Autoimmune thyroid disease (AITD) pathogenesis may result from a loss of immune tolerance to thyroid antigens. Regulatory T cells (Tregs) control immune responses, prevent excessive inflammation, and ...may be dysfunctional in AITD. We investigated the role of Tregs in Hashimoto's thyroiditis (HT) and Graves' disease (GD), complicated by Down syndrome (DS). Our goal was to identify differences in CD4(+)CD25(high) Treg function or number in patients with GD and HT, compared to healthy controls (HC).
Treg number was assessed by flow cytometric analysis in samples from 20 AITD patients (seven GD, 13 HT), nine HC, and seven individuals with DS, a genetic disorder associated with multiple autoimmune disorders including AITD. Treg function was assessed by the inhibition of proliferation (radioactive thymidine incorporation into DNA) of blood-derived T effector (Teff) cells by Tregs in a coculture. Various methods of stimulation were contrasted. Cytokine levels were determined in conditioned media from the co-cultures.
No differences were found in the frequency of Tregs as a percentage of CD4(+) cells between AITD and HC. AITD Tregs were less capable of inhibiting the proliferation of Teff cells when compared to HC; however, the impairment was dependent on the type of stimulation used. DS patients without AITD exhibited normal Treg function. We observed few differences in cytokine production between HC and AITD patients.
Tregs from AITD patients are partly dysfunctional, possibly explaining their autoimmunity. Future work will elucidate the diagnostic potential and pathophysiology of Tregs in AITD.
Glomerular hypertrophy in minimal change disease predicts subsequent progression to focal glomerular sclerosis. The study sought a diagnostic clue to identify the group of pediatric patients with ...apparent minimal change disease who subsequently develop focal glomerular sclerosis (FGS). Review of all renal biopsy material at our institutions identified 42 pediatric patients who met the standard criteria for minimal change disease (MCD) on initial biopsies. Of those, 10 deteriorated clinically and on rebiopsy showed focal glomerular sclerosis (FGS). The initial renal biopsies of these 10 patients were analyzed morphometrically to determine the mean glomerular tuft area (GA). The results were compared to those of the remaining 32 patients whose subsequent benign clinical course was consistent with MCD, and to randomly selected, age-matched autopsy controls without renal disease (CONT, N = 10). The mean age was comparable among the three groups studied. Separate groups of adult (N = 12) and pediatric (N = 18) patients with initial biopsies with FGS were also studied. The initial biopsy of pediatric patients who subsequently showed FGS (rebiopsy performed on average 3.3 years later) had an average GA of 13.5 × 10-3 mm2, 76% larger than glomeruli from children with MCD (7.7 × 10-3 mm2, P < 0.0005) and 62% larger than CONT (8.4 × 10-3 mm2, P < 0.005). Patients with FGS on initial biopsy, whether adult or pediatric, also had significantly larger GA than the age-matched MCD or CONT groups. Evaluation of GA in all the 42 pediatric biopsies with initial MCD further showed that in 23 patients GA was equal to or smaller than the CONT average. Of these, one (4%) was found at the rebiopsy to have FGS. Fifteen patients had GA 1.00 to 1.75× the CONT average; five (33%) of these were found at the rebiopsy to have FGS. Finally, four had GA >1.75× the CONT average at the initial biopsy, all of whom (100%) were found to have FGS at the rebiopsy. The presence of glomerular hypertrophy in biopsies of apparent MCD, therefore, appears to be a highly specific indicator of increased risk for progression to FGS. The data are supportive of the view that the subset of MCD which develops FGS represents a distinctive entity in which pathophysiologic mechanism(s) promoting glomerular hypertrophy are imposed.
