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ID PMID Title PublicationDate abstract
1335804 Renal potassium wasting in distal renal tubular acidosis: role of aldosterone. 1992 Aug The pathogenesis of renal potassium wasting and hypokalemia in classic renal tubular acidosis (type 1 RTA) remains uncertain. The prevailing theory is that K(+)-Na+ exchange is stimulated due to an inability of the distal tubule to establish a normal steep lumen-peritubular H+ gradient. We encountered a 42-year-old woman with type 1 RTA associated with Sjögren's syndrome, in whom renal potassium wasting and hypokalemia persisted despite sustained correction of systemic acidosis with alkali therapy and increased intake of potassium. In addition, plasma renin activity was markedly increased and the serum aldosterone level was upper-normal despite the hypokalemia. Increased intake of sodium resulted in suppression on the serum aldosterone and correction of renal potassium wasting and hypokalemia. This case shows that secondary hyperaldosteronism, possibly due to an impairment of sodium conservation in the distal tubule, may contribute to the loss of potassium from the distal tubule even after the correction of acidosis.
9158218 Sjögren's syndrome with acute renal failure caused by renal pseudolymphoma. 1996 Nov A 56-year-old man with Sjögren's syndrome was found to have acute renal failure. Immunopathologic analysis of renal biopsy specimens showed polyclonal lymphocytic interstitial infiltration. DNA analysis of the T-cell receptor and the heavy chain immunoglobulin genes showed a polyclonal pattern of gene rearrangements. Renal failure caused by this pseudolymphoma regressed dramatically with steroid therapy. This is the first reported case of proven renal pseudolymphoma that regressed with steroid therapy.
8082300 Cytotoxic effects of antibodies to proteinase 3 (C-ANCA) on human endothelial cells. 1994 Sep Autoantibodies directed against cytoplasmic antigens of neutrophils (ANCA), especially those with specificity for proteinase 3 (PR-3) and myeloperoxidase, are valuable markers for differential diagnosis and monitoring of disease activity in Wegener's granulomatosis (WG) and other vasculitides. Till now, several concepts concerning a direct role of antibodies against PR-3 in the pathogenesis of WG have been discussed. Recently we were able to show that these antibodies recognize PR-3 translocated into the membrane of human endothelial cells. The aim of this study was to investigate putative cytotoxic effects of antibodies to PR-3 on human endothelial cells. Antibodies were obtained by affinity purification of sera from patients with active WG. Purified antibodies to Ro (SS-A), La (SS-B) and RNP served as controls. Purified antibodies to PR-3 displayed a lytic activity against endothelial cells treated with tumour necrosis factor-alpha (TNF-alpha) with the help of cytokine-primed neutrophils as measured in a Cr-release assay. About 100% specific cytotoxicity occurred after 4 h and was independent of complement. Cytotoxic effects were inhibited by coincubation with unprimed neutrophils or preincubation of PR-3 antibodies with purified antigen. Antibodies to Ro (SS-A), La (SS-B) or RNP had no cytotoxic effect. In summary, PR-3 antibody-induced cytotoxicity required (i) expression of PR-3 on the surface of TNF-alpha-treated endothelial cells; and (ii) co-cultivation of cytokine-primed neutrophils. This is to the best of our knowledge the first report on direct cytotoxic effects of PR-3 antibodies on vascular endothelium. Our data give a hint at a PR-3 antibody-mediated mechanism of endothelial injury via antibody-dependent cellular cytotoxicity in WG and other ANCA-related vasculitides.
1570482 Rheumatic complaints as a presenting symptom in patients with coeliac disease. 1992 Twenty-three cases of coeliac disease were found after a small bowel biopsy had been carried out on seventy patients with various rheumatic complaints. The prevalence of coeliac disease in patients with rheumatic disorders was estimated to be 1 in 243. The majority (19) of these cases were found by screening patient sera with a reticulin antibody test. Sjögren's syndrome was the most frequent rheumatic diagnosis, with a total of six cases. Coeliac disease may occur concomitantly with various rheumatic complaints, and serological screening is advisable.
