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HLA type as a predictor of mixed connective tissue disease differentiation. Ten-year clinical and immunogenetic followup of 46 patients.

OBJECTIVE: To determine any clinical or genetic markers of differentiation and outcome in a previously described cohort of 46 patients with mixed connective tissue disease (MCTD). METHODS: Patients were clinically evaluated, chart notes reviewed, and HLA subtyping and immunology profiles performed where possible. Eleven had died and 7 were lost to followup. RESULTS: MCTD had differentiated into systemic lupus erythematosus in 12 patients and into systemic sclerosis in 13. The latter was associated with HLA-DR5 (P = 0.038), and nondifferentiation was associated with HLA-DR2 or DR4 (P = 0.007). Three HLA-DR4 positive patients had MCTD that evolved into rheumatoid arthritis. Erosive and/or deforming arthritis was associated with HLA-DR1 or DR4 (P = 0.015). HLA-DR3 was associated with interstitial lung fibrosis (P = 0.044) and keratoconjunctivitis sicca (0.001 < P < 0.01). Severe Raynaud's phenomenon predicted higher mortality (0.01 < P < 0.05). CONCLUSION: We suggest that MCTD is, for most patients, an intermediate stage in a genetically determined progression to a recognized connective tissue disease. Those whose disease remains undifferentiated might be considered a distinct subset.

Adolescent↗

Systemic sclerosis in childhood: clinical and immunologic features of 153 patients in an international database.

OBJECTIVE: To determine the clinical and immunologic features of systemic sclerosis (SSc) in a large group of children and describe the clinical evolution of the disease and compare it with the adult form. METHODS: Data on 153 patients with juvenile SSc collected from 55 pediatric rheumatology centers in Europe, Asia, and South and North America were analyzed. Demographic, clinical, and immunologic characteristics of children with juvenile SSc at the onset, at diagnosis, and during the disease course were evaluated. RESULTS: Raynaud's phenomenon was the most frequent symptom, followed by skin induration in approximately 75% of patients. Musculoskeletal symptoms were present in one-third of patients, and the most frequently involved internal organs were respiratory and gastrointestinal, while involvement of renal, cerebral, and cardiovascular systems was extremely rare. Antinuclear antibodies were present in the sera of 81% of patients. Anti-topoisomerase I (Scl-70) and anticentromere antibodies were found to be positive in 34% and 7.1% of patients, respectively. Involvement of the respiratory, gastrointestinal, and cardiovascular systems was more frequent and occurred earlier in patients who died than in those who survived. Compared with the adult form, juvenile SSc appears to be less severe, with the involvement of fewer internal organs, particularly at the time of diagnosis, and has a less characterized immunologic profile. CONCLUSION: This study provides information on the largest collection of patients with juvenile SSc ever reported. Juvenile SSc appears to be less severe than in adults because children have less internal organ involvement, a less specific autoantibody profile, and a better long-term outcome.

Adolescent↗

Oncogenic Mutations and Tumor Microenvironment Alterations in Diffuse Large B-Cell Lymphoma With Bulky Disease.

BACKGROUND: Bulky disease represents a clinically aggressive subset of diffuse large B-cell lymphoma (DLBCL) associated with adverse clinical outcomes. The aim of this study was to investigate the influence of oncogenic mutations and tumor microenvironment alterations on bulky disease in DLBCL. METHODS: We analyzed a cohort of 939 patients with newly diagnosed DLBCL. Using DNA (n&#x2009;=&#x2009;934) and RNA (n&#x2009;=&#x2009;524) sequencing, we compared oncogenic mutations and tumor microenvironment (TME) alterations based on tumor diameter, with cutoff values at 5.0&#x2009;cm and 10.0&#x2009;cm. Further stratification by mutations in key genes (CD58, STAT6, EBF1) correlated with tumor diameter revealed distinct transcriptomic and immunologic profiles. Subsequent single-cell RNA sequencing, guided by these mutational signatures, resolved the cellular heterogeneity within the TME. RESULTS: Integrative analysis revealed that tumor diameter correlated with increased incidence of mutations in CD58, STAT6, and EBF1; adverse genetic subtypes such as EZB-like MYC+ and TP53Mut; activation of oncogenic pathways (JAK/STAT, BCR, PI3K, and MYC); and an immunosuppressive tumor microenvironment. Notably, immune checkpoint molecules varied across the bulky stages, with CTLA-4, TIGIT, ICOS, and CD28 expression inversely correlated with tumor diameter, while CD70 and 4-1BBL expression positively correlated. Single-cell RNA sequencing further revealed mutation-specific tumor microenvironment insights. CD58-mutated tumor exhibited a profoundly immune-deserted microenvironment dominated by malignant B cells with minimal immune infiltration, whereas STAT6-mutated tumor was associated with increased fibroblasts and CD4&#x2009;+&#x2009;T cells, particularly regulatory T cells (Treg) and Th1-like cells; EBF1-mutated tumor was characterized by increased proportions of malignant B cells. CONCLUSIONS: Collectively, our findings highlight the biological complexity of bulky disease, identifying candidate molecular targets and providing a biological framework for future therapeutic hypothesis generation in this clinically aggressive subset of DLBCL.