Hepatosplenic γδ T cell lymphoma (TCL) is a rare, aggressive subset of peripheral TCL that presents with hepatosplenomegaly and cytopenias. Detailed clinicopathological, ultrastructural, and ...cytogenetic analyses of these lymphomas are limited; functional characteristics of these lymphomas are unknown. We have undertaken a clinicopathological, immunophenotypic, ultrastructural, cytogenetic, and functional analysis of three hepatosplenic γδ TCLs. All patients presented with massive hepatosplenomegaly and anemia, thrombocytopenia, or severe neutropenia; terminal blastlike transformation occurred in one patient. Combination chemotherapy had no response in two patients, but induced complete remission in one. γδ T cell receptor (TCR) expression and clonal TCRδ gene rearrangements were documented in each case. Two different subsets of γδ TCL were identified based on δ chain variable region usage; two lymphomas were Vδ1+, whereas the third was negative for both Vδ1 and Vδ2. Cytogenetic analysis was performed on two lymphomas; isochromosome 7q and probable trisomy 8 was shown in one of the Vδ1+ lymphomas, whereas the Vδ1 negative lymphoma had 14p+ with t(1; 14)(q21; p13). NK cell-associated antigens (CD11c, CD16, or CD56) and cytotoxic T lymphocyte (CTL) effector proteins (perforin, granzyme B, TIA-1, and Fas ligand) were expressed by each lymphoma; dense core cytolytic granules were observed by electron microscopy in both lymphomas studied. Functional studies performed in two cases showed TCR-mediated cytolysis of P815 × 2 FcR+ cells induced by anti-CD3 in a redirected cytolysis assay in one of the CD56+, Vδ1+ lymphomas, whereas IFNγ secretion was induced by anti-CD3 in the CD56-, Vδ1 negative lymphoma. These studies show that hepatosplenic γδ TCLs have CTL differentiation, retain functional activity in vitro, and are derived from at least two yS T cell subsets.
Natural killer (NK)-like T cells are major histocompatibility complex-unrestricted cytotoxic T cells that are surface CD3-positive, express NK-cell antigens, and rearrange their T-cell receptor. Most ...neoplasms arising from this T-cell subpopulation have been a chronic lymphoproliferative disease referred to as T-large granular lymphocyte (LGL) leukemia. Only 10 NK-like T-cell lymphomas have been described in detail previously; this study presents the clinicopathologic features of six others and distinguishes these lymphomas from T-LGL leukemia. All patients presented with B-symp-toms and often had marked hepatosplenomegaly without significant peripheral lymphadenopathy. Four of the six patients were immunosuppressed. All had CD3, CD8, CD56-positive tumors, presumably of hepatosplenic (n = 3), intestinal (n = 1), pulmonary (n = 1), or nodal (n = 1) origin. Three patients had lymphomatous bone marrow infiltrates, and four had peripheral blood involvement by neoplastic large lymphocytes, some of which had a blastic appearance or resembled virocytes. Azurophilic granules, urtrastructurally corresponding to cytoplasmic dense core and/or double density granules, were seen in all cases. T-cell clonality was shown in five tumors by Southern blot analysis, and three had abnormal karyotypes. Two untreated patients died 20 days after presentation, and three patients who received combination chemotherapy died within 5 months of presentation. One patient remains in complete remission 22 months after treatment. These findings suggest NK-like T-cell lymphomas are aggressive, are clinicopathologically distinct from T-LGL leukemia, and should be in the differential diagnosis of extranodal T-cell lymphoproliferations, including those in immunosuppressed patients. Furthermore, the LGL morphology, phenotype, and tissue distribution of some NK-like T-cell lymphomas suggest they may arise from thymic-independent T cells of the hepatic sinusoids and intestinal mucosa.
Serial micropuncture analysis of single nephron function in subtotal renal ablation. We developed a series of methodology to analyze function-structure relationship at single nephron level in animal ...models of chronic renal disease. Micropuncture measurements were repeated to measure single nephron GFR (SNGFR) and glomerular capillary hydraulic pressure (PGC) in the same nephrons, and subsequently examine the morphology of these glomeruli by serial section histological analysis. Using this approach, a potential causal link between early functional pattern and late structural abnormalities was examined in glomeruli of 10 Munich-Wistar rats up to six weeks after surgical removal of 5/6 total renal mass. After two weeks all SNGFR and PGC values increased uniformly but to varying degrees within each remnant kidney. Thereafter, values for SNGFR were highly variable, many declining while others increased in the same kidney. PGC showed an initial increase with subsequent decrease by four to six weeks. Serial section histological analysis of these same glomeruli revealed that the extent of glomerular sclerosis positively correlated with the functional deterioration, that is, the degree of reduction in SNGFR (P < 0.01). However, the degree of sclerosis had no tendency to correlate with the levels of SNGFR or PGC recorded in early stage. These studies indicate that pathophysiologic mechanisms other than, or in addition to, early hyperfunction are involved in determining the extent of glomerular structural damage in this model of chronic renal failure.