8579891 Noncalcemic actions of 1,25-dihydroxyvitamin D3 and clinical applications. 1995 Aug Vitamin D is absolutely essential for the maintenance of a healthy skeleton. Without vitamin D, children develop rickets and adults exacerbate their osteoporosis and develop osteomalacia. Casual exposure to sunlight is the major source of vitamin D for most people. During exposure to sunlight, ultraviolet B photons photolyze cutaneous stores of 7-dehydrocholesterol to previtamin D3. Previtamin D3 undergoes a thermal isomerization to form vitamin D3. Increased skin pigmentation, changes in latitude, time of day, sunscreen use, and aging can have a marked influence on the cutaneous production of vitamin D3. Once vitamin D3 is formed in the skin or ingested in the diet, it must be hydroxylated in the liver and kidney to 1,25-dihydroxyvitamin D3 [1,25(OH)2D3]. It is now recognized that a wide variety of tissues and cells, both related to calcium metabolism and unrelated to calcium metabolism, are target sites for 1,25(OH)2D3. 1,25(OH)2D3 stimulates intestinal calcium absorption and mobilizes stem cells to mobilize calcium stores from bone. Noncalcemic tissues that possess receptors for 1,25(OH)2D3 respond to the hormone in a variety of ways. Of great interest is that 1,25(OH)2D3 is a potent antiproliferative and prodifferentiation mediator. As a result, 1,25(OH)2D3 and its analogs have wide clinical application in such diverse clinical disorders as rheumatoid and psoriatic arthritis; diabetes mellitus type I; hypertension; cardiac arrhythmias; seizure disorders; cancers of the breast, prostate, and colon; some leukemias and myeloproliferative disorders; chemotherapy-induced hair loss; and skin rejuvenation as well as skin diseases like psoriasis and ichthyosis.
8091128 Sustained and distinctive patterns of gene activation in synovial fibroblasts and whole sy 1994 Sep Fibroblastoid synovial lining cells isolated from rheumatoid and other chronic inflammatory synovial tissue exhibit distinctive and sustained alterations in serial culture not commonly found in similarly cultured cells from osteoarthritic synovium. These are demonstrable using a multi-gene dot blot assay by labelling reverse transcribed fibroblast cDNA which is hybridized to plasmids containing relevant target gene inserts. Cultured synovial fibroblastoid cells from patients with chronic inflammatory synovitis expressed significantly higher levels of stromelysin, vimentin and TIMP-1 mRNA and lower levels of c-myc compared to cells isolated from osteoarthritis synovium although with considerable variation. Early fetal synovial lining cells were similar to cells from osteoarthritis synovium but vimentin expression was higher. Marked differences in patterns of gene expression between cell lines persisted through 10 serial passages over 6-8 months. In whole synovia, the average level of mRNA for stromelysin, vimentin, IL-4, IL-6, TIMP-1, cathepsin D, gelatinase, TGF alpha, c-fms and DR beta were preferentially expressed in inflammatory tissue while c-myc expression was higher in osteoarthritis synovium. Inflammatory synovium also expressed TNF alpha, IL-1 alpha, IL-1 beta, IL-2, c-sis, tissue plasminogen activator, CSF-1, and GM-CSF. This pattern resembles, in part, that found in cultured inflammatory fibroblasts but, in addition, gene products apparently reflecting the presence of activated monocytes and lymphocytes were detected. These results provide evidence that profiles of certain gene activation in cells from patients with inflammatory synovitis differ from those with non-inflammatory disease and suggest that the fibroblastoid cells are responsible for a considerable proportion of the altered phenotypic expression pattern in whole tissue. Furthermore, this modulated pattern of gene activation appears to be an intrinsic pro-inflammatory characteristic of the fibroblastoid cells initiated in response to chronic inflammation and persists for a prolonged period in the absence of other inflammatory cells.
