Viral panniculitis in a patient with disseminated opportunistic Enterovirus infection.

Infection-induced panniculitis has been described in association with a broad range of microorganisms. Among those, viral panniculitis represents a minor category, with only a few anecdotal reports in the literature documenting viral infection in the subcutaneous fat. Herein, we report a woman in her 30s with seropositive rheumatoid arthritis on rituximab and prednisone, who presented with a 6-month history of progressive multisystem manifestations, including unintentional weight loss, fever, fatigue, myopathy, pancreatitis, and sensorineural hearing loss. She had indurated plaques on her thighs characterized by predominantly lobular panniculitis with chronic lymphohistiocytic inflammation. Molecular studies performed at the Centers for Disease Control and Prevention identified evidence of Enterovirus group with the highest identity of Coxsackievirus A9. Enterovirus RNA was also detected in the cerebrospinal fluid and muscle. Based on the findings, a diagnosis of disseminated enteroviral infection in the setting of B-cell depletion was rendered. To the best of our knowledge, this represents the first reported case of viral panniculitis with documentation of Coxsackievirus A9 in the skin. Since rituximab may be used for the treatment of autoimmune dermatological diseases, familiarity of the potential occurrence of severe enteroviral infections in the setting of immunosuppressive treatment is important for dermatopathologists.

Life-long control of cytomegalovirus (CMV) by T resident memory cells in the adipose tissue results in inflammation and hyperglycemia.

Cytomegalovirus (CMV) is a ubiquitous herpesvirus infecting most of the world's population. CMV has been rigorously investigated for its impact on lifelong immunity and potential complications arising from lifelong infection. A rigorous adaptive immune response mounts during progression of CMV infection from acute to latent states. CD8 T cells, in large part, drive this response and have very clearly been demonstrated to take up residence in the salivary gland and lungs of infected mice during latency. However, the role of tissue resident CD8 T cells as an ongoing defense mechanism against CMV has not been studied in other anatomical locations. Therefore, we sought to identify additional locations of anti-CMV T cell residency and the physiological consequences of such a response. Through RT-qPCR we found that mouse CMV (mCMV) infected the visceral adipose tissue and that this resulted in an expansion of leukocytes in situ. We further found, through flow cytometry, that adipose tissue became enriched in cytotoxic CD8 T cells that are specific for mCMV antigens from day 7 post infection through the lifespan of an infected animal (> 450 days post infection) and that carry markers of tissue residence. Furthermore, we found that inflammatory cytokines are elevated alongside the expansion of CD8 T cells. Finally, we show a correlation between the inflammatory state of adipose tissue in response to mCMV infection and the development of hyperglycemia in mice. Overall, this study identifies adipose tissue as a location of viral infection leading to a sustained and lifelong adaptive immune response mediated by CD8 T cells that correlates with hyperglycemia. These data potentially provide a mechanistic link between metabolic syndrome and chronic infection.

Involvement of adipose tissue inflammation and dysfunction in virus-induced type 1 diabetes.

The etiopathogenesis of type 1 diabetes (T1D) remains poorly understood. We used the LEW1.WR1 rat model of Kilham rat virus (KRV)-induced T1D to better understand the role of the innate immune system in the mechanism of virus-induced disease. We observed that infection with KRV results in cell influx into visceral adipose tissue soon following infection prior to insulitis and hyperglycemia. In sharp contrast, subcutaneous adipose tissue is free of cellular infiltration, whereas ß cell inflammation and diabetes are observed beginning on day 14 post infection. Immunofluorescence studies further demonstrate that KRV triggers CD68+ macrophage recruitment and the expression of KRV transcripts and proinflammatory cytokines and chemokines in visceral adipose tissue. Adipocytes from naive rats cultured in the presence of KRV express virus transcripts and upregulate cytokine and chemokine gene expression. KRV induces apoptosis in visceral adipose tissue in vivo, which is reflected by positive TUNEL staining and the expression of cleaved caspase-3. Moreover, KRV leads to an oxidative stress response and downregulates the expression of adipokines and genes associated with mediating insulin signaling. Activation of innate immunity with Poly I:C in the absence of KRV leads to CD68+ macrophage recruitment to visceral adipose tissue and a decrease in adipokine expression detected 5 days following Poly (I:C) treatment. Finally, proof-of-principle studies show that brief anti-inflammatory steroid therapy suppresses visceral adipose tissue inflammation and protects from virus-induced disease. Our studies provide evidence raising the hypothesis that visceral adipose tissue inflammation and dysfunction may be involved in early mechanisms triggering ß cell autoimmunity.

