Screening tests using serum tissue transglutaminase IgA may facilitate the identification of undiagnosed celiac disease among Japanese population.

The prevalence of celiac disease (CD) among Japanese population has been unknown, whereas it has been increasingly recognized in the US and in the European countries. The aim of the present study is to identify possible cases with CD among Japanese population and clarify the relevance of screening for the disease. We conducted a serologic screening for the disease among 710 Japanese patients and 239 healthy volunteers at a local tertiary teaching hospital, using an anti-tissue transglutaminase IgA (TTG-IgA) test, and histological examination of the small intestines from the TTG-IgA positive subjects. There were no TTG-IgA positive sera among the healthy volunteers. Twenty of the patients (2.8%), including eight with malignant lymphoma, were tested positive for TTG-IgA. The histological examination of the eleven patients among those with positive TTG-IgA, seven showed villous atrophy and partial lymphocytes infiltration in the mucosa, which could be compatible to mucosal changes observed in CD. Five of them had non-Hodgkin lymphoma in the gastrointestinal tracts. Serologic tests using TTG-IgA might be relevant to screen for those with undiagnosed CD among Japanese population.

STAT3 gene mutations and their association with pure red cell aplasia in large granular lymphocyte leukemia.

Large granular lymphocyte leukemia (LGL L) has been morphologically characterized as a group of lymphoproliferative diseases that include T-cell large granular lymphocytic leukemia (T-LGL L) and chronic lymphoproliferative disorders of natural killer cells (CLPD-NK). We investigated mutations in the Src homology 2 (SH2) domain of the signal transducer and activator of transcription 3 (STAT3) gene in Asian cohorts of T-LGL L and CLPD-NK (n = 42 and 11, respectively). Two mutations, Y640F and D661Y, were identified using direct sequencing or allele-specific (AS) PCR. Y640F and D661Y mutations were found in seven and 18 patients, respectively. Two patients were positive for both mutations. Frequencies of STAT3 mutations in T-LGL L and CLPD-NK were 47.6% and 27.2%, respectively. Pure red cell aplasia (PRCA) was associated with the mutations (P = 0.005). The mutations were persistently found at stable levels in some patients after more than 5 years using AS-quantitative PCR. The results of the present study indicate that the SH2 domain of the STAT3 gene is frequently mutated in Asian T-LGL L and CLPD-NK, and that PRCA is closely correlated with the mutations.

Elevated serum granulysin and its clinical relevance in mature NK-cell neoplasms.

Mature natural killer (NK)-cell neoplasms include extranodal NK/T cell lymphoma, nasal type (ENKL), aggressive NK-cell leukemia (ANKL) and chronic lymphoproliferative disorders of NK cells (CLPD-NK). Granulysin, a cytolytic granule protein, is expressed in cytotoxic T cells and NK cells, and is found in the sera as well, and functions as a cytotoxic and proinflammatory protein. Cytolytic proteins, such as granzyme B and perforin, have been shown to play crucial pathophysiological roles in NK/T cell neoplasms and have also been utilized for diagnostic purposes. Granulysin in NK-cell proliferative disorders, however, has yet to be fully analyzed. To elucidate the clinical relevance of granulysin in mature NK-cell neoplasms, we measured serum granulysin and analyzed cytolytic molecules immunohistologically. The median concentrations of serum granulysin were 39.0, 2.85, 2.8 and 1.35 ng/ml in ANKL, ENKL, CLPD-NK and healthy subjects, respectively (P < 0.01). Serum granulysin was significantly elevated in patients with ANKL compared with the levels in ENKL (P = 0.006) and CLPD-NK (P = 0.037). Furthermore, serum granulysin was correlated with whole-blood EBV viral load in ENKL and ANKL (P = 0.005) and was significantly reduced after treatment. Different expression patterns of cytolytic granule proteins were observed among the mature NK-cell neoplasms. Granulysin is closely associated with the characteristics of NK-cell neoplasms and serum granulysin may serve as a novel biomarker for these disorders.

Peripheral T-cell lymphoma following diffuse large B-cell lymphoma associated with celiac disease.

Celiac disease is a risk factor for lymphoma. Previously, we reported a case of diffuse large B-cell lymphoma (DLBCL) associated with celiac disease in a Japanese patient. Without any signs of DLBCL recurrence, he suddenly developed gastrointestinal symptoms and subcutaneous masses after resuming a gluten-containing diet. Peripheral T-cell lymphoma (PTCL) was diagnosed. Although a complete response was seen for 8 months, he was later admitted again with pleural and pericardial effusion due to PTCL. Expression of cytotoxic molecules, CCR4 and CXCR4 were all confirmed in PTCL cells, and the patient died soon afterwards. Clinically speaking, even though no gastrointestinal symptoms were seen, a gluten-free diet should have been strongly recommended for this patient.

Close resemblance between chemokine receptor expression profiles of lymphoproliferative disease of granular lymphocytes and their normal counterparts in association with elevated serum concentrations of IP-10 and MIG.

T-cell large granular lymphocyte (T-LGL) leukemia and chronic natural killer (NK) cell lymphocytosis (CNKL) are major subtypes of lymphoproliferative disease of granular lymphocytes (LDGL). To clarify the mechanism of LGL proliferation and the relationship with the chemokine system in LDGL, we enrolled 22 T-LGL leukemia patients and 8 CNKL cases, analyzed the expression profiles of chemokine receptors, and measured the serum concentrations of the corresponding chemokines. There were no significant differences in chemokine receptor expression profiles between T-LGL leukemia patients and healthy donors. An association of CCR5 and CXCR3 expression levels on LGLs was recognized in T-LGL leukemia patients (r = 0.84; P < .001). Among the chemokines, serum IP-10 and MIG levels were significantly higher in LDGL patients than in healthy donors (P < .05, and P < .001, respectively), and MIG expression was associated with the number of circulating LGLs (r = 0.73; P < .01). The chemokine receptor phenotypes of LDGL cells are essentially similar to those of normal T-cells and NK cells. The roles of IP-10 and MIG in the pathophysiology of LDGL need further examination.

Chemokine system and tissue infiltration in aggressive NK-cell leukemia.

NK cell-type lymphoproliferative disease of granular lymphocytes can be subdivided into aggressive NK-cell leukemia (ANKL) and chronic NK-cell lymphocytosis (CNKL). Hepatosplenomegaly is observed in ANKL patients, and hepatic failure is a common cause of death. Significant numbers of ANKL cells were pathologically observed in sinusoidal and interlobular regions of the liver, and in the splenic red pulp. In our previous study, ANKL cells were simultaneously positive for CXCR1 and CCR5. So, in order to elucidate the mechanism in the systemic migration of ANKL cells, we investigated the expression of the corresponding chemokines in ANKL compared with CNKL. The serum level of IL-8, MIP-1alpha and MIP-1beta was significantly elevated in ANKL patients, and ANKL cells were highly positive for IL-8, RANTES, MIP-1alpha and MIP-1beta according to intracellular staining and RT-PCR. These chemokines were also positively stained in hepatocytes. The interaction between Fas and Fas ligand (FasL) is supposed to be one of the mechanisms for liver dysfunction in ANKL. The serum concentration of soluble FasL was significantly high in ANKL patients, and ANKL cells expressed FasL protein in the cytoplasm. These results suggest that the chemokine system plays an important role in the transmigration of FasL-expressing ANKL cells.