Obstructive Lymphangitis Precedes Colitis in Murine Norovirus-Infected Stat1-Deficient Mice.

Murine norovirus (MNV) is an RNA virus that can prove lethal in mice with impaired innate immunity. We found that MNV-4 infection of Stat1-/- mice was not lethal, but produced a 100% penetrant, previously undescribed lymphatic phenotype characterized by chronic-active lymphangitis with hepatitis, splenitis, and chronic cecal and colonic inflammation. Lesion pathogenesis progressed from early ileal enteritis and regional dilated lymphatics to lymphangitis, granulomatous changes in the liver and spleen, and, ultimately, typhlocolitis. Lesion development was neither affected by antibiotics nor reproduced by infection with another enteric RNA virus, rotavirus. MNV-4 infection in Stat1-/- mice decreased expression of vascular endothelial growth factor (Vegf) receptor 3, Vegf-c, and Vegf-d and increased interferon (Ifn)-γ, tumor necrosis factor-α, and inducible nitric oxide synthase. However, anti-IFN-γ and anti-tumor necrosis factor-α antibody treatment did not attenuate the histologic lesions. Studies in Ifnαßγr-/- mice suggested that canonical signaling via interferon receptors did not cause MNV-4-induced disease. Infected Stat1-/- mice had increased STAT3 phosphorylation and expressed many STAT3-regulated genes, consistent with our findings of increased myeloid cell subsets and serum granulocyte colony-stimulating factor, which are also associated with increased STAT3 activity. In conclusion, in Stat1-/- mice, MNV-4 induces lymphatic lesions similar to those seen in Crohn disease as well as hepatitis, splenitis, and typhlocolitis. MNV-4-infected Stat1-/- mice may be a useful model to study mechanistic associations between viral infections, lymphatic dysfunction, and intestinal inflammation in a genetically susceptible host.

A TNF-p100 pathway subverts noncanonical NF-κB signaling in inflamed secondary lymphoid organs.

Lymphotoxin-beta receptor (LTßR) present on stromal cells engages the noncanonical NF-κB pathway to mediate RelB-dependent expressions of homeostatic chemokines, which direct steady-state ingress of naïve lymphocytes to secondary lymphoid organs (SLOs). In this pathway, NIK promotes partial proteolysis of p100 into p52 that induces nuclear translocation of the RelB NF-κB heterodimers. Microbial infections often deplete homeostatic chemokines; it is thought that infection-inflicted destruction of stromal cells results in the downregulation of these chemokines. Whether inflammation per se also regulates these processes remains unclear. We show that TNF accumulated upon non-infectious immunization of mice similarly downregulates the expressions of these chemokines and consequently diminishes the ingress of naïve lymphocytes in inflamed SLOs. Mechanistically, TNF inactivated NIK in LTßR-stimulated cells and induced the synthesis of Nfkb2 mRNA encoding p100; these together potently accumulated unprocessed p100, which attenuated the RelB activity as inhibitory IκBδ. Finally, a lack of p100 alleviated these TNF-mediated inhibitions in inflamed SLOs of immunized Nfkb2-/- mice. In sum, we reveal that an inhibitory TNF-p100 pathway modulates the adaptive compartment during immune responses.

Infiltrados pulmonares alveolares difusos: un reto diagnóstico para el clínico / No disponible

La presencia de infiltrados pulmonares bilaterales es un hallazgo radiológico frecuente en la práctica clínica habitual. En un varón de edad media no siempre es indicativo de infección y hay que considerar otras entidades diagnósticas (procesos no infecciosos). La sospecha de metástasis pulmonares debe incluirse dentro de estas entidades, aunque se trate de un diagnóstico clínico poco frecuente. La clínica es variable y depende del tumor primario, la edad del paciente, la situación cardiorrespiratoria del mismo y del mecanismo de diseminación tumoral. La linfangitis carcinomatosa es un patrón poco frecuente de metástasis pulmonares y el diagnóstico diferencial se realiza con procesos infecciosos (como neumonías atípicas) e inflamatorios (neumonía intersticial, neumonitis por hipersensibilidad o eosinofilias pulmonares). El paciente que se presenta debutó con clínica respiratoria e infiltrados pulmonares bilaterales y fue diagnosticado de linfangitis carcinomatosa, cuyo origen era un adenocarcinoma gástrico