Adipokines levels in HIV infected patients: lipocalin-2 and fatty acid binding protein-4 as possible markers of HIV and antiretroviral therapy-related adipose tissue inflammation.

BACKGROUND: Metabolic and cardiovascular diseases (CVD) represent a major problem in HIV infection. The aim of this study was to evaluate the relationship of HIV infection and antiretroviral therapy (ART) with circulating levels of two adipokines (Lipocalin-2 and Fatty Acid Binding Protein-4, FABP-4), known to be associated with adipose tissue dysfunction and cardiovascular disease in the general population. METHODS: We enrolled 40 non-obese HIV-infected patients and 10 healthy controls of similar age and Body Mass Index (BMI). Body composition, metabolic syndrome, lipid profile, 10-years CVD risk score, and adipokines levels were compared between groups. ART-regimen status (naïve, non-nucleoside reverse transcriptase inhibitors - NNRTIs - and protease inhibitors - PIs) association with adipokines levels was tested with linear regression models. RESULTS: HIV patients showed a worse metabolic profile than controls. Lipocalin-2 levels were higher in HIV-infected subjects (+53%; p = 0.007), with a significant trend (p = 0.003) for higher levels among subjects taking NNRTIs. Association of lipocalin-2 with fat-mass and BMI was modulated by ART regimens, being positive among subjects treated with NNRTIs and negative among those treated with PIs ("ART-regimens-by-BMI" interaction p = 0.0009). FABP-4 levels were correlated with age, fat mass, BMI, lipid profile and CVD risk (all R ≥ 0.32, p < 0.05), but not influenced by HIV-status (+20%; p = 0.12) or ART-regimen (p = 0.4). CONCLUSIONS: Our data confirm that HIV-infection is associated with adipose tissue inflammation, as measured by Lipocalin-2 levels, and ART does not attenuate this association. While FABP-4 is a marker of worse metabolic and CVD profile independently of HIV status or ART regimen, lipocalin-2 could represent a useful marker for HIV- and ART-related adipose tissue dysfunction.

Adipose Tissue Is a Neglected Viral Reservoir and an Inflammatory Site during Chronic HIV and SIV Infection.

Two of the crucial aspects of human immunodeficiency virus (HIV) infection are (i) viral persistence in reservoirs (precluding viral eradication) and (ii) chronic inflammation (directly associated with all-cause morbidities in antiretroviral therapy (ART)-controlled HIV-infected patients). The objective of the present study was to assess the potential involvement of adipose tissue in these two aspects. Adipose tissue is composed of adipocytes and the stromal vascular fraction (SVF); the latter comprises immune cells such as CD4+ T cells and macrophages (both of which are important target cells for HIV). The inflammatory potential of adipose tissue has been extensively described in the context of obesity. During HIV infection, the inflammatory profile of adipose tissue has been revealed by the occurrence of lipodystrophies (primarily related to ART). Data on the impact of HIV on the SVF (especially in individuals not receiving ART) are scarce. We first analyzed the impact of simian immunodeficiency virus (SIV) infection on abdominal subcutaneous and visceral adipose tissues in SIVmac251 infected macaques and found that both adipocytes and adipose tissue immune cells were affected. The adipocyte density was elevated, and adipose tissue immune cells presented enhanced immune activation and/or inflammatory profiles. We detected cell-associated SIV DNA and RNA in the SVF and in sorted CD4+ T cells and macrophages from adipose tissue. We demonstrated that SVF cells (including CD4+ T cells) are infected in ART-controlled HIV-infected patients. Importantly, the production of HIV RNA was detected by in situ hybridization, and after the in vitro reactivation of sorted CD4+ T cells from adipose tissue. We thus identified adipose tissue as a crucial cofactor in both viral persistence and chronic immune activation/inflammation during HIV infection. These observations open up new therapeutic strategies for limiting the size of the viral reservoir and decreasing low-grade chronic inflammation via the modulation of adipose tissue-related pathways.