1620812 Type II essential mixed cryoglobulinaemia: presentation, treatment and outcome in 13 patie 1992 Feb The long-term clinical course of patients with primary Type II essential mixed cryoglobulinaemia is unclear as many reports fail to separate this group from patients with Type III disease. We have reviewed 13 patients with Type II essential mixed cryoglobulinaemia who presented to the Hammersmith Hospital between 1976 and 1990. All patients had a cryoglobulin level greater than 0.1 mg/ml (range 0.27-6.50 mg/ml), and characterization of the cryoglobulin in all cases revealed the presence of a monoclonal IgM kappa component with rheumatoid factor activity together with polyclonal IgG. All patients had evidence of activation of the classical pathway of complement with greatly reduced levels of C4, while C3 levels were moderately reduced in three patients. All patients had skin disease and joint symptoms were reported by nine patients, with erosive arthritis in one. Eight patients had peripheral sensorimotor neuropathy. Renal disease was observed in 10 patients, manifesting as raised creatinine level, proteinuria or haematuria. Renal tissue was examined in eight patients: in six the appearances were those of a mesangiocapillary glomerulonephritis Type I while in the other two patients there was a mesangioproliferative glomerulonephritis, in one diffuse and in the other focal and segmental. Glomerular capillary 'hyaline thrombi' were found in six biopsies, extracapillary proliferation was found in three and evidence of vasculitis was found in all eight. Liver biopsy showed macronodular cirrhosis in one patient, while a second with recurrent episodes of jaundice showed only chronic inflammatory changes. No patient was positive for hepatitis B surface antigen; however one patient had low titre anti-hepatitis B surface antibody. Normochromic normocytic anaemia was present in nine patients. Bone marrow examination was carried out in 13 patients at presentation to our unit: 10 showed no evidence of a lymphoproliferative disorder, while three suggested the presence of a non-Hodgkin's lymphoma (some years after original presentation in all three). Unusual clinical features included one patient with retinal vasculitis and one patient with severe pulmonary haemorrhage.
8719111 Anti-actin antibodies in sera from patients with autoimmune liver diseases and patients wi 1995 Dec Smooth muscle antibodies (SMA) were initially detected in sera of patients with chronic active hepatitis (CAH). Subsequently, their presence was demonstrated in a wide variety of other diseases. SMA are a mixture of antibodies directed towards different cytoskeletal antigens. Sera with high titers of anti-actin antibodies (AAA), a subgroup of SMA, are most frequently found among patients with autoimmune chronic active hepatitis (CAH) and, to a lesser extent, among patients with primary biliary cirrhosis (PBC) and other diseases. It is therefore established that AAA are a reliable marker to autoimmune CAH. The purpose of this study was to determine the titer of AAA in sera of patients with liver, autoimmune diseases and carcinomas, using the enzyme-linked immunoabsorbent assay (ELISA) method. The results were expressed as the optical density (OD) of the examined sera divided by the OD of a sera from a healthy control (presented as percentages +/- standard deviation). Sera of 33 patients with cirrhosis, nine patients with autoimmune CAH, fifteen patients with non-autoimmune CAH, eight patients with PBC, 30 patients with Sjogren's syndrome, 60 patients with SLE, 142 patients with carcinomas of different kinds, and 34 healthy donors were examined for the presence of AAA by ELISA. Statistically significant (P < 0.003) higher titers of AAA were detected in patients with autoimmune CAH (57 +/- 23%) compared with the control group and to other groups of diseases. AAA titers in non-autoimmune CAH were not significantly higher compared to the control group. High titers of AAA were detected in 67% of the patients with autoimmune CAH, as compared with other diseases in which only up to 13% of the patients exhibited AAA positivity. CONCLUSION: existence of higher levels of AAA noted in 67% of the patients with autoimmune CAH with regard to other groups of diseases, emphasizes the value of AAA as sensitive and specific markers, capable of characterizing the patients with autoimmune chronic active hepatitis.
