Functional significance of the perforin/granzyme cell death pathway.

Perforin/granzyme-induced apoptosis is the main pathway used by cytotoxic lymphocytes to eliminate virus-infected or transformed cells. Studies in gene-disrupted mice indicate that perforin is vital for cytotoxic effector function; it has an indispensable, but undefined, role in granzyme-mediated apoptosis. Despite its vital importance, the molecular and cellular functions of perforin and the basis of perforin and granzyme synergy remain poorly understood. The purpose of this review is to evaluate critically recent findings on cytotoxic granule-mediated cell death and to assess the functional significance of postulated cell-death pathways in appropriate pathophysiological contexts, including virus infection and susceptibility to experimental or spontaneous tumorigenesis.

Reactive granular histiocytosis secondary to arthroplasty prosthesis: a novel reaction pattern.

A reactive histiocytic infiltrate can be seen as an incidental finding in a lymph node biopsy from a patient with a history of joint arthroplasty. We report the case of a 74-year-old female who underwent surgical revision of a polyethylene-based right total knee prosthesis due to chronic wear. At the time of surgery, a soft tissue mass adjacent to the tibial prosthetic insert was noted and excised. Histopathologic examination revealed a sheet-like proliferation of large, histiocytoid cells within the subcutis and superficial fascia. The cells showed abundant eosinophilic, granular cytoplasm and small round bland nuclei. Immunohistochemical evaluation revealed the cells to be positive only for CD68. In addition, abundant PAS-positive cytoplasmic granules were found, and minute particles of polarizable material were noted intracellularly and scattered throughout the interstitium of the infiltrate. These findings were interpreted as consistent with a reactive, non-Langerhans cell histiocytosis secondary to the patient's polyethylene knee prosthesis. This finding appears to be a local correlate of the process previously described in regional lymph nodes as reactive granular histiocytosis. Dermatopathologists should be cognizant of this uncommon reaction pattern to avoid mistaking it for a neoplastic process.

Multicentric reticulohistiocytosis and urologic carcinomas: a possible paraneoplastic association.

Multicentric reticulohistiocytosis (MR) is a rare non-Langerhans histiocytosis that is characterized by cutaneous nodules and severe destructive arthritis. Although 25-30% of reported cases have been associated with internal malignancies, the pathophysiology of MR is unknown. Herein, we report two cases of MR that were associated with urologic neoplasms. Because the tumor suppressor gene p53 may play a role in the biology of other histiocytoses, we investigated its p53 immunoexpression in these two cases. Both cases were positive immunohistochemically, but it remains to be seen whether this finding is truly important in the pathogenesis of MR associated with underlying visceral neoplasms.

[Paraneoplastic multicentric reticulohistiocytosis]. / Histiocytose multicentrique paranéoplasique.

BACKGROUND: Multicentric histiocytosis (MH) is a rare form of histiocytosis of unknown aetiology and is associated with a malignant neoplasm in 25% of cases. Herein, we report the case of a female patient in whom HM enabled us to diagnose gastric carcinoma. OBSERVATION: A 74-year-old woman consulted for papules and nodules on the hands associated with destructive polyarthralgia of the interphalangeal joints and asthenia. Biopsy of a nodule revealed infiltration of the superficial dermis by numerous multinucleated giant cells containing eosinophilic cytoplasm; immunohistochemical analysis showed positive staining for CD68, confirming the diagnosis of MH. Additional screening tests for malignancy enabled us to diagnose gastric carcinoma. The cutaneous lesions disappeared several weeks after gastrectomy and no recurrence of HM or malignancy was seen in the ensuing 7 years. DISCUSSION: Fewer than 200 cases of HM have been reported. This non-Langerhans proliferative histiocytosis is a rare systemic disorder of unknown aetiology characterized clinically by papules and nodules associated with destructive polyarthralgia, and histologically by dermal proliferation of histiocytic multinucleated giant cells of skin, mucous membrane and synovial membrane. Routine screening for neoplasia should be performed following the discovery of HM as an association is seen in 25% of cases. However, the two diseases do not generally progress in parallel. In our case, the rapid disappearance of lesions within a few weeks of surgery suggests that HM was a true paraneoplastic syndrome.

Xanthogranulomas associated with hematologic malignancy in adulthood.