Epstein-Barr virus-infected subcutaneous panniculitis-like T-cell lymphoma associated with methotrexate treatment.

Methotrexate-associated lymphoproliferative disorder (MTX-LPD) is a lymphoid proliferation or lymphoma in patients treated with MTX. We report a case of Epstein-Barr virus (EBV)-positive subcutaneous panniculitis-like T-cell lymphoma (SPTCL) in a 60-year-old Japanese man treated with MTX for rheumatoid arthritis (RA). SPTCL is a rare cytotoxic T-cell lymphoma characterized by involvement of subcutaneous fat mimicking panniculitis. The patient, who had been on MTX therapy for RA, manifested high fever and lumbago. Physical examination showed multiple subcutaneous nodules on the trunk including axillary and inguinal regions. Biopsy of the inguinal nodule showed profuse infiltration of CD8(+) T-cell lymphoma cells in the subcutaneous adipose tissues. A diagnosis of SPTCL was made according to the diagnostic criteria of World Health Organization classification. EBV-encoded small RNA in situ hybridization revealed that the lymphoma cells contained EBV genome. The cells were positive for EBV latent membrane protein 1, but not for EBNA2. After discontinuation of MTX, the nodules regressed spontaneously. Studies have reported that most MTX-LPDs are B-cell type lymphomas and Hodgkin lymphoma. To the best of our knowledge, EBV-positive SPTCL has not been reported in patients receiving MTX. Our case emphasizes the importance of clinical and virological characterization of MTX-associated SPTCL.

Pathological features of heterologous immunity are regulated by the private specificities of the immune repertoire.

Heterologous immunity associated with cross-reactive T-cell responses is proposed to contribute to variations among individuals in the pathogenesis of human viral infections. In genetically identical mice with similar infection histories, marked variations in the magnitude and specificities of T-cell responses under conditions of heterologous immunity occur and have been linked to the private specificity of T-cell repertoires in individual immune mice. Variations in immunopathology in the form of panniculitis are observed in lymphocytic choriomeningitis virus-immune mice after vaccinia virus infection. By adoptively transferring splenocytes from individual lymphocytic choriomeningitis virus-immune donors into paired recipients, we show here that, on vaccinia virus infection, similar levels of panniculitis were generated in recipients from a single donor, but the severity of panniculitis varied among recipients receiving cells from different donors. This indicates that virus-induced immunopathology under conditions of heterologous immunity is a function of the private specificity of the immune repertoire.

A case with an indolent course of subcutaneous panniculitis-like T-cell lymphoma demonstrating Epstein-Barr virus positivity and simulating dermatitis artefacta.

Subcutaneous panniculitis-like T-cell lymphoma (SPTCL) is a rare form of cytotoxic T-cell lymphoma. The disease has a poor prognosis in patients with the complication of hemophagocytic syndrome, especially in those with Epstein-Barr virus (EBV) positivity. A 20-year-old woman presented with multiple, itchy, purplish nodules and excoriations on both of her upper limbs. The histopathologic, immunohistochemical staining, and clonal T-cell receptor gene rearrangement examinations of skin lesions revealed the diagnosis of SPTCL. In situ hybridization performed for EBV was positive. There were no findings suggesting systemic involvement of SPTCL, or hemophagocytic syndrome. The lesions improved with systemic corticosteroid therapy and radiotherapy, with no recurrence. We present a patient with a protracted course of SPTCL in whom EBV positivity was demonstrated. This apparent conflict may be explained by geographic and ethnic variations in EBV infection. Further studies may shed light on the real relationship between EBV-RNA and the course of SPTCL.

Subcutaneous panniculitis-like T-cell lymphoma: a clinicopathologic, immunophenotypic, and molecular study of 22 Asian cases according to WHO-EORTC classification.