7768037 Autoreactivity in HIV-1 infection: the role of molecular mimicry. 1995 Jun Autoimmunity during HIV-1 infection may contribute to the immunopathogenesis of AIDS. Titers of autoantibodies to HLA molecules and other surface markers of CD4+ T cells appear to increase with the progression of disease and may correlate with lymphopenia. Other autoantibodies are directed at a number of regulatory molecules of the immune system. Genesis of autoreactivity may be related to structural homologies of HIV-1 env-products to such functional molecules involved in the control of self-tolerance. The most impressive similarities include the HLA-DR4 and DR2, the variable regions of TCR alpha-, beta-, and gamma-chain, the Fas protein, and several functional domains of IgG and IgA. Thus, HIV-1 infection may induce dysregulation leading to autoimmune response, through a number of molecular mimicry mechanisms. Pathogenicity of antibodies to T cells could also include the activation of membrane-to-nucleus signal transducers resulting in increased apoptosis. The evolution of autoimmune mechanisms during HIV-1 infection cannot exclude, however, progression to immunoproliferative malignancy, since aspects of oligoclonal immune response to HIV-1 components may occur in several autoimmune diseases which in some instances evolve to lymphoma.
7598870 Ultrastructure and three-dimensional imaging of epimyoepithelial islands in benign lymphoe 1995 Benign lymphoepithelial lesions of the salivary glands associated with Sjögren's syndrome are characterized by extensive infiltration of lymphoid cells, atrophy of acini and the presence of so-called epimyoepithelial islands. This report describes ultrastructural and three-dimensional reconstructive studies of epimyoepithelial islands performed at Tokyo Women's Medical College. Ultrastructural examination showed that these islands are composed mainly of epithelial cells containing intermediate filaments and/or tonofilament bundles, scattered lymphocytes and plasma cells. Myoepithelium-like cells containing myofilaments were sometimes found in the peripheral portion of the myoepithelial islands. Also, mitotic figures were rarely found in these islands. Three-dimensional reconstructive study revealed that the epimyoepithelial islands are not isolated cell clusters but are continuous hypertrophic duct-like structures. These results suggest that the epimyoepithelial islands are derived from proliferating duct epithelial cells, especially those of large peripheral ducts.
7554451 Effects of calorie restriction on transforming growth factor beta 1 and proinflammatory cy 1995 Sep The present study was carried out to determine whether restricting dietary calories prevents salivary gland abnormalities and modulates expression of transforming growth factor beta and proinflammatory cytokines, IL-6, and TNF alpha in major salivary glands (SG) of autoimmune lupus-prone (NZB x NZW)F1 (B/W) female mice. These mice develop focal lymphocytic interstitial and periductal round cell infiltrates in salivary glands similar to those of humans with Sjogren's syndrome. Weanling B/W mice were fed a nutritionally adequate semipurified diet either ad libitum (AL) or a calorie-restricted (CR; 40% less calories than AL) diet. The mice were sacrificed at 3.5 months (young) and 8.5 months (old) of age. Histopathologic and histomorphometric analyses as well as growth factor and cytokine protein and mRNA expression were carried out in the SG. Histomorphometric analysis of SG from young mice showed no differences between AL and CR mice, but old AL (vs old CR) had a 7.3-fold higher focus score and a 34-fold increase in percentage area inflammation. mRNA analysis revealed significantly higher levels of TGF beta 1 in SG of old CR (6.8-fold) mice. In contrast, CR reduced mRNA expression of proinflammatory cytokines (IL-6, 2.9-fold for young and 4.8-fold for old; TNF alpha, old 3.9-fold). By immunoblotting, significantly higher levels of TGF beta 1 protein was detected in old CR mice (vs old AL; 13.2-fold). IL-6 and TNF alpha proteins were undetectable in both young and old CR groups, whereas an increase in IL-6 (4.7-fold) and TNF alpha (9.3-fold) was observed in old AL mice. These results indicate that amelioration of the histological severity of disease in SG of B/W mice is paralleled and possibly mediated by increased expression of immunosuppressive TGF beta 1 and decreased expression of proinflammatory cytokines.
