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Pericarditis is an uncommon manifestation of infection of Neisseria meningitidis. Pericarditis may be caused by direct invasion or immune-complex-mediated (reactive) inflammation. We outline the case of a two-year-old girl with probable reactive pericarditis, review the cases reported in the English literature since 1966 and discuss the pathogenesis of meningococcal pericarditis.
PURPOSE: To discuss the pathogenesis of severe vaso-occlusive retinopathy in systemic lupus erythematosus (SLE), the association with antiphospholipid antibodies, and its implications for management and prognosis. METHODS: An illustrative case history of a woman with SLE and severe vaso-occlusive retinopathy in the presence of antiphospholipid antibodies is presented. A literature review of previously reported cases and previously published data on the topic was performed and forms the basis for discussion. RESULTS: This is a rare form of retinopathy in SLE as distinct from the more common, benign form, being classically a microangiopathy with diffuse capillary non-perfusion and small arterial or arteriolar occlusions in the retina. Poor visual outcomes with visual loss are reported in 80% of cases with neovascularization occurring in 40% of cases. It is associated with antiphospholipid antibodies, typically characterized by microthrombosis and immune complex mediated vasculopathy rather than a true vasculitis. There is a strong association between this severe form of retinopathy and central nervous system manifestations of SLE. Anticoagulation has a role in the secondary prevention of thrombosis in the presence of antiphospholipid antibodies, but the role of aspirin and immunosuppression is unclear in the treatment of this condition. Vigilant ophthalmic follow up and aggressive treatment of neovascularization and vitreous haemorrhage can prevent further visual loss. These points are highlighted in the brief case report presented. CONCLUSION: Severe vaso-occlusive retinopathy is a rare form of retinopathy in SLE often associated with poor visual prognosis and neovascularization. It may be a manifestation of the antiphospholipid syndrome. Treatment is aimed at preventing further thrombosis and complications arising from neovascularization.
BACKGROUND: Papulopustular lesions (PPL), the most common type of cutaneous lesions in Behçet's disease (BD), clinically may not be differentiated from ordinary acne. Disagreement exists as to the exact nature of these acneiform and folliculitis-like lesions and whether to include them as a major criterion. OBJECTIVE: We investigated whether PPL can be a useful tool for the diagnosis of BD when non-follicular lesions over the trunk or extremities were selected, and were correlated with histological and/or immunofluorescence study. METHODS: Seventeen patients with BD (five women, 12 men; mean +/- SEM age, 32 +/- 7.9 years), were enrolled in the study with blind histopathological and immunofluorescence studies. Biopsies of the PPL and adjacent (approximately 2 cm distant) normal-appearing skin were performed from the extremities and trunk. Follicle-based acneiform lesions and those lesions over face were excluded. Histological evaluation primarily included epidermal and dermal alterations, cellular infiltration and vascular changes. We also performed direct immunofluorescence studies, using polyclonal antibodies for IgA, IgG, IgM, C3 and fibrin. RESULTS: Lesional specimens of the patients with BD revealed a significant leucocytoclastic vasculitis as compared with non-lesional skin (P<0.05). The vessels of the lesional skin showed a higher IgM deposition than non-lesional skin (52.9% and 17.6%) (P<0.05). IgG, C3 and fibrin deposits on the vessels of the lesional skin were also higher than non-lesional skin (35.3, 11.8%; 41.2, 17.6%; and 47.1, 17.6%, respectively), but the differences were not statistically significant. CONCLUSIONS: Our findings indicate that non-follicular PPL over the trunk or extremities are more specific, and immune complex-mediated vasculitis is likely to be the main feature of these lesions, as they are in other cutaneous lesions of BD.
