.Results-The mean ages of patients with sepsis and controls were 71.7 (SD, 15.9) and 52.7 (SD, 15.0) years, respectively. The median number of ICU days for patients with sepsis was 8 (range, 1-195 days), while control patients were in ICUs for 4 or fewer days. The median duration of sepsis was 4 days (range, 1-40 days). Compared with controls, anti-CD3/anti-CD28-stimulated splenocytes from sepsis patients had significant reductions in cytokine secretion at 5 hours: tumor necrosis factor, 5361 (95% CI, 3327-7485) pg/mL vs 418 (95% CI, 98-738) pg/mL; interferon γ, 1374 (95% CI, 550-2197) pg/mL vs 37.5 (95% CI, −5 to 80) pg/mL; interleukin 6, 3691 (95% CI, 2313-5070) vs 365 (95% CI, 87-642) pg/mL; and interleukin 10, 633 (95% CI, −269 to 1534) vs 58 (95% CI, −39 to 156) pg/mL; (P<.001 for all). There were similar reductions in 5-hour lipopolysaccharide-stimulated cytokine secretion. Cytokine secretion in sepsis patients was generally less than 10% that in controls, independent of age, duration of sepsis, corticosteroid use, and nutritional status. Although differences existed between spleen and lung, flow cytometric analysis showed increased expression of selected inhibitory receptors and ligands and expansion of suppressor cell populations in both organs. Unique differences in cellular inhibitory molecule expression existed in immune cells isolated from lungs of sepsis patients vs cancer patients and vs transplant donors. Immunohistochemical staining showed extensive depletion of splenic CD4, CD8, and HLA-DR cells and expression of ligands for inhibitory receptors on lung epithelial cells.Conclusions-Patients who die in the ICU following sepsis compared with patients who die of nonsepsis etiologies have biochemical, flow cytometric, and immunohistochemical findings consistent with immuno...

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