7601505 Antiinflammatory effects of second-generation leukotriene B4 receptor antagonist, SC-53228 1995 Apr Leukotriene B4 (LTB4) and 12(R)-hydroxyeicosatetraenoic acid [12(R)-HETE] are proinflammatory products of arachidonic acid metabolism that have been implicated as mediators in a number of inflammatory diseases. When injected intradermally into the guinea pig. LTB4 and 12(R)-HETE elicit a dose-dependent migration (chemotaxis) of neutrophils (PMNs) into the injection sites as assessed by the presence of a neutrophil marker enzyme myeloperoxidase. SC-41930 (7-[3-(4-acetyl-3-methoxy-2-propylphenoxy)propoxyl]-3,4-dihy dro-8-propyl-2H - 1-benzopyran-2-carboxylic acid), a first-generation LTB4 receptor antagonist, inhibited the chemotactic actions of LTB4 when given orally with an ED50 value of 1.7 mg/kg. The second-generation LTB4 receptor antagonist, SC-53228 [(+)-(S)-7-(3-(2-(cyclopropylmethyl)-3-methoxy-4- [(methylamino)carbonyl]phenoxy)propoxy)-3,4-dihydro-8-propyl-2H-1- benzopyran-2-propanoic acid], inhibited LTB4-induced chemotaxis when given intragastrically with an ED50 value of 0.07 mg/kg. Furthermore, SC-53228 inhibited 12(R)-HETE-induced granulocyte chemotaxis with an oral ED50 value of 5.8 mg/kg. When dosed orally over a range of 0.03-100 mg/kg, SC-53228 gave Cmax plasma concentrations of 0.015-41.1 micrograms/ml. SC-53228 inhibited LTB4-primed membrane depolarization of human neutrophils with an IC50 value of 34 nM. As a potent LTB4 receptor antagonist, SC-53228 may well have application in the medical management of disease states such as asthma, rheumatoid arthritis, inflammatory bowel disease, contact dermatitis, and psoriasis, in which LTB4 and/or 12(R)-HETE are implicated as inflammatory mediators.
7691456 Characterization of a cross-reactive idiotype on two human autoantibodies associated with 1993 Nov A human-human hybridoma was derived from a patient with primary Sjogren's Syndrome. The monoclonal antibody from this hybridoma, P36, was found to be polyreactive. P36 shared idiotypic cross-reactivity with a lupus-associated monoclonal antibody called 4B4. There was a strong correlation between P36 and 4B4 idiotype levels in systemic lupus erythematosus sera. Western blot studies showed that this shared idiotype was found on the heavy chain of both antibodies. This study shows that the heavy chain is important in the expression of this idiotype and provides another immunologic link between these two rheumatic diseases.