BACKGROUND: The presence of IgA together with the myeloid IgA-receptor FcalphaRI/CD89 in the circulation of patients with IgA nephropathy (IgAN) has been suggested as a specific pathogenic factor for mesangial deposition. However, in a recent study we found these complexes also in serum samples from healthy subjects. To investigate whether these circulating complexes are specific for IgAN, the levels and characteristics of IgA-CD89 complexes were analyzed in patients with IgAN and healthy controls. METHODS: Specific ELISAs with different poly- and monoclonal antibodies and a sensitive dot-blot method were used to measure IgA-CD89 levels in serum and purified IgA samples obtained from healthy volunteers (N = 30) and patients with IgAN (N = 35). Fractionated samples of purified IgA were used to compare the size characteristics of the IgA-CD89 complexes. RESULTS: Almost all CD89 in serum of patients with IgAN and controls was associated with high molecular weight IgA. Quantitative analysis of IgA-CD89 complexes in purified IgA revealed no significant difference between patients with IgAN and controls. No correlation was found between levels of IgA-CD89 complexes and clinical parameters associated with progressive IgAN. CONCLUSIONS: CD89 in the circulation is found mainly linked to high molecular weight IgA. The presence of these complexes is not specific for IgAN. Therefore, if IgA-CD89 complexes are involved in the pathogenesis of primary IgA nephropathy, additional factors are required to explain the IgA-CD89 complex-mediated renal inflammation.
Since the description of a new renal syndrome in patients with the acquired immunodeficiency syndrome (AIDS) in the middle 1980s, much has been learned regarding the association of human immunodeficiency virus (HIV) infection and renal disease. The HIV-associated renal diseases represent a spectrum of clinical and histopathologic conditions. In this review, epidemiologic and clinical aspects of HIV-associated renal diseases are presented. Particular attention is placed on the pathologic and pathophysiologic mechanisms involved in HIV-associated focal glomerulosclerosis, immune complex-mediated disease, and thrombotic microangiopathies. Pharmaceutical treatment options, including the use of glucocorticoids, angiotensin-converting enzyme (ACE) inhibitors, and highly active antiretroviral therapy, are discussed. The therapeutic option of renal transplantation is presented, with insight into new clinical and basic research supporting a possible role of immunosuppressive therapy in this already immunocompromised patient population.
Therapeutic removal of immune complexes and antibodies by plasmapheresis has been used in patients with systemic lupus erythematosus (SLE) since 1974. Modern methods of selective adsorption of immunoglobulins from the patient plasma (immunoadsorption, IAS) have been developed; they deserve to be investigated as a tool in the management of difficult cases of SLE. We report our experience in an uncontrolled series of five consecutive SLE patients, in whom cytotoxic immunosuppression was contraindicated or not sufficient to control the disease. Ig-Therasorb columns containing polyclonal sheep antihuman immunoglobulin antibodies were used for IAS for periods of 4 to 54 weeks. In order to prevent rebound autoantibody production, low doses of normal human immunoglobulin were substituted. Improvement in clinical and laboratory signs of disease activity was observed in all patients. In two patients the effect of cyclophosphamide therapy for lupus pneumonitis and lupus-associated thrombopenic purpura was consolidated. In three patients suffering from pancytopenia or lupus vasculitis, the use of cytotoxic substances could be avoided for more than a year. IAS seems to be a safe replacement of conventional plasmapheresis in difficult cases of severe lupus complications. Although controlled studies are lacking, this method may occupy a few important niches as an adjunct in managing immune complex mediated diseases.
Although the pathogenesis of immunoglobulin A (IgA) nephropathy and Henoch-Schönlein nephritis (HSN) remains uncertain, there is substantial evidence that they are immune complex-mediated diseases. Recently, Haemophilus parainfluenzae antigens were shown in the glomerular mesangium of adult patients with IgA nephropathy, and greater levels of IgA antibody against H parainfluenzae were also shown in the sera of adult patients with IgA nephropathy. The present study was performed to detect H parainfluenzae antigens and antibody against H parainfluenzae in children with IgA nephropathy and HSN. H parainfluenzae antigens in the mesangium were examined by indirect immunofluorescence, and antibody against H parainfluenzae was examined by enzyme-linked immunosorbent assay. Diffuse global staining of the mesangium with rabbit antisera against H parainfluenzae was shown in 10 of the 32 patients (31%) with IgA nephropathy and 12 of the 34 patients (35%) with HSN. Conversely, only 2 of the 47 patients (4%) with other renal diseases showed staining of glomeruli with rabbit antisera against H parainfluenzae (IgA nephropathy versus other renal diseases, P = 0.003; HSN versus other renal diseases, P = 0.0006). Patients with IgA nephropathy and those with HSN showed significantly greater levels of plasma IgA1 antibody against H parainfluenzae than patients with other renal diseases (IgA nephropathy versus other renal diseases, P = 0.008; HSN versus other renal diseases, P = 0.025). These findings suggest that H parainfluenzae has a role in the cause of these two conditions in a subset of patients.
