Necrotizing lymphadenitis may be induced by overexpression of Toll-like receptor7 (TLR7) caused by reduced TLR9 transport in plasmacytoid dendritic cells (PDCs).

Necrotizing lymphadenitis (NEL) is a self-limited systemic disease exhibiting characteristic clinical features. The pathogenesis of the disease remains unclear, but it may be associated with viral infection. In lymph nodes affected by this disease, innumerable plasmacytoid dendritic cells produce interferon-α when triggered by certain viral stimuli. IFN-α presents antigens causing the transformation of CD8+ cells into immunoblasts and apoptosis of CD4+ cells. From the perspective of innate immunity, UNC93B1, an endoplasmic reticulum (ER)-resident protein, associates more strongly with TLR9 than TLR7. Homeostasis is maintained under normal conditions. However, in NEL, TLR 7 was observed more than TLR 9, possibly because mutant type UNC93B1 associates more tightly with TLR7. The inhibitory effects against TLR7 by TLR9 were reported to disappear. It is likely that more TLR7 than TLR9 is transported from the ER to endolysosomes. In conclusion, overexpression of TLR7, an innate immune sensor of microbial single-stranded RNA, is inferred. Consequently, NEL may be induced.

Plasmacytoid Dendritic Cells Producing Interferon-α (IFN-α) and Inducing Mx1 Play an Important Role for CD4(+) Cells and CD8(+) Cells in Necrotizing Lymphadenitis.

We confirmed the characteristic clinical features of necrotizing lymphadenitis (NEL) in 66 cases (23 male, 43 female) in Japan, which included high fever (38-40°), painful cervical lymphadenopathy (62/66, 93.9%), and leukopenia (under 4,000/mm(3)) (25/53, 47.2%), without seasonal occurrence, in a clinicopathological, immunohistochemical, electron microscopic serological study. Patient age varied from 3-55 years, and 72.7% (44/66) of patients were younger than 30 years. Histopathology of NEL was characterized by the presence of CD8(+) immunoblasts, CD123(+) cells (plasmacytoid dendritic cells; PDCs), histiocytes and macrophages phagocytizing CD4(+) apoptotic lymphocytes, but no granulocytes or bacteria. The number of PDCs and CD8(+) cells in lesions tended to increase with time, and PDCs tended to be larger and irregular in the lesions compared with the non-lesion tissue of the lymph nodes. In addition, PDCs showed no temporal morphological change in the lymph nodes. The number of CD4(+) cells in the lymph node lesions sharply decreased from the 2nd to the 4th week, and then tended to increase; however, CD4(+) cells gradually decreased with time in non-lesion tissue. PDCs may produce interferon-α (IFN-α), which induces Mx1 expression. Strong Mx1 immunoreactivity is indicative of IFN-α production. IFN-α induces transformation of CD8(+) cells into immunoblasts, as well as phagocytosis of apoptotic cells derived from CD4(+) cells by macrophages. Thus, PDCs may play an important role with immune cells, including CD8(+) and CD4(+) cells, in necrotizing lymphadenitis.

Necrotizing lymphadenitis (NEL) is a systemic disease characterized by blastic transformation of CD8+ cells and apoptosis of CD4+ cells.

This clinicopathological, immunohistochemical, electron microscopic, and serological study of 382 cases (148 male, 234 female) of necrotizing lymphadenitis (NEL) in Japan confirms NEL as a self-limited disease with characteristic clinical features: high fever (38-40 °C), painful cervical lymphadenopathy (88.3 %), and leukopenia (under 4,000/mm(3)) without seasonal occurrence. Patient age varied from 5 to 80 years, but 62.8 % was younger than 30 years. There were five recurrent cases and four familial cases. In several cases, elevated serum aminotransaminase and antinuclear antibodies were found. Early in the disease, peripheral blood CD8+ cells were more abundant than CD4+ cells, but CD8+ cells decreased gradually with clinical progression, leading to an increasing ratio of CD4+/CD8+ cells during clinical course. Morphological features of involved lymph nodes are numerous CD8+ large immunoblasts, smaller CD4+ lymphocytes, plasmacytoid dendritic cells, histiocytes, and macrophages, the latter with phagocytized CD4+ apoptotic lymphocytes. Granulocytes are generally absent. These characteristics suggest that NEL is a reactive disease characterized by diploid disrupted CD4+ cells and CD8+ cells transforming to blastic cells. The etiology of the disease remains unknown, although viral infection is suggested, and its pathogenesis might include autoimmunity. Clinical characteristics and cytological and histological findings on lymph node biopsies can improve NEL diagnosis.

Temporal differences of onset between primary skin lesions and regional lymph node lesions for tularemia in Japan: a clinicopathologic and immunohistochemical study of 19 skin cases and 54 lymph node cases.

For tularemia, a zoonosis caused by the gram-negative coccobacillus Francisella tularensis, research of the relation between skin lesions and lymph node lesions has not been reported in the literature. This report describes skin lesions and lymph node lesions and their mutual relation over time for tularemia in Japan. Around the second day after infection (DAI), a subcutaneous abscess was observed (abscess form). Hand and finger skin ulcers formed during the second to the fourth week. Subcutaneous and dermal granulomas were observed with adjacent monocytoid B lymphocytes (MBLs) (abscess-granulomatous form). From the sixth week, large granulomas with central homogeneous lesions emerged diffusely (granulomatous form). On 2-14 DAI, F. tularensis antigen in skin lesions was detected in abscesses. During 7-12 DAI, abscesses with adjacent MBLs appeared without epithelioid granuloma (abscess form) in regional lymph nodes. During the second to fifth week, granulomas appeared with necrosis (abscess-granulomatous form). After the sixth week, large granulomas with a central homogeneous lesion (granulomatous form) appeared. F. tularensis antigen in lymph node lesions was observed in the abscess on 7-92 DAI. Apparently, F. tularensis penetrates the finger skin immediately after contact with infected hares. Subsequently, the primary lesion gradually transfers from skin to regional lymph nodes. The regional lymph node lesions induced by skin lesion are designated as dermatopathic lymphadenopathy. This study revealed temporal differences of onset among the skin and lymph node lesions.

[Significance of tissue PyNPase, TS, and DPD activities in breast cancer].

We analyzed the interim results of prognostic significance of pyrimidine nucleoside phosphorylase (PyNPase), thymidylate synthase (TS), and dihydropyrimidine dehydrogenase (DPD) in 5-FU-based chemotherapy for breast cancer. In surgical specimens of tumor tissues and normal mammary gland tissues from 102 breast cancer patients, TS, PyNPase, and DPD activities were measured, and p53 and c-erbB-2 overexpression were also examined. TS, d-Thd-Pase/Urd-Pase (PyNPase), and DPD activities were significantly higher in tumor tissues than in normal tissues. There was a strong correlation between d-Thd-Pase and Urd-Pase in tumor tissues. No relationship was found between patient characteristics and any of the enzyme activities. PyNPase activities were significantly higher in the tissues having a c-erbB-2 overexpression of 75% (4+) or more than in those having less than 75%, and the tissues with a p53 of 50% (3+) or more had significantly higher TS activities than those with less than 50%. However, the other parameters showed no significant difference. The data obtained so far suggest no clear correlation between the activity of any of these enzymes and prognosis.