Subcutaneous panniculitis-like T-cell lymphoma (SPTL) is defined as a rare cytotoxic alpha/beta T-cell lymphoma characterized by primary involvement of subcutaneous tissue mimicking panniculitis and a predominant CD3+/CD4-/CD8+ phenotype in 2005 World Health Organization-European Organization for Research and Treatment of Cancer (WHO-EORTC) classification for cutaneous lymphomas. We presented a detailed study of SPTL, describing clinicopathologic, immunophenotypic, and molecular features of 22 cases in China. Strict diagnostic criteria according to the WHO-EORTC definition were applied to the diagnosis of all SPTL cases. Besides the common features described before, unusual CD4+/CD8- and CD4-/CD8- T-cell phenotypes were noted in 2 of our cases, respectively. CD30 was negative in all cases and CD56 was focally positive in 2 cases. Mortality in cases with angioinvasion (75%) was significantly higher than that in cases without angioinvasion (14.3%). Epstein-Barr virus (EBV) infection was detected in 1 immunocompetent patient by in situ hybridization. The frequency of rearranged TCRB, TCRG, and TCRD genes detected by BIOMED-2 multiplex polymerase chain reaction tubes was 80%, 67%, and 13%, respectively, with a total clonality detection rate of 100%. Clinical follow-up was available in 18 patients, ranging from 6 to 80 months. Most patients obtained complete or partial remission after therapy including one accompanied with EBV infection; 5 patients died: 3 of disease progression, 1 of severe infection, and 1 of complications caused by diabetes and hypertension. We conclude that SPTL as a cytotoxic lymphoma derived from alpha/beta T cell has a predominant CD4-/CD8+ phenotype, but unusual CD4+/CD8- and CD4-/CD8- phenotypes do exist. Owing to its indolent clinical course and relatively high survival rate, SPTL should be differentiated from cutaneous gamma/delta T-cell lymphoma. EBV is generally absent in SPTL but can rarely be detected especially in Asian population. Angioinvasion is a poor prognostic factor in SPTL.

Inflammation of Hoffa's fat pad in the setting of HIV: magnetic resonance imaging findings in six patients.

OBJECTIVE: To describe MR imaging findings of inflammation of Hoffa's fat pad as a cause of nonspecific knee pain in the HIV-infected population. DESIGN: Retrospective review. PATIENTS: A retrospective review of 400 consecutive MR imaging studies of the knee performed at two institutions over a six-month period was conducted. Inclusion criteria included HIV infection in conjunction with diffuse high signal intensity throughout Hoffa's fat pad on fluid sensitive sequences. Medical histories and images were reviewed by two musculoskeletal radiologists. Exclusion criteria included post-surgical changes, internal derangement, and/or changes consistent with an active synovial inflammatory process. RESULTS: Seven HIV-infected subjects with non-specific knee pain were identified, six of whom met imaging inclusion criteria. Findings in Hoffa's fat pad were present in nine MR studies (bilateral in three, and unilateral in three subjects). Other findings include bilateral enlargement of Hoffa's fat pad in one subject, global increase in signal intensity of the suprapatellar fat pad on fluid sensitive sequences in three subjects and of the prefemoral fat pad in four subjects, avascular necrosis in one subject, and a diffuse pattern of patchy bone marrow edema in one subject. Subjects were diagnosed with HIV from 1993-1999, with imaging performed in 2005. Subjects were on HAART medication for an indeterminate, extended duration of time prior to imaging. CD4 levels of subjects ranged from 448-1262 cells/muL (X=727.33 cells/muL). CONCLUSIONS: While the MR imaging findings of diffuse inflammation of Hoffa's fat pad are nonspecific and unclear in etiology, an association with HIV may exist.

Posttransplant diffuse large B-cell lymphoma of "lymphomatoid granulomatosis" type.

The exact relationship between lymphomatoid granulomatosis (LyG) and posttransplant lymphoproliferative disorders (PTLDs) is not clear. Both are observed in immunodeficient patients and are Epstein-Barr virus driven. These disorders are, however, considered distinct based upon the immune response elicited; LyG is T-cell rich while PTLDs are T-cell poor. We describe a case of LyG-type diffuse large B-cell lymphoma (DLBCL) in a lung transplant recipient. The unusual features include rare occurrence of LyG in a posttransplant setting, systemic involvement by LyG variant of DLBCL in a solid organ transplant recipient, paucity of T-cells in this LyG type lymphoma, and subcutaneous panniculitic pattern in a B-cell lymphoproliferative disorder. This first report of systemic LyG variant of DLBCL in a posttransplant setting has features suggesting similarities and overlap between LyG and PTLD.

