Cryoglobulins in Behcet's syndrome and recurrent oral ulceration: assay by laser nephelometry.
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The presence of cryoglobulins was investigated in ninety patients with recurrent oral ulcers (ROU) and sixty-one patients with Behcet's syndrome (BS). The immunodiffusion method was compared with Laser nephelometry for the analysis of IgG, IgM, IgA and C3 in cryoglobulins. Although the two methods of assessment showed a very significant agreement. Laser nephelometry was more sensitive than the double diffusion precipitation method and was used for quantitative analysis of cryoglobulins. The prevalence of any type of cryoglobulins was 64% in ROU and 75% in BS, as compared with controls (15%). In ROU significant levels of IgA were found in minor (P = 0.0196) and major (P = 0.0114) aphthous ulcers and to a lesser extent in herpetiform ulcers (P = 0.0624). Among the four types of BS signficant increases in C3 were found in the arthritic type (P = 0.0068) and ocular type (P = 0.0275), whereas IgM (P = 0.0031) and IgG (P = 0.0369) were increased only in the muco-cutaneous type. Sequential studies showed that disease remissions or exacerbations were correlated with a decrease or increase in IgM or IgG classes of cryoglobulins. However, the converse was found with IgA which may inhibit some functions of polymorphonuclear leucocytes, and this may be responsible for the failure to remove damaging IgG, IgM and C3 complexes from the circulation. (+info)
Cryoglobulinaemia in patients with infectious endocarditis.
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Serum cryoglobulins were found in nineteen out of twenty patients with infectious endocarditis. The cryoglobulins were of the 'mixed type' consisting of IgG, IgM and IgA. C3 and fibrinogen were present in some specimens. The concentration of the cryoglobulins tended to fall with therapy and clinical improvement of the patients. Serum antibodies to the offending bacterial organism were not preferentially concentrated in the cryoglobulins. In contrast, IgM rheumatoid factor was present in the cryoglobulins, though undetectable in the corresponding serum. These findings are consistent with the view that cryoglobulins represent circulating immune complexes which may be important in the pathogenesis of immunological sequelae sometimes found in patients with infectious endocarditis. (+info)
Molecular study of an IgG1kappa cryoglobulin yielding organized microtubular deposits and glomerulonephritis in the course of chronic lymphocytic leukaemia.
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Glomerulonephritis with organized microtubular monoclonal immunoglobulin deposits (GOMMID) and glomerulonephritis related to type I cryoglobulin are well-known but rare complications of B cell derived chronic lymphocytic leukaemia. In these disorders, monoclonal Ig have never been studied at the molecular level. We conducted a pathological and molecular analysis in a patient with chronic lymphocytic leukaemia, glomerulonephritis and a single circulating monoclonal Ig. Unusual IgG1kappa kidney deposits were observed. The heavy and light chain variable region sequences of that cryoprecipitating monoclonal Ig were characterized. Light microscopy revealed glomerulonephritis typical of cryoglobulinaemia, with neutrophil and macrophage infiltration, endocapillary hyperplasia and few protein thrombi. Electron microscopic study clearly evidenced numerous subepithelial mixed granular and organized deposits with a unique microtubular organization, reminiscent of the GOMMID. The Ig molecule sequence revealed alterations of charge and hydrophobicity potentially promoting a crystal-like aggregation and the aggregation of microtubules. This description suggests that common mechanisms are involved in various forms of precipitation and/or deposition of complete Ig molecules, with a variable extent of organization and with a possible overlap between pathological patterns of either glomerulonephritis with microtubular deposits or type I cryoglobulinic glomerulonephritis. (+info)
Evidence for involvement of a hydrophobic patch in framework region 1 of human V4-34-encoded Igs in recognition of the red blood cell I antigen.
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The monoclonal IgM cold agglutinins that bind to the I/i carbohydrate Ags on the surface of RBCs all have Ig H chains encoded by the V4-34 gene segment. This mandatory use indicates that distinctive amino acid sequences may be involved in recognition. Critical amino acids exist in framework region 1 (FR1) of V4-34-encoded Ig, and these generate a specific Id determinant which apparently lies close to the I binding site. However, I binding by Id-expressing Ig can be modulated by sequences in complementarity-determining region (CDR)(H)3. Examination of the crystal structure of an anti-I cold agglutinin has revealed a hydrophobic patch in FR1 involving residue W7 on beta-strand A and the AVY motif (residues 23-25) on beta-strand B. In this study we used mutagenesis to show that each of the strand components of the hydrophobic patch is required for binding the I carbohydrate Ag. In addition, the crystal structure reveals that amino acids in the carboxyl-terminal region of CDR(H)3 form a surface region adjacent to the hydrophobic patch. We propose that the I carbohydrate Ag interacts simultaneously with the entire hydrophobic patch in FR1 and with the outside surface of CDR(H)3. This interaction could leave most of the conventional binding site available for binding other Ags. (+info)
Molecular dynamics simulations on SDF-1alpha: binding with CXCR4 receptor.
