Presence Of Lymphocyte Aggregates Research Articles

Autophagy occurs in lymphocytes infiltrating Sj\xf6gren\u2019s syndrome minor salivary glands and correlates with histological severity of salivary gland lesions

BackgroundsThe organization of minor salivary glands (MSG) infiltrates, in patients with Sjögren’s syndrome (SS), associates with disease severity and progression. Aberrant regulation of lymphocyte autophagy is involved in autoimmunity, and in previous work, we provided the first evidence of upregulated autophagy in CD4+ T cells infiltrating SS MSG. The aim of this study was to further explore autophagy in SS infiltrating and circulating lymphocytes and to investigate its role in disease histopathological progression.MethodsAfter collection of 20 SS MSG, the presence of lymphocyte aggregates (foci) and the formation of germinal center (GC)-like structures were observed by H&E and confirmed by immunohistochemistry. The expression of autophagy-related genes, Atg5 and MAP1LC3A, was detected by RT-PCR on microdissected salivary gland tissue and control tonsils. In MSG and tonsils, autophagic lymphocytes were identified by the detection of the autophagosome protein LC3B visualized as LC3 puncta staining by immunofluorescence. Peripheral blood autophagy was assessed by flow cytometry in SS and healthy controls (HC).ResultsReal-time PCR demonstrated higher expression in the autophagy genes Atg5 and MAP1LC3A in MSG GCs as compared to both small foci (p = 0.0075, p = 0.0002) and GCs from tonsils (p = 0.0001, p = 0.0037). In MSG, LC3 puncta staining was detectable on both CD3+ and CD20+ lymphocytes; in tonsils, LC3 puncta was almost undetectable on all lymphocytes. Compared to HC (n = 20), flow cytometry did not reveal any increase of autophagy in SS circulating lymphocytes (n = 30).ConclusionsIn SS MSG, lymphocytes’ autophagy is a feature of infiltrating T and B cells and is associated with histological severity. Interestingly, in MSG aberrant regulation of autophagy is detectable in GC-like structures possibly indicating its involvement in the development and persistence of the autoimmune process within the lesions.

Interest of the Immunohistological Analysis of Architecture and Cells Distribution of the Synovial Membrane in Rheumatoid Arthritis

Introduction: Rheumatoid arthritis (RA) is an immune-mediated disease in which synovial inflammatory lesions resemble those found in secondary lymphoid organs. The histopathological characteristics of several synovial tissue specimens from RA patients were compared to the characteristics of synovial samples from patients with osteoarthritis (OA) in order to highlight histological features of RA synovium that could be associated with clinical phenotypes. Methods: Synovial tissue specimens obtained from 17 patients with RA were compared to synovial samples from 9 patients with OA. Krenn’s synovitis score and synovial microarchitecture were analysed. Immuno-histological analysis of synovium tissue was performed to observe the cells distribution in the inflammatory infiltrates, using CD3, CD20 and CD68 markers. Results: Synovitis scores were of high-grade synovitis in 76.4% of the RA tissue specimens against 55.5% in the OA samples but the median synovitis score was higher in the RA group (p=0.05). The synovial tissue architecture in the RA group was characterised by the presence of lymphocyte aggregates in 70.5% of tissue specimens and diffuse infiltration in all others. Significant differences between the RA and OA samples were also observed with respect to the distribution of macrophages in the stroma. Conclusion: This study highlights the importance of inflammatory infiltrates in the RA synovium and suggests that histopathological analysis of RA synovium can still bring data on the pathophysiological mechanisms and potential therapeutic targets in RA.

AB0132 Presence of Synovial Lymphocyte Aggregates Correlates with A More Severe Clinical Phenotype in Patients with Early Inflammatory Arthritis

BackgroundAlthough many observations have suggested that ectopic lymphoid structures within the inflamed synovium are immunologically functional and can support chronic inflammation, their clinical significance is still controversial. Moreover, most of...