Humans↗

The olfactory nerve contains two populations of glia, identified both in vivo and in vitro.

The peripheral olfactory nervous system exhibits, uniquely, neuronal cell body replacement and reestablishment of central connections in adult mammals. The role of the olfactory nerve glia in these phenomena is unknown, but information might be provided by in vitro systems. This paper reports on the characterization of olfactory nerve glia in dissociated cell cultures of newborn rat nasal mucosal tissues. The predominant type of glial cell resembled Schwann cells and immunostained for the S-100 protein, found in all glial cell types; glial fibrillary acidic protein (GFAP), found in astrocytes and nonmyelinating Schwann cells; and showed binding of 217C, a monoclonal Schwann-cell marker that binds to the low-affinity NGF receptor in glioma cells. They were negative for A2B5. The Schwann-cell-like olfactory glia changed morphology upon culturing in serum-free medium, with further shape changes after plating on laminin. Plating on laminin increased cell numbers. A second population, found only after GFAP-immunostaining, was astrocyte-like in morphology and represented approximately 10 percent of all glial cells. These were S-100-, A2B5-, and 217C-negative, a unique glial cell immunological profile. At low dilutions of anti-GFAP (1/10,000), or with weak fluorescent secondary antibodies, astrocyte-like glia were immunostained but Schwann-cell-like glia were not detectable. Astrocyte-like glia were not an artifact of the dissection, since they were detectable in tissue sections of newborn-rat olfactory nerves immunostained with a low dilution of anti-GFAP. The presence of two types of glial cells in culture suggests similarities between olfactory glia and enteric glia.

Animals↗

Epstein-Barr virus related lymphoepithelioma-like carcinoma of lung.

A malignant neoplasm localized to the lung is reported in a rather unusual host: a 40-year-old female, nonsmoker, of South-East Asiatic origin. The histology was of nasopharyngeal-like carcinoma character and ultrastructural examination confirmed a diagnosis of nonkeratinizing, poorly differentiated squamous cell carcinoma. The clinicopathologic findings were more suggestive of a primary pulmonary origin than the manifestation of an occult nasopharyngeal primary. The immunological profile was highly suggestive of an Epstein-Barr virus (EBV) associated epithelial neoplasia. This case might widen the spectrum of EBV-associated neoplasia, by inclusion of lower respiratory tract as a target organ.

Adult↗

Clinical features and pathophysiological basis of sensory neuronopathies (ganglionopathies).

Sensory ganglionopathies have a frequent association with neoplastic disorders (paraneoplastic subacute sensory neuronopathy, or SSN) or dysimmune disorders (Sjögren's syndrome, SS; Miller Fisher syndrome; and Bickerstaff's brainstem encephalitis, BBE), with drugs, such as cisplatin or pyridoxine, and with inherited disorders with degeneration of dorsal root ganglion cells. Unsteady gait and pseudoathetoid movements of the hand are the distinctive signs encountered in these disorders. The chronic disorders are characterized by non-length-dependent abnormalities of sensory nerve action potentials (SNAPs) and differ from other sensory neuropathies in showing a global, rather than distal, decrease in SNAP amplitudes. This review focuses on recent advances in defining the mechanisms involved in sensory ganglionopathies. Specific topics include a summary of their clinical features, pathological findings, and immunopathology. In SSN, early diagnosis by the detection of anti-Hu antibodies and early treatment of the cancer gives the best chance of stabilizing the disorder. In SS sensory ganglionitis, response to treatment has been disappointing, but immunomodulating treatments are emerging. The immunological profile common to BBE and Fisher syndrome supports a common pathogenesis. In toxic sensory neuronopathy, no treatment is available. The differential diagnosis involves separating sensory ganglionopathies from other ataxic polyneuropathies, such as infectious neuropathies, sensory neuropathies with various autoantibodies, and the neuropathies seen in celiac disease.