7561701 52-kD SS-A/Ro: genomic structure and identification of an alternatively spliced transcript 1995 Oct 1 The 52-kD SS-A/Ro protein is one of the antigenic targets strongly associated with the autoimmune response in mothers whose children have manifestations of neonatal lupus. In addition to the cDNA clone we previously reported for the full-length 52-kD SS-A/Ro protein, an interesting MOLT-4 cDNA clone, p52-2, was found to have an internal deletion of 231 nucleotides including the domain encoding the leucine zipper motif. To further investigate the nature of this deletion, genomic DNA clones were isolated from a lambda FIXII library. The complete gene for the full-length 52-kD protein (alpha form, 52 alpha) spans 10 kb of DNA and is composed of seven exons. Exon 1 contains only the 5' untranslated sequence, while the translation initiation codon is located 3 kb downstream in exon 2, which also encodes the three zinc finger motifs. Exon 4 encodes amino acids 168-245, including the coiled coil/leucine zipper domain. Exon 7 is the longest and encodes the rfp-like domain and the 3' untranslated region. The cDNA p52-2 can now be accounted for as a product of alternative messenger RNA (mRNA) derived from the splicing of exon 3 to exon 5, skipping exon 4, which results in a smaller protein (52 beta) with a predicted molecular weight of 45,000. An initial approach to identifying this alternatively spliced form in the human heart used a ribonuclease protection assay. Using an RNA probe corresponding to bases 674-964 of the full-length cDNA, two protected mRNA fragments were identified, a 290-bp fragment corresponding to expression of 52 alpha and a smaller fragment of 144 bp, the predicted size of 52 beta. Using reverse transcription followed by polymerase chain reaction, cDNAs from a 16-wk fetal heart, 24-wk heart, and adult heart were amplified with primers flanking exon 4. Two polymerase chain reaction products were observed in each tissue, one 1.0 kb likely representing 52 alpha and a second 0.78 kb, consistent with 52 beta. The 0.78-kb fragment identified in the 16-wk heart was cloned, and DNA sequencing confirmed the 52 beta type. Immunoprecipitation of in vitro-translated 35S-labeled 52 beta form was performed to evaluate the antigenicity of this novel form of 52-kD SS-A/Ro. 26 (87%) of 30 sera tested from mothers whose children were known to have neonatal lupus immunoprecipitated the 52 beta form.(ABSTRACT TRUNCATED AT 400 WORDS)
8137550 Induction of autoimmune disease by graft-versus-host reaction across MHC class II differen 1994 Mar We examined the effect of IL-6 on the development of autoimmune diseases (primary biliary cirrhosis, Sjögren's syndrome) employing murine graft-versus-host reaction (GVHR) model with MHC class II disparity. For this purpose, we used IL-6 transgenic (B6.6) mice in which a high level of IL-6 was detected. C57Bl/6 (B6) spleen T cells were injected into B6.6 mated with B6.C-H-2bm12 (bm12) mutant mice ((bm12 x B6.6)F1) and GVHR with MHC class II disparity was induced. The transgenic hybrid mice with GVHR showed a larger spleen index and contained a higher serum level of IL-6 than those without GVHR. Autoimmune-like lesions in transgenic recipients became weakened compared with those in non-transgenic (bm12 x B6)F1 recipients. In contrast, levels of antimitochondrial antibodies in (bm12 x B6.6)F1 GVHR group were significantly higher than that of (bm12 x B6)F1 GVHR group. These results indicate that IL-6 excessively produced in vivo might regulate the progression of autoimmune diseases.
8938157 HLA class II genes in chronic hepatitis C virus-infection and associated immunological dis 1996 Dec To investigate the factors that may confer susceptibility or protection to hepatitis C virus (HCV) infection and to HCV-associated immunological disorders, we designed two studies on 420 Sardinian transfusion-dependent thalassemia patients followed in our department in Cagliari since 1974. The first one was an epidemiological survey aimed to evaluate the prevalence of HCV infection and HCV-associated immunological disorders. In the second study, the distribution of different HLA class II genes was examined by DNA analysis in 116 HCV positive patients, 30 HCV negative patients, and 606 healthy controls. Three hundred fourteen patients became infected with HCV (74.7%) after 5.6 +/- 2.8 years of regular transfusion program. Mixed cryoglobulinemia, purpura, arthritis, proteinuria, decreased complement levels, rheumatoid factor and anti-GOR, smooth muscle antibody (SMA), anti-nuclear antibody (ANA), and liver, kidney microsome (LKM) autoantibodies were significantly more represented in HCV positive patients than in negative ones (P < .05). A significant increase of HLA class II DR2 subtype (DRB1*1601,DQB1*0502) was observed in a group of 30 HCV negative patients who despite 10.3 +/- 2.2 years in a regular blood transfusion program did not show any evidence of HCV infection (Pc < .0092). Our results represent clear evidence for a relationship between HCV infection and immune extrahepatic abnormalities. A gene(s) located in the human major histocompatibility complex (MHC) region may play an important role in conferring protection against HCV infection.
