Tomoyasu Tachibana

T helper 2 and regulatory T-cell cytokine production by mast cells: a key factor in the pathogenesis of IgG4-related disease

IgG4-related disease is a systemic disorder with unique clinicopathological features and uncertain etiological features and is frequently related to allergic disease. T helper 2 and regulatory T-cell cytokines have been reported to be upregulated in the affected tissues; thus, the production of these cytokines by T helper 2 and regulatory T cells has been suggested as an important factor in the pathogenesis of IgG4-related disease. However, it is not yet clear which cells produce these cytokines in IgG4-related disease, and some aspects of the disorder cannot be completely explained by T-cell-related processes. To address this, we analyzed paraffin-embedded sections of tissues from nine cases of IgG4-related submandibular gland disease, five cases of submandibular sialolithiasis, and six cases of normal submandibular gland in order to identify potential key players in the pathogenesis of IgG4-related disease. Real-time polymerase chain reaction analysis confirmed the significant upregulation of interleukin (IL)4, IL10, and transforming growth factor beta 1 (TGFβ1) in IgG4-related disease. Interestingly, immunohistochemical studies indicated the presence of mast cells expressing these cytokines in diseased tissues. In addition, dual immunofluorescence assays identified cells that were double-positive for each cytokine and for KIT, which is expressed by mast cells. In contrast, the distribution of T cells did not correlate with cytokine distribution in affected tissues. We also found that the mast cells were strongly positive for IgE. This observation supports the hypothesis that mast cells are involved in IgG4-related disease, as mast cells are known to be closely related to allergic reactions and are activated in the presence of elevated non-specific IgE levels. In conclusion, our results indicate that mast cells produce T helper 2 and regulatory T-cell cytokines in tissues affected by IgG4-related disease and possibly have an important role in disease pathogenesis.

Interleukin 13-positive mast cells are increased in immunoglobulin G4-related sialadenitis

Interleukin (IL)-13 is a T helper 2 (Th2) cytokine that plays important roles in the pathogenesis of asthma. IL-13 induces hypersensitivity of the airways, increased mucous production, elevated serum immunoglobulin (Ig) E levels, and increased numbers of eosinophils. Many patients with IgG4-related disease have allergic backgrounds and show elevated serum IgE levels and an increase in the number of eosinophils. Upregulation of Th2/regulatory T (Treg) cytokines, including IL-13, has been detected in affected tissues of patients with IgG4-related disease. We previously reported that mast cells might be responsible for the production of the Th2/Treg cytokines IL-4, IL-10, and transforming growth factor (TGF)-β1 in IgG4-related disease. In this study, immunohistochemical analysis showed increased numbers of IL-13-positive mast cells in IgG4-related disease, which suggests that mast cells also produce IL-13 and contribute to elevation of serum IgE levels and eosinophil infiltration in IgG4-related disease.

A subset of ocular adnexal marginal zone lymphomas may arise in association with IgG4-related disease

We previously suggested a relationship between ocular immunoglobulin (Ig)G4-related disease (IgG4-RD) and marginal zone lymphomas (MZLs). However, the cytokine background associated with these disorders and whether it differs between ocular adnexal MZLs with (IgG4-associated MZL) and without (IgG4-negative MZL) numerous IgG4+ plasma cells are unknown. In this study, we identified the mRNA expression pattern of Th2 and regulatory T-cell (Treg) cytokines in IgG4-RD and in IgG4-associated MZL and IgG4-negative MZL using real-time polymerase chain reaction analysis. Ocular IgG4-RD and IgG4-associated MZL exhibited significantly higher expression ratios of interleukin (IL)-4/β-actin, IL-10/β-actin, IL-13/β-actin, transforming growth factor (TGF) β1/β-actin, and FOXP3/β-actin than did IgG4-negative MZL (p < 0.05). This finding further supports our prior observations that a significant subset of ocular MZLs arises in the setting of IgG4-RD. Furthermore, the presence of a different inflammatory background in IgG4-negative MZLs suggests that IgG4-associated MZLs may have a different pathogenesis.

Epstein-Barr virus-infected cells in IgG4-related lymphadenopathy with comparison with extranodal IgG4-related disease.