Animals↗

T-cell lymphomas in adults: a clinicopathological study of eighteen cases.

Eighteen cases of adult T-cell lymphoma have been studied with respect to clinical presentation, response to treatment, histology, enzyme histochemistry, immunocytochemistry, and gene rearrangement. Seven cases (39 per cent) presented at extra-nodal sites, and the age range was from 18 to 79. Treatment was with combination chemotherapy in most cases, and 11 of the 18 patients died within the three year follow-up period. The lymphomas were classified morphologically into six types; T-lymphoblastic lymphoma (TLL), angioimmunoblastic lymphadenopathy (AIL)-like T-cell lymphoma, T-zone lymphoma, pleomorphic mixed medium and large cell T-cell lymphoma (PMMLC), pleomorphic large cell T-cell lymphoma (PLC), and monomorphic large cell T-cell lymphoma (MLC). Enzyme histochemistry was found to be of limited value in the identification of T-cell lymphomas. Immunocytochemistry showed a degree of correlation between the immunological profile and morphology, with cases in the PLC and MLC groups showing limited expression of T-cell antigens. Re-arrangement of the beta chain of the T-cell receptor gene was detected in 12 of the 14 cases studied, and all showed germ-line immunoglobulin genes. The study emphasizes the varied morphological and clinical appearances of adult T-cell lymphoma.

Adolescent↗

Effects of therapy with interferon-alpha on peripheral blood lymphocyte subsets and NK activity in patients with chronic hepatitis C.

Longitudinal changes in lymphocyte subpopulations, including total and activated T cells, B cells, and NK cells as well as NK activity and 2',5'-oligoadenylate synthetase (2'5' AS) levels were determined in peripheral blood before, during, and after therapy with human recombinant interferon-alpha (HurIFN-alpha) in 39 patients with serologically and biopsy-confirmed chronic hepatitis C. Immunologic data obtained at baseline and during IFN-alpha administration were correlated with the clinical response to IFN-alpha therapy defined as a normalization of the serum alanine aminotransferase level. There were 23 responders (R) and 13 nonresponders (NR) to IFN-alpha and 3 patients were not evaluable. Prior to the use of IFN-alpha, the patients tended to have higher numbers of activated (DR+) T and NK cells but a lower number of CD3+CD25+ T cells than normal controls. During IFN-alpha therapy, highly significant induction of 2'5'AS was observed. The numbers of circulating WBC, total lymphocytes, and T and B cells were reduced during IFN-alpha therapy. In contrast, both the absolute number and percentage of activated CD3+CD25+ and CD4+DR+ T cells increased in response to the IFN-alpha therapy. The percentage of activated CD56+DR+ NK cells was also significantly elevated over the pretreatment baseline. IFN-alpha therapy had no effect on NK activity in peripheral blood mononuclear cells. No differences in the immunologic profile of R vs NR were noted, except that the number of IL2R+ T cells was increased transiently early during IFN-alpha therapy but only in the NR group. It was not possible to reliably discriminate between R vs NR to IFN-alpha therapy on the basis of longitudinal changes in the phenotype or function of immune effector cells.

2',5'-Oligoadenylate Synthetase↗

Metastatic potential of metastases, tumor cell heterogeneity, and therapeutic implications.

The metastasizing capacity of spontaneous metastases of several murine tumors of different histology, origin, and disseminative pattern was investigated to test the hypothesis that metastases originate from various subpopulations within the primary tumor. Overall, tumor cells from individual metastases did not show greater metastasizing capacity than the cells of the original tumor, although a degree of heterogeneity was seen. Differences in the immunologic profile among metastases of the same tumor were also observed. The possible therapeutic implications of these findings are discussed.

Animals↗

Solitary fibrous tumour (myofibroblastoma) of the breast.

Three new cases of the spindle cell tumour of the breast, usually termed myofibroblastoma, are reported. The histology and the immunological profile (expression of vimentin, CD34 antigen and of muscular markers) appear similar to those of solitary fibrous tumours recently described in various sites. It is proposed to include these mammary lesions into the group of solitary fibrous tumours and to regard breast as an additional site of origin.

Aged↗

Immune status of Greek patients with beta-thalassemia major negative for anti-HIV.