The presence of bilateral pulmonary infiltrates is a frequent radiological finding in routine clinical practice. In a middle-aged man is not always indicative of infection and you need to consider other diagnostic entities (non-infectious processes). Suspected pulmonary metastases should be included in these entities, although it is a rare clinical diagnosis. The clinical course is variable and depends on the primary tumor, the patient’s age, cardiopulmonary status thereof and the mechanism of tumor dissemination . Carcinomatous lymphangitis is a rare radiographic pattern of pulmonary metastases and the differential diagnosis includes infectious processes (such as atypical pneumonia) and inflammatory diseases (interstitial pneumonia, hypersensitivity pneumonitis or pulmonary eosinophilia). We report the case of a man with respiratory symptoms and bilateral pulmonary infiltrates who was diagnosed of carcinomatous lymphangitis, whose origin was a gastric adenocarcinoma

[Intralymphatic accumulation of lymphocytes mimicking intravascular lymphomatosis].

OBJECTIVE: To study the significance and differential diagnosis of intralymphatic accumulation of lymphocytes. METHODS: The clinical and pathologic features of 4 cases of intralymphatic accumulation of lymphocytes were reviewed retrospectively. Immunohistochemical study was carried out and follow-up data were analyzed. RESULTS: The sites of involvement included tonsil (2 cases), pharynx (1 case) and appendix (1 case). The duration of disease ranged from 1 week to 3 months. Follow up of the patients (from 3 to 84 months) showed no evidence of disease recurrence. Gross examination of the tissues (except in the case of appendiceal involvement) showed polypoid changes. Histologically, the lymphatic channels were filled up with small lymphocytes and associated with fibrosis in the vicinity. Immunohistochemical study revealed a T-cell phenotype of the intralymphatic lymphoid cells. CONCLUSIONS: The accumulation of lymphocytes in lymphatic channels is associated with a benign clinical course. This phenomenon may be due to retention of lymphocytes secondary to the perilymphatic chronic inflammation and fibrosis. Although the lesion simulates intravascular lymphomatosis morphologically and shows a uniform T-cell phenotype, the lymphoid cells lack obvious cellular pleomorphism and mitotic activity. The solitary nature of the lesion, when coupled with the indolent clinical behavior, is also helpful in the differential diagnosis.

Vascular endothelial growth factor-C induces lymphangitic carcinomatosis, an extremely aggressive form of lung metastases.

The lymphatic system is an important pathway for tumor dissemination to the lymph nodes, but to which extent it contributes to the formation of distant metastases remains unknown. We report that induction of lymphangiogenesis by vascular endothelial growth factor-C (VEGF-C) at the secondary site, in the lung, facilitates expansion of already disseminated cancer cells throughout the lung tissue. By using orthotopic spontaneous metastasis models in nude mice, we show that VEGF-C expression by tumor cells altered the pattern of pulmonary metastases from nodular to diffuse and facilitated disease progression. Metastases expressing VEGF-C were tightly associated with the airways, in contrast to the control cells that were scattered in the lung parenchyma, throughout the alveolar region. VEGF-C induced lung lymphangiogenesis and promoted intralymphatic spread of metastases in the lung and formation of tumor emboli in the pulmonary arteries. This pattern of metastasis corresponds to lymphangitic carcinomatosis metastatic phenotype in human cancer patients, an extremely aggressive pattern of pulmonary metastases. In accordance, pulmonary breast cancer metastases from patients which were classified as lymphangitic carcinomatosis showed high levels of VEGF-C expression in cancer cells. These data show that VEGF-C promotes late steps of the metastatic process and identify the VEGF-C/VEGF receptor-3 pathway as the target not only for prevention of metastases, but also for treatment of established metastatic disease.