BACKGROUND: Although the pathogenesis of Henoch-Schönlein nephritis (HSN) remains unclear, there is substantial evidence that it is an immune complex-mediated disease. HSN is preceded by upper-respiratory tract infection in 30% to 50% of patients, but there is no evidence that group A streptococcal (GAS) infection has a pathogenetic role in this disease. Recently, nephritis-associated plasmin receptor (NAPlr), a GAS antigen, was found primarily in the glomerular mesangium of patients with early-stage acute poststreptococcal glomerulonephritis. METHODS: To determine the possible role of NAPlr in HSN, expression of the receptor was determined in glomeruli using fluorescein isothiocyanate-labeled rabbit polyclonal anti-NAPIr antibody, and serum antistreptolysin O (ASO) titers were measured in children with HSN. RESULTS: Ten of 33 patients (30%) with HSN showed segmental or global mesangial staining with NAPlr antibody, whereas only 4 of 120 patients (3%) with other renal diseases were positive (P < 0.001, Fisher's exact test). Patients with HSN also showed significantly greater ASO titers than patients with other renal diseases (P = 0.03, Mann-Whitney U test). Serum ASO titers were significantly greater in patients with HSN with than without glomerular NAPlr antigen (P = 0.03, Mann-Whitney U test). CONCLUSION: These findings suggest that the deposition of NAPlr in the mesangium, induced by GAS infection, may have a role in the pathogenesis of HSN in some patients. Am J Kidney Dis 41:366-370.
A distinct entity mimicking immune-complex-mediated glomerulonephritis characterized by a proliferative glomerulonephritis with monoclonal immunoglobulin G (IgG) deposits recently was described. We now report a case of a 35-year-old woman who presented with sudden onset of edema, proteinuria, hematuria, and hypertension. Renal biopsy showed diffuse endocapillary proliferation, mesangial cellularity, and amorphous material in the mesangium. Immunofluorescence examination showed mesangial and capillary wall staining for IgA (2+), C3 (2+), fibrinogen (2+), and lambda (2+). Congo red stain was negative. Electron microscopy showed mesangial and subendothelial deposits with a paracrystalline lattice-like substructure forming parallel linear arrays. Extensive laboratory evaluation showed a small population of monoclonal plasma cells with lambda restriction. The present case suggests that monoclonal IgA deposits also can cause proliferative glomerulonephritis. However, the presence of paracrystalline deposits in association with monoclonal IgA deposits has not been described previously.
Immunoglobulin A (IgA) nephropathy is an immune-complex-mediated glomerulonephritis characterized by the presence of immunoglobulin A deposits in mesangial and paramesangial regions. The patients with IgA nephropathy present with varying clinical symptoms (eg, microhematuria with preserved renal function or progressive deterioration of renal functions resulting in end-stage renal disease). The factors involved in the pathogenetic mechanisms of IgA nephropathy include (1). environmental factors, (2). genetic factors, (3). abnormality of the IgA1 molecule, and (4). various inflammatory mediators. The gene polymorphism studies for human leukocyte antigen (HLA), renin-angiotensin-aldosterone system, and selectin gene clusters, suggest a certain degree of genetic predisposition in patients for IgA nephropathy. Also, the genome-wide screening in familial IgA nephropathy showed linkage of IgA nephropathy to the 6q22-23 chromosome. Besides genetic influence in its pathogenesis, aberrant galactosylation in serum IgA and IgA1 eluted from kidneys with IgA nephropathy has been observed, and conceivably such abnormalities induce the expression of various cytokines, interleukin (IL)-6, platelet-derived growth factor (PDGF), tumor necrosis factor (TNF)-alpha, and transforming growth factor (TGF)-beta1 in the renal cells, which contributes to further glomerular injury. Despite an enormous amount of information available in the literature, further studies are needed to delineate the precise pathogenetic mechanisms involved in primary IgA nephropathy and also to facilitate the development of newer therapeutic interventions.