IgG4-related lymphadenopathy with increased numbers of Epstein-Barr virus (EBV)-infected cells has been reported but not fully described. We analyzed 31 cases of IgG4-related lymphadenopathy and 24 cases of extranodal IgG4-related diseases for their possible relationship with EBV. Other types of reactive lymph nodes (22) and angioimmunoblastic T-cell lymphoma (AITL) (10) were also studied for comparison. EBV-encoded RNA (EBER) in situ hybridization revealed EBER+ cells in 18 of 31 cases (58%) of IgG4-related lymphadenopathy. Increased EBER+ cells were found in only 4 of 22 (18.1%) non–IgG4-related reactive lymphoid hyperplasia in patients of a similar age (P=0.002) and in only 5 of 24 (21%) extranodal IgG4-related biopsies (P=0.006). Interestingly, all patients with EBER+ progressively transformed germinal center–type IgG4-related lymphadenopathy had systemic lymphadenopathy and/or extranodal involvement. AITL also is associated with EBV, and IgG4-related lymphadenopathy sometimes mimics the morphology of AITL; however, the number of IgG4+ cells in AITL was significantly less than that in IgG4-related lymphadenopathy (P<0.001). Increased numbers of regulatory T cells are seen in IgG4-related disease; however, there was not a significant difference between the EBER+ and EBER− cases. In conclusion, the presence of increased numbers of EBV-infected cells in IgG4-related lymphadenopathy, compared with other reactive lymphadenopathy or extranodal IgG4-related disease, suggests that there may be a relationship at least between nodal IgG4-related disease and EBV. It is important to avoid overdiagnosing these cases as malignant lymphomas or EBV-related lymphoproliferative disorders.

Prognostic factors and effects of early surgical drainage in patients with peritonsillar abscess.

Peritonsillar abscess is a frequently encountered otorhinolaryngological emergency, but the characteristics of patients with this disease have not been described in detail. The objective of this study was to delineate prognostic factors associated with peritonsillar abscess and the effects of early surgical drainage for the treatment of peritonsillar abscess. We conducted a retrospective analysis of the medical records of 240 consecutive patients with PTA during the period from 2007 to 2013. Univariate analysis indicated that the period between symptom onset and relief was significantly longer in patients with high levels of C-reactive protein (CRP) (>8.53 mg/dL, p = 0.0073) and without early surgical drainage of pus (p < 0.0001). Multivariate analysis identified both of these values as independently associated with longer duration of symptoms (high CRP, P < 0.0001; no early drainage, P < 0.0001). Univariate analysis indicated that the duration between symptom onset and complete recovery from the disease was significantly longer with age ≥40 years (P = 0.0004), no history of recurrent tonsillitis (P = 0.022), high CRP level (P = 0.0017), and no early surgical drainage of the abscess (P = 0.0014). Multivariate analysis identified older age (P = 0.0004), high CRP level (P = 0.0001), and no early drainage (P < 0.0001) as independently associated with longer duration between symptom onset and complete recovery. Early surgical drainage of the abscess is important for the treatment of peritonsillar abscess. Patients ≥40 years old with peritonsillar abscess and high CRP levels should be recognized as a high-risk group.

Clinicopathological analysis of methotrexate-associated lymphoproliferative disorders: Comparison of diffuse large B-cell lymphoma and classical Hodgkin lymphoma types

Patients with rheumatoid arthritis often develop methotrexate‐associated lymphoproliferative disorders (MTX‐LPD) during MTX treatment. MTX‐LPD occasionally regresses spontaneously after simply discontinuing MTX treatment. In patients without spontaneous regression, additional chemotherapy is required to avoid disease progression. However, the differences between spontaneous and non‐spontaneous regression have yet to be elucidated. To clarify the factors important for spontaneous regression, we analyzed the clinicopathological features of 51 patients with rheumatoid arthritis who developed MTX‐LPD (diffuse large B‐cell lymphoma [DLBCL]‐type [n = 34] and classical Hodgkin lymphoma [CHL]‐type [n = 17]). We examined the interval from MTX discontinuation to the administration of additional chemotherapy. The majority of DLBCL‐type MTX‐LPD patients (81%) exhibited remission with MTX discontinuation alone. In contrast, the majority of CHL‐type MTX‐LPD patients (76%) required additional chemotherapy. This difference was statistically significant (P = 0.001). However, overall survival was not significantly different between DLBCL‐type and CHL‐type (91% vs 94%, respectively; P > 0.05). Thus, the morphological differences in the pathological findings of MTX‐LPD may be a factor for spontaneous or non‐spontaneous regression after discontinuation of MTX.