Cytophagic histiocytic panniculitis and subcutaneous panniculitis-like T-cell lymphoma: report of 7 cases.

BACKGROUND: Cytophagic histiocytic panniculitis (CHP) is a rare subtype of panniculitis that usually follows a fatal course, with a terminal hemophagocytic syndrome. Recent reports on a subset of peripheral T-cell lymphoma named subcutaneous panniculitis-like T-cell lymphoma (SPTL) raised the question about the relationship between these entities. OBSERVATIONS: We describe 7 patients in the study: 1 with fatal CHP, 4 with SPTL, and 2 with long-term CHP. The 5 patients with fatal CHP and SPTL died of complications of hemophagocytic syndrome, with a disease duration ranging from 8 to 74 months. The other 2 patients were still alive 6 and 41 years after disease onset. Immunohistochemical results proved that 2 of the SPTL cases were type alpha/beta and expressed the cytotoxic/suppressor antigen CD8, while the other 2 were type gamma/delta and were positive for the natural killer-associated antigen CD56. In these 4 cases, molecular biology studies by polymerase chain reaction detected T-cell receptor gamma gene rearrangement, indicating a clonal process. In contrast, in the 2 patients who had long-term CHP, the polymerase chain reaction results failed to disclose clonality. In the subject with fatal CHP, genotypic analysis was not performed. CONCLUSION: Our observations suggest that CHP and SPTL may span a clinicopathologic spectrum in which there is a natural disease progression from CHP to SPTL.

Subcutaneous panniculitis by Epstein-Barr virus-infected natural killer (NK) cell proliferation terminating in aggressive subcutaneous NK cell lymphoma.

We describe here a case involving a patient presenting initially with subcutaneous panniculitis, which developed after 12 years into aggressive subcutaneous natural killer (NK) cell lymphoma with peripheral blood involvement and hemophagocytosis. The surface marker of lymphoid cells in peripheral blood was CD2+3-7+8-16+56+. Skin biopsies were taken in May 1986 and June 1998. The initial biopsy revealed a diffuse proliferation of atypical lymphoid cells in the subcutaneous tissue with panniculitis, while the second biopsy revealed the presence of large lymphoid cells in the subcutaneous tissue with necrotic changes, consistent with a diagnosis of malignant lymphoma (diffuse pleomorphic type). The lymphoid cells from these two specimens were positive for CD56 and such cytotoxic molecules as T-cell intracellular antigen-1 (TIA-1), granzyme B, and, interestingly, also positive for Epstein-Barr (EB) virus by in situ hybridization. This suggests that chronic EB virus infections play an important role in the early stages of tumorigenesis and in the progression of NK cell lymphoproliferative disorders.

[Subcutaneous panniculitis-like T-cell lymphoma: expression of cytotoxic-granule-associated protein TIA-1 and its relation with Epstein-Barr virus infection].

OBJECTIVE: To study the clinicopathologic features, the expression of cytotoxic-granule-associated protein TIA-1 and Epstein-Barr virus (EBV) infection in subcutaneous panniculitis-like T-cell lymphoma (SPTCL). METHODS: Totally 17 cases of SPTCL were studied. Immunohistochemical staining was done for TIA-1, CD45RO, CD3, CD20 and CD68, and in situ hybridization for EBV encoded small nuclear RNA (EBER1/2). RESULTS: In the 17 cases of SPTCL, the ratio of male-to-female was 1:1.1 and the median age was 24 years old. The main clinical manifestations were asymptomatic plaques, nodules and masses. Histologically, the pattern of lymphoid cells infiltration was panniculitis. The infiltrated lymphoid cells were pleomorphic and their mitotic figures were few (0 - 2/hpt). In the tumor tissue, there might be epithilioid granulomas, multinuclear cells, beanbag cells, small pieces of necrosis and small vessels with lymphoid cells infiltration in the vascular wall. Immunohistochemically, all the cases showed a T-cell phenotype and the expression rate of TIA-1 was 100% (16/16). By in situ hybridization, the positive rate of EBV-EBER1/2 was 29.4% (5/17). CONCLUSIONS: SPTCL has a specific histopathologic picture. It may originate from cytotoxic T lymphocytes or NK cells. Some of them may be accompanying with EBV latent infection.