1309881 Characterization of kinin receptors on human synovial cells and upregulation of receptor n 1992 Jan Bradykinin has been implicated in the pathogenesis of inflammatory arthritis by virtue of its potent proinflammatory properties. We have previously shown bradykinin to be a potent stimulus for the release of prostanoids from interleukin-1 (IL-1)-treated, but not untreated, human synovial cells. We hypothesize that one mechanism by which IL-1 induces responsiveness to bradykinin is by upregulation of number or affinity of kinin receptors on human synovial cells. We performed [3H]bradykinin binding studies in intact human synovial tissue and in cultured human synovial cells. Specific, saturable [3H]bradykinin binding sites in intact synovia were identified by autoradiographic localization and were present in much higher density in rheumatoid, than in osteoarthritis, synovia. In untreated human synovial cells in culture, a single (B2) class of kinin binding sites with a Kd of 2.3 nM and Bmax of 58 +/- 9 fmol/10(6) cells was demonstrated. In matched experiments, IL-1 treatment enhanced specific [3H]bradykinin binding 1.5- to 2.0-fold above that observed in untreated cells. This enhancement was attributable to an increase in Bmax (53 +/- 4 vs. 105 +/- 24 fmol/10(6) cells in untreated and IL-1-treated cells, respectively), rather than an alteration in Kd (1.7 and 1.4 nM, respectively). The potencies of a series of kinin analogs and antagonists and unrelated peptides in displacing [3H]bradykinin from IL-1-treated cells correlated well with their abilities to induce prostanoid release. These studies provide novel information regarding the nature of kinin receptors in intact human synovia and in cultured human synovial cells, their regulation by IL-1 and their role in IL-1-treated cells in kinin-mediated prostaglandin E2 production.
1381726 Cultured human synovial fibroblasts rapidly metabolize kinins and neuropeptides. 1992 Sep Kinins and substance P have been implicated in the pathogenesis of inflammatory arthritis by virtue of their abilities to induce vasodilation, edema, and pain. The relative biological potencies of these peptides in vivo would depend at least in part upon their rates of catabolism in the joint. We hypothesized that human synovial lining cells may regulate intraarticular levels of kinins and neuropeptides via degradation by cell surface-associated peptidases. We exposed intact human synovial fibroblasts to kinins and substance P, in the presence or absence of specific peptidase inhibitors, and measured the amount of intact substrate remaining and degradation product(s) generated over time. Aminopeptidase M (AmM; EC 3.4.11.2), neutral endopeptidase-24.11 (NEP-24.11; EC 3.4.24.11), and dipeptidyl(amino)peptidase IV (DAP IV; EC 3.4.14.5) were identified on the cell surface of synovial cells. Bradykinin degradation was due entirely to NEP-24.11 (1.39 +/- 0.29 nmol/min per well). Lysylbradykinin was also degraded by NEP-24.11 (0.80 +/- 0.19 nmol/min per well); however, in the presence of phosphoramidon, AmM-mediated conversion to bradykinin (3.74 +/- 0.46 nmol/min per well) could be demonstrated. The combined actions of NEP-24.11 (0.93 +/- 0.15 nmol/min per well) and DAP IV (0.84 +/- 0.18 nmol/min per well) were responsible for the degradation of substance P. AmM (2.44 +/- 0.33 nmol/min per well) and NEP-24.11 (1.30 +/- 0.45 nmol/min per well) were responsible for the degradation of the opioid peptide, [Leu5]enkephalin. The identity of each of the three peptidases was confirmed via synthetic substrate hydrolysis, inhibition profile, and immunological identification. The profiles of peptidase enzymes identified in cells derived from rheumatoid and osteoarthritic joints were identical. These data demonstrate the human synovial fibroblast to be a rich source of three specific peptidases and suggest that it may play a prominent role in regulating peptide levels in the joint.