Characteristic ultrasound features of mucosa-associated lymphoid tissue lymphoma of the salivary and thyroid gland

Abstract Conclusion: The characteristic ultrasound appearance of mucosa-associated lymphoid tissue (MALT) lymphoma of the head and neck provides diagnostic information regarding masses or swellings in the head and neck region. Objectives: There are only a few reports about ultrasound features of malignant lymphoma (ML) of the head and neck. We have noticed that the ultrasound appearances of cases with MALT lymphoma resembled each other even when the appearances of other images like computed tomography were absolutely different. The objective of this study was to delineate the reliability of this characteristic ultrasound appearance of MALT lymphoma of the head and neck. Methods: The ultrasound examinations of 30 patients with histopathologically proven primary ML of the head and neck (15 cases of MALT) were reviewed. The ultrasound results of each case were independently compared to the results of the histopathological examination. Results: Two ultrasound patterns were observed for MALT lymphoma. The first was characterized by a marked hypoechoic area with interspersed linear echogenic strands (linear echogenic strands pattern), and the second was characterized by multiple, relatively large, hypoechoic segments (segmental pattern). Histopathologically, these patterns could be explained on the basis of the expansion of lymphoma cells demarcated by narrow or wide fibrous bands.

Diffuse large B-cell lymphoma of the lacrimal sac arising from a patient with IgG4-related disease

Abstract A rare case of diffuse large B-cell lymphoma (DLBCL) possibly induced by IgG4-related disease is described. A 78-year-old woman was presented with a mass of the right lacrimal sac that extended to the inferior nasal meatus through the nasolacrimal duct. Pathological diagnosis was DLBCL with diffuse distribution of IgG4 + cells in the background of this lesion. The chronic inflammatory state of IgG4-related disease could have caused the development of DLBCL.

Regulatory T cells function at the early stage of tumor progression in a mouse model of tongue squamous cell carcinoma.

The objective of this study was to observe the distribution of regulatory T cells (Tregs) in the development of tongue squamous cell carcinoma (SCC) and to determine the role of Tregs in the progression of tongue SCC. A mouse model of 4-nitroquinoline-1-oxide (4NQO)-induced-tongue SCC was established. The expression of Forkhead box P3 (Foxp3), interleukin 10, transforming growth factor-β, chemokine CC motif ligands 17, 20, and CC chemokine receptor 4 was determined using real-time quantitative polymerase chain reaction. Foxp3 expression was also analyzed using immunohistochemistry. The results were compared with those of control mice and of 4NQO-treated mice treated with a cyclooxygenase-2 (COX-2) inhibitor. Well to moderately differentiated tongue SCC was induced in all of the experimental mice. The amount of Tregs of the experimental mice was over 10 times as much as control mice at the early stage of tumor progression. COX-2 inhibitor did not prevent the progression of tongue SCC and did not reduce the total amount of Tregs. Tregs function at the early stage of the development of tongue SCC, and it may be effective to suppress Tregs at the early stage of tumor progression for the treatment and/or prevention of tongue SCC.

Kikuchi-Fujimoto disease: evaluation of prognostic factors and analysis of pathologic findings

Abstract Conclusion: In Kikuchi-Fujimoto disease (KFD), a low ratio of blastic cells (<70%) in lymph node specimens and absence of atypical lymphocytes in peripheral blood are predictive of a protracted clinical course. Objectives: Since KFD is a self-limiting disorder that does not require any specific management, prognostic factors have received little attention. The present study identified clinical and pathological factors that may affect the period from onset to cure of KFD. Methods: This retrospective study investigated 43 KFD patients who underwent lymph node biopsy diagnosed by immunohistochemical staining at Okayama University Hospital and Okayama Medical Center from January 2001 to December 2013. Results: Mean total period from onset to cure was 6 months (median =9.4 months; range =1–37 months). Low ratios of blastic cell proliferation area (<70%) in lymph node specimens (p = 0.011) and absence of atypical lymphocytes in peripheral blood (p = 0.026) were associated with a relatively long duration of KFD.