Desmoplastic melanocytic nevi with lymphocytic aggregates

Desmoplastic melanocytic nevi can be difficult to distinguish from desmoplastic melanoma. The presence of lymphocytic aggregates in association with a sclerosing melanocytic proliferation is commonly regarded as a feature in support of a diagnosis of desmoplastic melanoma. However, the finding is not specific for melanoma. Herein we report six cases of sclerosing melanocytic nevi with associated lymphocytic aggregates. They occurred in five women and one man, ranging in age from 11 to 61 years. Three lesions were sclerosing Spitz nevi; one was an amelanotic sclerosing blue nevus, one an acquired intradermal sclerosing nevus, and one was a congenital compound melanocytic nevus with sclerosis of its dermal component. The lesions were interpreted as benign, i.e. melanocytic nevi, because of their histopathologic attributes (symmetric silhouette, benign cytologic features) and results from immunohistochemical studies (all lesions strongly expressed Melan-A and p16) and fluorescence in situ hybridization (FISH). Three lesions tested by FISH lacked copy number changes of 11p, 6q or 6p. None of the lesions recurred. The cases highlight that contextual information is essential for the diagnosis of desmoplastic melanoma and sclerosing nevus. The presence of lymphocytic aggregates per se does not prove that a sclerosing melanocytic proliferation is malignant.

Presence of lymphocyte aggregates in the synovium of patients with early arthritis in relationship to diagnosis and outcome: is it a constant feature over time?

ObjectivesTo evaluate the presence of lymphocyte aggregates in synovial tissue of patients with early arthritis in relationship to clinical outcome and to determine whether this is a stable feature over...

The relationship between synovial lymphocyte aggregates and the clinical response to infliximab in rheumatoid arthritis: A prospective study

Some patients with rheumatoid arthritis (RA) exhibit lymphocyte aggregates in the synovium. This study was undertaken to address whether the presence of lymphocyte aggregates before treatment could serve as a biomarker for the clinical response to tumor necrosis factor (TNF) blockade, and to confirm whether the aggregation of synovial lymphocytes is reversible after anti-TNF treatment. Synovial tissue biopsy samples were obtained from 97 patients with active RA before the initiation of infliximab treatment. Lymphocyte aggregates in the synovial tissue were counted and also graded for size. Logistic regression analysis was performed to identify whether the presence of lymphocyte aggregates could be a predictor of the clinical response at week 16. Furthermore, the effects of TNF blockade on lymphocyte aggregates were compared between patients with RA and patients with psoriatic arthritis (PsA). Fifty-seven percent of RA synovial tissue samples contained lymphocyte aggregates, and 32% of the patients had large aggregates. Aggregates were found in 67% of clinical responders compared with 38% of nonresponders. The presence of aggregates at baseline was a highly significant predictor of the clinical response to anti-TNF treatment (R(2) = 0.10, P = 0.008). Positivity for lymphocyte aggregates increased the power to predict the clinical response (R(2) = 0.29), when analyzed in a prediction model that included baseline disease activity evaluated by the Disease Activity Score in 28 joints, anti-cyclic citrullinated peptide antibody positivity, and synovial TNFalpha expression. There was a reduction in lymphocyte aggregates after anti-TNF antibody therapy in both RA and PsA. RA patients with synovial lymphocyte aggregates have, on average, a better response to infliximab treatment than those with only diffuse leukocyte infiltration. Moreover, the aggregation of synovial lymphocytes is reversible after anti-TNF antibody treatment.