In certain long-lasting cases of Menière's disease with recurrent attacks, despite of saccotomy, the removal of the vestibular ganglion is the only procedure that relieves vertigo. During ganglionectomy of this group of patients all fresh tissues gotten and gathered from operation are frozen immediately and preserved for immunohistochemical assay with direct and indirect incubations. The positive findings such as ASMA+, AEA+ and ANA+ in tissues of patient's own as well as in control tissues further confirmed the results previously reported by us. The immune-complex mediated arteriolar and capillary vasculitis on the basis of an autoimmune disorder as a secondary autoimmune marker might play a dominant role in this patients group. The demyelination of vestibular neurons in the Ganglion Scarpae might be the cause of the Menière symptoms. To confirming the hypothesis, the research plan must be continuously carried out.
A 31-year-old women with chronic active hepatitis B (HBs antigen-positive, HBe antigen-negative) developed a painful petechia rash on both lower legs and the inner surface of the thighs. Histology of a skin biopsy revealed leucocytoclastic vasculitis. The affected skin areas contained HBs antigen and immunoglobulins. Immunosuppressive treatment with initially 60mg/d prednisolone improved the skin condition but activated the chronic hepatitis, GPT rising up to 240 U/l. The steroid treatment had to be discontinued. Subsequently the transaminases became normal but the vasculitis foci recurred. The patient was therefore given alpha-interferon, three times 5 mill. IU weekly subcutaneously for 6 months. The skin lesions disappeared and the circulating HBV-DNA decreased. But the HBs antigen could not be eliminated. It is to be noted that 12 months after the end of the alpha-interferon treatment the vasculitis has not recurred. - This case and published reports indicate that interferon treatment is effective against HBV-associated and immunoglobulin-complex mediated disease.
The effects on the title reaction of collision energy (E(col)) and five H(2)CO(+) vibrational modes have been studied over a center-of-mass E(col) range from 0.1 to 2.3 eV. Electronic structure and Rice-Ramsperger-Kassel-Marcus calculations were used to examine properties of various complexes and transition states that might be important. Only the hydrogen abstraction (HA) product channel is observed, and despite being exoergic, HA has an appearance energy of approximately 0.4 eV, consistent with a transition state found in the electronic structure calculations. A precursor complex-mediated mechanism might possibly be involved at very low E(col), but the dominant mechanism is direct over the entire E(col) range. The magnitude of the HA cross section is strongly, and mode specifically affected by H(2)CO(+) vibrational excitation, however, vibrational energy has no effect on the appearance energy.
OBJECTIVE: Transplanted porcine hearts are hyperacutely rejected by human immunoglobulin M antibodies against a porcine vascular endothelial molecule, galactose alpha-1,3-galactose, with ensuing human complement activation and membrane attack complex deposition. It is unclear, however, whether porcine valve endothelium triggers a similar immune response. We sought to investigate whether fresh porcine valves implanted into primates are rejected. METHODS: Wild-type porcine hearts before (n = 6) and after (n = 3) heterotopic transplantation into baboons underwent sectioning and were examined by hematoxylin and eosin staining and immunohistochemistry for galactose alpha-1,3-galactose, primate immunoglobulin M, and membrane attack complex. RESULTS: Examination of untransplanted porcine hearts showed that although cardiac microvascular endothelium strongly expressed the galactose alpha-1, 3-galactose antigen, galactose alpha-1,3-galactose was not detected on the endothelium of porcine aortic and pulmonary valves. Porcine hearts transplanted into baboon recipients were hyperacutely rejected 60 to 80 minutes after implantation. Despite dramatic tissue damage associated with extensive immunoglobulin M and membrane attack complex binding on the microvascular endothelium, the aortic and pulmonary valves were entirely spared. Valves remained morphologically intact at explant and showed no signs of immunoglobulin M- and membrane attack complex-mediated damage. CONCLUSIONS: The absence of galactose alpha-1,3-galactose expression may protect unfixed porcine valves from xenograft rejection in primates. Further investigation of viable porcine valves appears warranted.