Although xanthogranulomatosis (XG), defined as multiple xanthogranulomas occurring simultaneously, was originally described in infants and children, a number of adult cases have been reported. Adult XG, which generally presents in the absence of hyperlipidemia, has many similarities to the childhood variant. Among the similarities are reports of the simultaneous development of XG and hematologic disorders. Herein we report a case of XG in a 45-year-old man with B-cell acute lymphoblastic leukemia and review the literature regarding the association of XG and hematologic disorders in adults. We propose that xanthogranulomas seen in children and adults bear many similarities, clinically and histopathologically, and share an association with hematologic malignancies.

[Multicentric reticulohistiocytosis is a rare form of paraneoplasia].

A 59-year-old woman developed a rash and severe arthralgia, which primarily affected her fingers. She displayed digital arthritis and nodules on the hands, chest, face, and oral cavity. Blood samples were normal. Skin biopsies revealed histiocytic proliferation. The surface marker profile and clinical findings were consistent with multicentric reticulohistiocytosis, which may occur as a paraneoplastic phenomenon. On workup, she was diagnosed with an otherwise asymptomatic stage IVC fallopian tube cancer. She experienced little effect of prednisolone, but her condition improved on antineoplastic treatment.

Functional redundancy of Rab27 proteins and the pathogenesis of Griscelli syndrome.

Griscelli syndrome (GS) patients and the corresponding mouse model ashen exhibit defects mainly in two types of lysosome-related organelles, melanosomes in melanocytes and lytic granules in CTLs. This disease is caused by loss-of-function mutations in RAB27A, which encodes 1 of the 60 known Rab GTPases, critical regulators of vesicular transport. Here we present evidence that Rab27a function can be compensated by a closely related protein, Rab27b. Rab27b is expressed in platelets and other tissues but not in melanocytes or CTLs. Morphological and functional tests in platelets derived from ashen mice are all within normal limits. Both Rab27a and Rab27b are found associated with the limiting membrane of platelet-dense granules and to a lesser degree with alpha-granules. Ubiquitous transgenic expression of Rab27a or Rab27b rescues ashen coat color, and melanocytes derived from transgenic mice exhibit widespread peripheral distribution of melanosomes instead of the perinuclear clumping observed in ashen melanocytes. Finally, transient expression in ashen melanocytes of Rab27a or Rab27b, but not other Rab's, restores peripheral distribution of melanosomes. Our data suggest that Rab27b is functionally redundant with Rab27a and that the pathogenesis of GS is determined by the relative expression of Rab27a and Rab27b in specialized cell types.

Upregulation of tumor necrosis factor-alpha gene by Epstein-Barr virus and activation of macrophages in Epstein-Barr virus-infected T cells in the pathogenesis of hemophagocytic syndrome.

A potentially fatal hemophagocytic syndrome has been noted in patients with malignant lymphomas, particularly in EBV-infected T cell lymphoma. Cytokines, such as interferon-gamma (IFN-gamma), TNF-alpha, and IL-1alpha, are elevated in patients' sera. To verify whether infection of T cells by EBV will upregulate specific cytokine genes and subsequently activate macrophages leading to hemophagocytic syndrome, we studied the transcripts of TNF-alpha, IFN-gamma, and IL-1alpha in EBV-infected and EBV-negative lymphoma tissues. By reverse transcription PCR analysis, transcripts of TNF-alpha were detected in 8 (57%) of 14 EBV-infected T cell lymphomas, higher than that detected in EBV-negative T cell lymphoma (one of six, 17%), EBV-positive B cell lymphoma (two of five, 40%) and EBV-negative B cell lymphomas (one of seven, 14%). Transcripts of IFN-gamma were consistently detected in T cell lymphoma and occasionally in B cell lymphoma, but were independent of EBV status. IL-1alpha expression was not detectable in any category. Consistent with these in vivo observations, in vitro EBV infection of T cell lymphoma lines caused upregulation of TNF-alpha gene, and increased secretion of TNF-alpha, but not IFN-gamma or IL-1alpha. Expression of TNF-alpha, IFN-gamma, and IL-1alpha was not changed by EBV infection of B cell lymphoma lines. To identify the specific cytokine(s) responsible for macrophage activation, culture supernatants from EBV-infected T cells were cocultured with a monocytic cell line U937 for 24 h. Enhanced phagocytosis and secretion of TNF-alpha, IFN-gamma, and IL-1alpha by U937 cells were observed, and could be inhibited to a large extent by anti-TNF-alpha (70%), less effectively by anti-IFN-gamma (31%), but almost completely by the combination of anti-TNF-alpha and anti-IFN-gamma (85%). Taken together, the in vivo and in vitro observations suggest that infection of T cells by EBV selectively upregulates the TNF-alpha expression which, in combination with IFN-gamma and probably other cytokines, can activate macrophages. This study not only highlights a probable pathogenesis for virus-associated hemophagocytic syndrome, but also suggests that anti-TNF-alpha will have therapeutic potential in the context of their fatal syndrome.