Patients with thalassemia who receive multiple blood transfusions are at risk for the acquired immunodeficiency syndrome. Peripheral blood lymphocyte subpopulations were studied in 22 multitransfused thalassemic patients; 10 patients were without splenectomy and 12 were studied after splenectomy. Both groups were negative for anti-HIV. Four additional patients who were found positive for anti-HIV and ten healthy controls were also included in this study. Patients without splenectomy compared to controls and to patients after splenectomy showed a significant decrease of both percentage (p less than 0.001) and absolute numbers (p less than 0.001) of Leu-7+ cells without significant abnormalities of T4/T8 ratio (1.56 +/- 0.4). Patients after splenectomy compared to controls and to patients without splenectomy showed a significant increase of the absolute numbers of lymphocytes and lymphocytes subsets T11+, T3+, T4+, T8+ and SmIg+ cells. In the seropositive patients for HIV only a significant increase of the absolute number of T8+ cells was observed while the T4/T8 ratio was 1.24 +/- 0.73. The decrease in the percentage of Leu-7+ cells in patients without splenectomy correlated inversely to the total amount of blood transfused. In conclusion patients with thalassemia had normal T4/T8 ratio and did not show the abnormal immunologic profile that has been reported in haemophiliacs.

Adolescent↗

The effect of ketoconazole on experimental paracoccidioidomycosis in the Syrian hamster: immunological and histopathological study.

The effect of Ketoconazole (KTZ) on the hamster experimental intratesticular paracoccidioidomycosis was studied employing different treatment schedules. KTZ long course treatment beginning at an early stage of the infection was effective in preventing fungal proliferation, dissemination to lymph nodes, spleen and kidneys, and in maintaining low levels of humoral and cellular specific immune responses. KTZ short course treatment starting at an advanced stage of disease resulted in a more severe histopathological picture without significant changes in the immunological profile. The drug prolonged the life span of hamsters infected with Paracoccidioides brasiliensis, but did not prevent mortality. Toxic necrosis of the bone marrow occurred in normal animals receiving 120 mg/kg/day of KTZ but with lower doses no morphologic alterations were observed in heart, lungs, kidneys, adrenals, spleen, liver, intestine or bone marrow.

Animals↗

Indeterminate western blot patterns in a cohort of individuals at high risk for human immunodeficiency virus (HIV-1) exposure.

Our objective was to map serial patterns of Western blot reactivity over time of a cohort of initially ELISA-negative, Western blot-indeterminate individuals from a high-risk group and to determine if these individuals were at increased risk of harboring occult HIV-1 infection. A 2-year prospective study used serial ELISA, two types of Western blot, immunologic profiles, HIV-1 culture, and analysis by polymerase chain reaction. Subjects were 20 ELISA-negative, Western blot indeterminate homosexual volunteers and 20 matched seronegative controls. Results showed that 19 of 20 study subjects completed a mean of 17.0 months of clinical and laboratory follow-up. Reactivities with p24 and/or with p55 were the two most commonly observed Western blot patterns, occurring in 70% of individuals. Specific Western blot reactivity was dependent upon the particular immunoblot preparation being used and varied considerably on a longitudinal basis. No individual pattern appeared predictive of an increased likelihood of subsequent seroconversion to HIV-1 relative to controls. By all other criteria including polymerase chain reaction analysis, samples from 17 of 19 individuals remained negative for HIV-1 at each time point. Two individuals evolved from an indeterminate to a positive Western blot and, simultaneously, from a negative to a positive polymerase chain reaction analysis, during follow-up. Our conclusions were as follows. ELISA-negative, Western blot-indeterminate individuals from a high-risk group show marked variability in immunoblot findings over time, and these patterns do not appear predictive of an increased likelihood of infection.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

Hepatic lymphoid aggregates in chronic hepatitis C and mixed cryoglobulinemia.

We have examined the clinical (virological and immunological), histological and immunohistochemical features of liver lymphoid nodules in hepatitis C virus-positive (HCV+)/mixed cryoglobulinemia (type II and III) and chronic hepatitis C. The clinical features of liver disease were found to be similar in all patients. In all these groups, liver lymphoid nodules were observed to a similar extent, being more frequent in earlier phases of liver disease and less in more advanced stages. These data were confirmed by studies in serial biopsy samples taken from individual patients with type II mixed cryoglobulinemia; the loss of lymphoid nodules with progression to more advanced histological stages of disease in these patients was accompanied by a decrease of the serum levels of cryoglobulins (although not statistically significant). By immunohistochemical analysis, the liver lymphoid nodules contained predominantly B cells with a CD5+/bcl2+/Ki67- phenotype, which were always polyclonal in type III mixed cryoglobulinemia and chronic hepatitis C, and monoclonal in type II mixed cryoglobulinemia. These immunological features were consistent with an active role of the immune system in HCV-associated liver necro-inflammation. Only in type II mixed cryoglobulinemia was there a clonal restriction of B cells. The immunological profile (autoantibodies) and viral genotypes were examined in some patients, but no significant correlation with clinical and immunohistochemical findings was found; however, the prevalence of genotype 2a was significantly higher in type II mixed cryoglobulinemia than in type III and chronic hepatitis without cryoglobulinemia.