Synovial lymphoid neogenesis does not define a specific clinical rheumatoid arthritis phenotype

To investigate the relationship between lymphoid neogenesis in the synovium of patients with rheumatoid arthritis (RA) and characteristics of inflammation and disease severity. Arthroscopic synovial biopsy was performed in 103 patients with active RA (Disease Activity Score 28-joint assessment >or=3.2) who had not received treatment with biologic agents. Sections were stained and assessed by digital image analysis. Lymphocyte aggregates were counted and graded for size (1-3). Synovial lymphoid neogenesis was defined as the presence of grade 2 or 3 aggregates and subclassified based on the presence of follicular dendritic cells (FDCs). Lymphoid neogenesis was present in 31% of the RA synovial tissues, whereas an additional 25% contained only grade 1 aggregates. FDCs were present in 28% of the samples with lymphoid neogenesis, corresponding to 8% of the total RA cohort. Histologically, synovia with lymphoid neogenesis showed increased infiltration by T and B lymphocytes, plasma cells, and macrophages, and increased expression of tumor necrosis factor alpha and lymphotoxin beta compared with samples without lymphoid neogenesis. Patients with lymphoid neogenesis also had higher C-reactive protein levels, erythrocyte sedimentation rates, and leukocyte and thrombocyte counts, but exhibited no increase in the severity of clinical signs and symptoms. Of importance, there was no relationship between the presence of lymphoid neogenesis and IgM rheumatoid factor or anti-citrullinated protein antibodies. The presence of lymphocyte aggregates with FDCs did not define a specific clinical phenotype compared with lymphocyte aggregates without FDCs. These findings indicate that synovial lymphoid neogenesis is associated with more severe synovial and systemic inflammation, but this is not confined to a specific clinical subset of RA.

The Changing Scenario of Hepatitis B and Hepatitis C Virus-Associated Chronic Liver Disease

Several histological features of chronic active hepatitis and cirrhosis were evaluated using paraffin sections of 175 liver biopsies collected from 1983 to 1993. These were used to identify tissue changes showing a relatively frequent association with chronic hepatitis C virus (HCV) infection. On this basis, an assessment of the temporal changes in HCV-associated and hepatitis B virus (HBV)-associated chronic liver disease was made. For the period 1992–1993, when almost all serum anti-HCV test results were available, 42 cases revealed that lymphocytic aggregate and macrovesicular fat correlated best with HCV infection. Using combinations of various grades of these two changes, all 175 biopsies were assigned to four HCV-related categories: highly probable, probable, possible and unlikely. HCV-associated chronic liver disease, as estimated from the summed figures for highly probable and probable categories, showed a steady increase from 40% in the mid-1980s to 75% in 1992–1993 (&p%lt; 0.01). Conversely, HBV infection and related chronic liver disease has declined. We conclude that the presence of lymphocytic aggregates in a liver showing chronic liver disease, particularly when it is accompanied by macrovesicular fat, is strongly suggestive of etiopathogenetic involvement of HCV. Furthermore, during the last decade, there has been a change in the pattern of the hepatitis virus-associated chronic liver disease from predominantly HBV-related to almost exclusively HCV-related.

Focal lymphocytic aggregates in chronic hepatitis C: Occurrence, immunohistochemical characterization, and relation to markers of autoimmunity

Intrahepatic lymphocytic aggregates are observed in chronic hepatitis C as well as in autoimmune chronic hepatitis. Autoantibodies and autoimmune manifestations may occur in hepatitis C. It has been suggested that the lymphocytic aggregates play a role in the liver injury of chronic hepatitis C by an immune-mediated mechanism. We studied the occurrence of intrahepatic lymphocytic aggregates and of autoantibodies in a consecutive series of 128 patients with chronic hepatitis C. For the phenotypic characterization of the lymphocytic aggregates cryostat sections and microwaved paraffin embedded sections were immunostained with monoclonal antibodies directed against T cell subsets, B cells, killer/natural killer cells, follicular dendritic cells, and macrophages. Autoantibodies were tested by immunofluorescence (antinuclear, anti-smooth muscle, antimitochondrial) and by enzyme-linked immunosorbent assay (anti-soluble liver antigen, anti-liver/kidney microsome, anti-human receptor for asialoglycoprotein). Focal lymphocytic aggregates in portal tracts were observed in 76 of 128 (59%) patients. The cellular composition of the aggregates was constant: a core of B cells mixed with many T helper/inducer lymphocytes, and an outer ring was prominently formed by T suppressor/cytotoxic lymphocytes. A germinal center was rarely identifiable. The presence of lymphocytic aggregates was inversely correlated with the degree of fibrosis. Lymphocytic aggregates appeared more frequently in chronic persistent and chronic active hepatitis in comparison with cirrhosis and in the presence of bile duct damage. No correlation was found between lymphocytic aggregates and autoantibodies or other markers of autoimmunity. The lymphocytic aggregates are frequent in chronic hepatitis C. Their cellular composition is similar to that of primary lymphoid follicles in lymph nodes. Their presence does not seem to be correlated with features of autoimmunity.