Xanthogranulomatous pancreatic abscess secondary to acute pancreatitis: two case reports.

Xanthogranuloma is a rare type of inflammation and very few cases have been reported in the pancreas. We report two cases with xanthogranulomatous pancreatic abscess that followed acute pancreatitis. In both cases, multiple pseudocysts in the pancreatic tail were infected with several species of bacteria and Candida albicans. In one case, abdominal angiography revealed a hypoperfused pancreatic tail due to prior atherosclerotic obliteration of the celiac and superior mesenteric arteries. In the other case, the splenic artery was completely occluded by a transarterial embolization performed to treat an aneurysm that appeared in the course of pancreatitis. In both cases, distal pancreatectomy was performed as inflammation of the pancreatic tail was resistant to conventional antibiotic therapy, and pathologic examination revealed xanthogranulomatous inflammation around the pancreatic tail and spleen. Although the underlying pathogenesis is unclear, the prolonged infection and/or relative hypoxia induced by hypoperfusion are likely causative factors for the xanthogranulomatous changes in these pancreatic abscesses.

Multicentric reticulohistiocytosis: a proliferation of macrophages with tropism for skin and joints, part II.

In this second part of the review of multicentric reticulohistiocytosis, the authors discuss its association with other diseases, in particular, cancer, and laboratory and therapeutic aspects of this incapacitating and disfiguring disease. Histopathologic aspects are characteristic: dense mononuclear infiltrate with typical multinucleated cells that contain periodic acid-Schiff-positive and diastasis-resistant material, conferring a "ground glass" aspect when stained with hematoxylineosin.

Macrophage activation syndrome in juvenile idiopathic arthritis.

UNLABELLED: Macrophage activation syndrome (MAS) is a rare and potentially lethal complication of chronic rheumatic diseases of childhood, in particular of systemic-onset juvenile idiopathic arthritis (s-JIA), resulting from uncontrolled activation and proliferation of T lymphocytes and macrophages. The onset, acute and dramatic, may mimic a flare of the underlying disease or a severe sepsis. Diagnosis is difficult and, until now, no specific criteria have been developed. Laboratory data show pancytopenia, coagulopathy, low ESR and low concentrations of serum albumin, and high levels of ferritin, liver enzymes and triglycerides. Activated macrophages are found in various organs, particularly in bone marrow. Most hypotheses on the mechanism underlying MAS are based on the data obtained in primary haemophagocytic lymphohistiocytosis (HLH), a genetic disease very similar to MAS. Prompt diagnosis is essential because prognosis is highly related to early treatment. The first approach was to use intravenous methylprednisolone pulse therapy; cyclosporin A was proposed in patients resistant to steroids. We describe nine patients affected by haemophagocytosis: seven patients developed MAS and two patients developed HLH. A child with s-JIA developed three episodes of MAS. After the third episode, as there was no improvement with pulses of methylprednisolone and cyclosporine, he was successfully given etanercept. CONCLUSION: Our data, together with a similar, published observation, suggest that the TNF inhibitor etanercept is potentially useful for obtaining remission in children not responding to steroids and cyclosporin A.

Review of hemophagocytic lymphohistiocytosis (HLH) in children with focus on Japanese experiences.

Hemophagocytic lymphohistiocytosis (HLH) is characterized by fever and hepatosplenomegaly associated with pancytopenia, hypertriglyceridemia and hypofibrinogenemia. Increased levels of cytokines and impaired natural killer activity are biological markers of HLH. HLH can be classified into two distinct forms, including primary HLH, also referred to as familial hemophagocytic lymphohistiocytosis (FHL), and secondary HLH. Although FHL is an autosomal recessive disorder typically occurring in infancy, it is important to clarify that the disease may also occur in older patients. It is now considered that FHL is a disorder of T-cell function; moreover, clonal proliferation of T lymphocytes is observed in a few FHL patients, and cytotoxicity of these T lymphocytes for target cells is usually impaired. In 1999, perforin gene (PRF1) mutation was identified as a cause of 20-30% of FHL (FHL2) cases. In Japan, two specific mutations of PRF1 were also detected. Furthermore, in 2003, MUNC13-4 mutations were identified in some non-FHL2 patients (FHL3). Identification of other genes responsible for remaining cases is a major concern. Hematopoietic stem cell transplantation (HSCT) has been established as the only accepted curative therapy for FHL. Thus, appropriate diagnosis and prompt treatment with HSCT are necessary for FHL patients. Genetic analysis for PRF1 and MUNC13-4 and functional assay of cytotoxic T lymphocytes are recommended to be performed in each patient. In those patients displaying impaired cytotoxic function but lacking genetic defects, samples should be employed for identification of unknown genes. In the near future, an entire pathogenesis should be clarified in order to establish appropriate therapies including immunotherapy, HSCT and gene therapy.