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Insights into the interacting mode of CXCR4 with SDF-1alpha are crucial in understanding the structural and functional characteristics of CXCR4 receptor. In this paper a computational pipeline, integrating protein structure prediction, molecular dynamics simulations, automated molecular docking, and Brownian dynamics simulations were employed to investigate the dynamic and energetic aspects of CXCR4 associating with SDF-1alpha. The entire simulation revealed the surface distribution feature of electrostatic potentials and conformational "open-close" process of the receptor. The possible binding conformation of CXCR4 was identified, and the CXCR4-SDF-1alpha binding complex was generated. Arg188-Glu277 salt bridge plays an important role for both the extracellular domain conformational change and SDF-1alpha binding. Two binding sites were mapped at the extracellular domain (Site 1) and inside the transmembrane domain (Site 2), which are composed of conserved residues. Sites 1 and 2 contribute approximately 60% and 40% to the binding affinity with SDF-1alpha, respectively. The binding model is in agreement with most of the experimental data. Transmembrane VI has more significant motion in the harmonious conformational transition of CXCR4 during SDF-1alpha binding, which may be possibly associated with signal transduction. Based on the modeling and simulation, a binding mechanism hypothesis between CXCR4 and SDF-1alpha and its relationship to the signal transduction has been proposed. (+info)
Paraproteins: a regional South Australian experience.
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We have performed a systematic review of all new serum and urinary paraproteins detected over a six year period in an immunodiagnostic laboratory serving a population of 400,000 people. Clinical diagnoses and associated laboratory features were ascertained from a computerized laboratory database or from clinical notes. Over the period of study, serum or urine paraproteins were detected in 613 new patients. These consisted of 568 patients with serum paraproteins and 45 patients with urinary monoclonal free light chain (in the absence of a serum paraprotein). These paraproteins occurred more commonly in males and the frequency increased with age. Approximately 30% of the serum paraproteins and 60% of urinary monoclonal free light chain were associated with B cell lymphoproliferative disorders (multiple myeloma, plasmacytoma, Waldenstrom's macroglobulinemia, non-Hodgkins lymphoma, chronic lymphocytic leukemia, etc) with the remainder being labeled as monoclonal gammopathies of uncertain significance (MGUS). At clinical presentation, patients with lymphoproliferative disorders tended to have higher levels of paraprotein, B2 microglobulin, the presence of free urinary light chain and demonstrated molecular size heterogeneity of the paraprotein but there was considerable overlap. A good correlation was noted between paraprotein concentration and viscosity in most patients. In conclusion paraproteins were most frequently encountered in the context of a gammopathy of uncertain significance. Features which suggested lymphoproliferative disorders included higher levels of serum paraprotein (> 15 g/l), elevated levels of B2-microglobulin and the presence of urinary free high chain. However, as much overlap was seen with patients with MGUS, regular monitoring of paraprotein level is considered mandatory in the management of these patients. (+info)
Immune complex type glomerulonephritis in cirrhosis of the liver.
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Glomerular lesions were detected in 9 of 10 patients with liver cirrhosis: these lesions consisted of a) thickening of basement-membrane-like material, b) electron-dense deposits in mesangial areas and in capillary walls, c) round areas of rarefaction in the membrane-like material and in some deposits, and d) presence of IgA, with IgG and/or IgM and/or C3, in the deposits. The association of these four abnormalities seems to be characteristic of "cirrhotic glomerulonephritis." The deposits could be the result of precipitation in the glomeruli of either aggregated immunoglobulins or circulating immune complexes. (+info)
Lepromatous leprosy presenting with polyarthritis, myositis, and immune-complex glomerulonephritis.
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A Pakistani man aged 19 years was admitted to a rheumatological unit in the United Kingdom with acute widespread polyarthritis accompanied by night sweats and fever. Preliminary examination suggested Reiter's disease, but further investigation showed acute glomerulonephritis with uraemia. The possibility of periarteritis nodosa, and the prominence of muscle tenderness in the legs, led to biopsies of striated muscle and skin, in both of which were changes typical of lepromatous leprosy, with many Mycobacterium leprae on Ziehl-Neelsen staining. Serum showed IgG-IgM cryoglobulinaemia without antiglobulin activity, and in the recovery phase renal biopsy showed a resolving proliferative glomerulonephritis with linear IgG and IgM immunofluorescence and granular deposits of C3. Clinical signs subsided rapidly under steroid treatment and subsequent progress on anti-leprosy drugs was uneventful. The term erythema nodosum leprosum is inadequate and misleading as a title for a common and important immune-complex reaction of lepromatous leprosy, in which numerous body systems may be involved. (+info)