7760718 One hundred anti-Ro (SS-A) antibody positive patients: a 10-year follow-up. 1995 May To explore further the varied clinical expression of anti-Ro(SS-A) antibody positive patients and to determine the outcomes of these patients, we followed 100 anti-Ro(SS-A) antibody positive patients, originally seen at the Johns Hopkins Medical Institutions in 1982 and 1983, over a 10-year period. The results of this study indicate that anti-Ro(SS-A) antibody positive patients have a diverse clinical presentation and that the anti-Ro(SS-A) antibody response generally persists for years. Some of these patients appear to have a static disease process for years. However, 65% (51, including 13 deaths, of 78 patients) of the patients for whom we had follow-up data had a chronic (10 years or greater) progressive disease process. Black patients, in general, have an earlier onset of disease and may have a more severe disease than white patients. At least 25% of our anti-Ro(SS-A) antibody positive patients demonstrated a dynamic change in clinical presentation with the development of Sjögren syndrome and/or a progressive "rheumatoid-like" arthritis. Interstitial pulmonary disease, central nervous system disease, and vasculitic insults occur frequently in these patients. Renal disease occurred in 19 anti-Ro(SS-A) positive patients, and in 47% of these renal disease patients, no anti-DNA antibodies (dsDNA or ssDNA) were detected. Cutaneous manifestations are prominent in anti-Ro(SS-A) antibody positive patients with lupus. Photosensitivity and a malar dermatitis were the most common features. Twenty percent of lupus patients had discoid lesions, and 20% had SCLE lesions. Based on this study, we believe that anti-Ro(SS-A) antibody positive patients should be routinely evaluated for the emergence of systemic features. Since these systemic features are at least in part, if not solely, the result of inflammation, early treatment with steroids and/or immunosuppressive agents may minimize the damage and influence in a positive manner the significant morbidity and mortality observed in some anti-Ro(SS-A) antibody positive patients.
9363179 Update on lymphoid interstitial pneumonitis. 1996 Sep Lymphoid interstitial pneumonitis (LIP) involves a clinicopathologic pattern of pulmonary disease characterized by diffuse interstitial reactive lymphoid infiltrates. In adults, it occurs most commonly in autoimmune diseases, such as Sjögren's syndrome (0.9% of these patients) and primary biliary cirrhosis, whereas in children it is usually seen in HIV infection. Dysproteinemias (hyper- and hypogammaglobulinemia) are found in more than 60% of patients. Children can show CD8-lymphocytosis in bronchoalveolar lavage fluid, lung tissue, peripheral blood, and salivary gland, associated with HLA-DR5 haplotype. Radiographically, most patients with LIP have reticulonodular infiltrates, with or without patchy areas of consolidation. CT scans can show both small nodular and ground glass patterns, patterns that are diagnostically nonspecific. Reduced lung volumes and diffusing capacities are consistent and sensitive indicators of disease in LIP. In an experimental model, diffusing capacity was the single most sensitive functional index of disease progression. Microscopically, LIP is part of a spectrum of pulmonary lymphoid proliferations, ranging from follicular bronchitis-bronchiolitis and pulmonary lymphoid hyperplasia (the latter in AIDS patients), proliferations largely limited to airways, to low-grade malignant lymphoma. These patterns may be difficult to differentiate from each other. It appears that LIP sometimes evolves to lymphoma; the frequency of this evolution is probably low but is difficult to assess because low-grade lymphomas may mimic LIP. A relatively high frequency of LIP patients have Epstein-Barr virus DNA in their lungs but not all patients with LIP show this finding, suggesting other possible etiologies.