Adult↗

Soluble CD23 antigen in Kawasaki disease and other acute febrile illnesses.

Kawasaki disease (KD) is an acute febrile illness of early childhood. Although the epidemiology of KD suggests an infectious agent, the cause still remains unknown. Intense immune activation during the acute disease has been well documented. Quantitative determination of soluble CD23 in serum can serve as an index of macrophage/monocyte or B-cell activation. To further characterize the immunological profile in KD, we investigated whether soluble CD23 levels in serum increase during the acute disease. In addition, we compared soluble CD23 levels in 33 patients with acute KD with levels in ten patients each with measles, rubella, infectious mononucleosis, and scarlet fever to determine if marked elevations in soluble CD23 were unique to acute KD. Patients with KD, rubella and infectious mononucleosis, but not patients with measles or scarlet fever, had increased soluble CD23 levels in serum during the acute stage, as compared to age-matched control subjects (P < 0.01). These data suggest infection with Epstein-Barr virus and rubella and acute KD are all characterized by B-cell and macrophage/monocyte activation.

Acute Disease↗

Value of isotypic characterization of antibodies to Echinococcus granulosus by enzyme-linked immuno-filtration assay.

In order to establish prognostic criteria for patients with hydatid cysts and to identify functional antigenic components of Echinococcus granulosus 87 sera from 36 patients were studied by enzyme-linked immuno-filtration assay (ELIFA) to characterize the four main classes of specific immunoglobulins and to determine compared immunological profiles (CIP) between samples or subjects. This method uses filtration with labelled antibodies to reveal precipitating systems preformed by immuno-electro-diffusion on cellulose acetate strips. IgG antibodies were demonstrated in the arc 5 and in 11 others bands. Specific IgA, IgE and IgM to Echinococcus granulosus was found in 19%, 53% and 69% respectively of patients with hydatids. The presence of IgM and/or IgE antibodies one year after treatment always correlated with disease. Specific IgA was detected more often in patients with pulmonary cysts. Pre- and post-operative monitoring by CIP-ELIFA proved simple and rapid to perform and of decided prognostic value. Two antigens, corresponding to arc 5 and arc X, were frequently associated with the poly-isotypic immune response.

Animals↗

An analysis of the organization and evolution of type 4 fimbrial (MePhe) subunit proteins.

We have analyzed and compared the amino acid sequences of the type 4 fimbrial subunits from Pseudomonas aeruginosa. Moraxella bovis, M. nonliquefaciens, Bacteroides nodosus, Neisseria gonorrhoeae, and N. meningitidis. We propose a consensus sequence for the highly conserved amino-terminal regions of these proteins. In the variable regions, a domain corresponding to an epitope common to N. gonorrhoeae and N. meningitidis fimbriae is conserved, both in sequence and in environment, in fimbrial subunits from B. nodosus. The subunits from M. bovis and P. aeruginosa do not show any homologies to this sequence. In all of the subunits, the carboxy-terminal half of the molecule consists of a series of fairly hydrophobic domains. The last three domains, two of which include the cysteines of the disulfide bridge in N. gonorrhoeae, P. aeruginosa, and M. bovis, are more or less conserved in sequence in all of the proteins including that of B. nodosus. We propose that these conserved hydrophobic regions, which have the potential to form a series of beta-sheets, form a structural framework around which more variable hydrophilic sequences determining immunological profile are arranged. The evolutionary relationships of the contemporary proteins and the distribution of type 4 fimbriae are also discussed.

Amino Acid Sequence↗

Experimental animal models resembling rheumatoid arthritis.

The experimental animal models of arthritis which in certain aspects share similarities to human rheumatoid arthritis are reviewed. Various methods have been applied to induce in animals experimental models of arthritis which would provide important insights into the aetiopathogenetic mechanisms of human RA. Immunological methods and infectious agents induced the most interesting models. The histology of the synovial tissue, regardless of the inducing mechanisms, is similar to the lesions of RA. Yet, none of these experimental models of arthritis reflects all the articular and systemic features, the immunological profile and the genetic factors which characterize the human disease. The animal models of arthritis reported here and the development of new ones may ultimately offer the information necessary for the understanding of the mechanisms involved in the aetiopathogenesis of human rheumatoid disease.

Animals↗