Focal lymphocytic aggregates in chronic hepatitis C: Occurrence, immunohistochemical characterization, and relation to markers of autoimmunity

Intrahepatic lymphocytic aggregates are observed in chronic hepatitis C as well as in autoimmune chronic hepatitis. Autoantibodies and autoimmune manifestations may occur in hepatitis C. It has been suggested that the lymphocytic aggregates play a role in the liver injury of chronic hepatitis C by an immune-mediated mechanism. We studied the occurrence of intrahepatic lymphocytic aggregates and of autoantibodies in a consecutive series of 128 patients with chronic hepatitis C. For the phenotypic characterization of the lymphocytic aggregates cryostat sections and microwaved paraffin embedded sections were immunostained with monoclonal antibodies directed against T cell subsets, B cells, killer/natural killer cells, follicular dendritic cells, and macrophages. Autoantibodies were tested by immunofluorescence (antinuclear, anti-smooth muscle, antimitochondrial) and by enzyme-linked immunosorbent assay (anti-soluble liver antigen, anti-liver/kidney microsome, anti-human receptor for asialoglycoprotein). Focal lymphocytic aggregates in portal tracts were observed in 76 of 128 (59%) patients. The cellular composition of the aggregates was constant: a core of B cells mixed with many T helper/inducer lymphocytes, and an outer ring was prominently formed by T suppressor/cytotoxic lymphocytes. A germinal center was rarely identifiable. The presence of lymphocytic aggregates was inversely correlated with the degree of fibrosis. Lymphocytic aggregates appeared more frequently in chronic persistent and chronic active hepatitis in comparison with cirrhosis and in the presence of bile duct damage. No correlation was found between lymphocytic aggregates and autoantibodies or other markers of autoimmunity. The lymphocytic aggregates are frequent in chronic hepatitis C. Their cellular composition is similar to that of primary lymphoid follicles in lymph nodes. Their presence does not seem to be correlated with features of autoimmunity.

Reinfection of mice with respiratory syncytial virus

A BALB/c model of respiratory syncytial virus infection has been developed in which high-titered replication occurs in lung, immunological infiltrates in lung can be detected histologically, and illness can be consistently reproduced. The immunodeterminants of RSV reinfection in this system were investigated by rechallenging mice with RSV early (less than 2 months after primary infection) and late (16 to 21 months after primary infection) and correlating illness and titer of RSV isolated from lungs and noses with RSV-specific serological responses and lung histology. After early rechallenge, RSV was cleared within 24 hours from both nose and lung. After late rechallenge, RSV was isolated at 72 hours from nose in 21/24 mice, but from lung in only 5/24 mice. Isolation of RSV from lung after rechallenge was associated with low RSV-specific antibody titers measured by ELISA and plaque-reduction neutralization. The presence of lymphocyte aggregates around the bronchovascular bundles was associated with inability to isolate RSV from lung and lack of illness. The basophilic lymphocytes were small and uniform in size with dense nuclei and a small amount of cytoplasm. These studies demonstrate that nasal and pulmonary reinfection with RSV is possible in mice after late rechallenge. The studies also indicate the potential importance of RSV-specific antibody in protecting lung from reinfection.