Proliferating multicentric reticulohistiocytosis associated with papillary serous carcinoma of the endometrium.

Multicentric reticulohistiocytosis (MRH) is a rare histocytic disease characterized by destructive arthritis in association with classic skin findings. Although MRH is not strictly a paraneoplastic disease, one quarter of cases are malignancy related. We report a case of MRH with an initial remission followed by an acute exacerbation several years later heralding the clinical presentation of endometrial carcinoma. During this flareup a skin biopsy specimen revealed a diffuse dermal infiltrate composed of histiocytes with ground-glass cytoplasm and multiple atypical mitoses. Approximately 40% of the cells stained with the proliferation marker Ki-67. Treatment of endometrial carcinoma resulted in improvement of skin and joint symptoms, and a repeat biopsy specimen no longer demonstrated mitotic figures. These findings support a reactive and proliferative cause of MRH.

Listeria monocytogenes skin infection with cerebritis and haemophagocytosis syndrome in a bone marrow transplant recipient.

In this report, we describe unusual and unreported manifestations of Listeria monocytogenes infection in a bone marrow transplant recipient, including cutaneous infection with an hamophagocytosis syndrome and cerebritis. L. monocytogenes occurred despite a broad spectrum antibiotherapy. L. monocytogenes was isolated from a skin biopsy. Outcome was favorable with amoxicillin and gentamicin therapy. L. monocytogenes infection should be suspected in patients with cerebritis despite large spectrum antibiotherapy and this report underscores the usefulness of skin biopsies in febrile immunocompromised patients.

Parvovirus B19-associated hemophagocytic syndrome.

Parvovirus B19 is a recently described pathogen, associated with an increasing spectrum of clinical manifestations. We present the first reported case, to our knowledge, of parvovirus B19-associated hemophagocytic syndrome, in which the diagnosis of parvovirus infection was documented by the presence of B19-specific IgM and IgG antibodies. Pancytopenia resolved immediately following splenectomy and the patient recovered completely.

Successful treatment of acute hepatitis A-associated hemophagocytic syndrome by intravenous immunoglobulin.

Virus-associated hemophagocytic syndrome (VAHS) is a rare complication in acute hepatitis A virus (HAV) infection. There is no standard therapy for VAHS and the clinical course is variable. Data on the use of intravenous immunoglobulin (IVIG) in the treatment of HAV-associated VAHS is limited. We report a previously healthy, 32-year-old man who presented with general malaise, fever, chills and splenomegaly. Laboratory examination showed marked elevation of aminotransferase, leukopenia and thrombocytopenia. Acute hepatitis A was documented by the presence of immunoglobulin M anti-HAV and compatible liver biopsy findings. Bone marrow examination revealed extensive hemophagocytosis. IVIG was administered after the diagnosis of HAV-associated VAHS. His symptoms and laboratory abnormalities improved, and following a smooth recovery he was discharged 1 month after admission.

Acute liver failure and severe hemophagocytosis secondary to parvovirus B19 infection.

Parvovirus infection presenting as severe hemophagocytosis is extremely rare. We report a 13-year-old girl with acute parvovirus infection who had severe hemophagocytosis resulting in severe pancytopenia and hepatic failure.

Dengue virus-associated hemophagocytic syndrome and dyserythropoiesis: a case report.

A 33-year-old man had dengue hemorrhagic fever with initial presentation of fever, leukocytosis, and thrombocytopenia. The cause of the subsequent rapid decline in red cell counts without evidence of intravascular hemolysis or massive bleeding was confirmed as hemophagocytosis and dyserythropoiesis by bone marrow study. The patient recovered with supportive care and the bone marrow pattern was normal on repeated bone marrow study. To our knowledge, this is the first reported case of dengue virus-associated hemophagocytosis and dyserythropoiesis in Taiwan. Clinicians should consider that the occurrence of hemophagocytosis and dyserythropoiesis could be due to dengue virus infection. That this dengue virus infection was confirmed by a positive serology result at the convalescent stage but not at the acute symptomatic stage underlines the need for a second dengue serology study, as dengue infection can be missed due to an initial negative serology result.