The splenic marginal zone is a morphologically and perhaps immunologically distinct B-cell compartment. Lymphomas arising from cells of the splenic marginal zone are rare. Here we describe the ...morphologic, immunologic, and clinical features of 14 cases. Patient age ranged from 35 to 79 years (median, 68 years) with a male-to-female ratio of 1:1.8. The spleen was uniformly enlarged (median, 1,540 g; range, 388-3,845 g) in all patients, the neoplastic infiltrate had a nodular pattern in three cases, nodular and diffuse in seven cases, and diffuse in four cases. The neoplastic cells had small to medium-sized nuclei with round, oval, or slightly indented contours, small eosinophilic nucleoli, and a moderate amount of pale cytoplasm. Extrasplenic involvement was present in 12 patients. Lymph nodes often had a vaguely nodular pattern and preservation of sinuses; bone marrow was infiltrated focally (seven cases) or diffusely (one case). Five patients had hepatic involvement. Ultrastructurally, neoplastic cells differed from other small B cells and resembled normal marginal zone cells by having long, serpentine rough endoplasmic reticulum profiles. All lymphomas marked as B cells and light chain restriction was demonstrated in 12 cases. Bcl-2 protein expression was present in all cases. Most cases (70%) were negative for DBA.44 (CD72). Plasmacytic differentiation was present in three cases. In conclusion, splenic marginal zone lymphoma is a B-cell neoplasm with distinctive clinical, morphologic, immunologic, and ultrastructural characteristics.
Forty-nine children with skin abscesses (36 methicillin-resistant Staphylococcus aureus and 13 methicillin-susceptible S aureus ) exhibited similar disease severity. Both pathogen groups were pulse ...field type USA300, multilocus sequence type 8, and possessed Panton-Valentine leukocidin genes. Related microbial genetic architecture may account for similarities in disease severity despite differences in antibiotic susceptibility.
The ninth St Gallen (Switzerland) expert consensus meeting in January 2005 made a fundamental change in the algorithm for selection of adjuvant systemic therapy for early breast cancer. Rather than ...the earlier approach commencing with risk assessment, the Panel affirmed that the first consideration was endocrine responsiveness. Three categories were acknowledged: endocrine responsive, endocrine non-responsive and tumors of uncertain endocrine responsiveness. The three categories were further divided according to menopausal status. Only then did the Panel divide patients into low-, intermediate- and high-risk categories. It agreed that axillary lymph node involvement did not automatically define high risk. Intermediate risk included both node-negative disease (if some features of the primary tumor indicated elevated risk) and patients with one to three involved lymph nodes without additional high-risk features such as HER2/neu gene overexpression. The Panel recommended that patients be offered chemotherapy for endocrine non-responsive disease; endocrine therapy as the primary therapy for endocrine responsive disease, adding chemotherapy for some intermediate- and all high-risk groups in this category; and both chemotherapy and endocrine therapy for all patients in the uncertain endocrine response category except those in the low-risk group.
A distinctive B-cell has been recognized recently in reactive lymph nodes, especially those of toxoplasmic lymphadenitis. Previously designated as "immature sinus histiocytes" or "monocytoid" cells, ...these B-lymphocytes proliferate in subcapsular and parenchymal sinuses and the parafollicular area of nodes. The authors now report a 55-year-old male who developed a malignant lymphoma composed of cells with light microscopic, immunologic, and ultrastructural characteristics identical with these newly described B-cells. The term parafollicular B-lymphocytes (PBLs) is recommended herein to emphasize their morphologic and immunologic features. An unusual feature of this PBL lymphoma is the numerous benign-appearing hyperplastic follicles surrounded by the neoplastic infiltrate, mimicking the cytologic appearance and distribution of PBLs seen in toxoplasmic lymphadenitis. The function of these recently recognized B-cells is unknown; their anatomic relationship with hyperplastic follicular centers in reactive states and the lymphoma herein described suggests a role in follicular function.
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