MHC-peptide complexes mediate key functions in adaptive immunity. In a classical view, MHC-I molecules present peptides from intracellular source proteins, whereas MHC-II molecules present antigenic peptides from exogenous and membrane proteins. Nevertheless, substantial crosstalk between these two pathways has been observed. We investigated the influence of autophagy on the MHC-II ligandome and demonstrated that peptide presentation is altered considerably upon induction of autophagy. The presentation of peptides from intracellular and lysosomal source proteins was strongly increased on MHC-II in contrast with peptides from membrane and secreted proteins. In addition, autophagy influenced the MHC-II antigen-processing machinery. Our study illustrates a profound influence of autophagy on the class II peptide repertoire and suggests that this finding has implications for the regulation of CD4(+) T cell-mediated processes.
Insulin-stimulated glucose uptake requires the fusion of GLUT4 transporter-containing vesicles with the plasma membrane, a process that depends on the SNARE (soluble N-ethylmaleimide-sensitive fusion factor attachment receptor) proteins VAMP2 (vesicle-associated membrane protein 2) and syntaxin 4 (Stx4)/SNAP23 (soluble N-ethylmaleimide-sensitive fusion factor attachment protein 23). Efficient SNARE-dependent fusion has been shown in many settings in vivo to require the generation of both phosphatidylinositol-4,5-bisphosphate (PIP2) and phosphatidic acid (PA). Addition of PA to Stx4/SNAP23 vesicles markedly enhanced the fusion rate, whereas its addition to VAMP2 vesicles was inhibitory. In contrast, addition of PIP2 to Stx4/SNAP23 vesicles inhibited the fusion reaction, and its addition to VAMP2 vesicles was stimulatory. The optimal distribution of phospholipids was found to trigger the progression from the hemifused state to full fusion. These findings reveal an unanticipated dependence of SNARE complex-mediated fusion on asymmetrically distributed acidic phospholipids and provide mechanistic insights into the roles of phospholipase D and PIP kinases in the late stages of regulated exocytosis.
CP12 is a small nuclear encoded chloroplast protein of higher plants, which was recently shown to interact with NAD(P)H-glyceraldehyde-3-phosphate dehydrogenase (GAPDH; EC 1.2.1. 13), one of the key enzymes of the reductive pentosephosphate cycle (Calvin cycle). Screening of a pea cDNA library in the yeast two-hybrid system for proteins that interact with CP12, led to the identification of a second member of the Calvin cycle, phosphoribulokinase (PRK; EC 2.7.1.19), as a further specific binding partner for CP12. The exchange of cysteines for serines in CP12 demonstrate that interaction with PRK occurs at the N-terminal peptide loop of CP12. Size exclusion chromatography and immunoprecipitation assays reveal the existence of a stable 600-kDa PRK/CP12/GAPDH complex in the stroma of higher plant chloroplasts. Its stoichiometry is proposed to be of two N-terminally dimerized CP12 molecules, each carrying one PRK dimer on its N terminus and one A2B2 complex of GAPDH subunits on the C-terminal peptide loop. Incubation of the complex with NADP or NADPH, in contrast to NAD or NADH, causes its dissociation. Assays with the stromal 600-kDa fractions in the presence of the four different nicotinamide-adenine dinucleotides indicate that PRK activity depends on complex dissociation and might be further regulated by the accessible ratio of NADP/NADPH. From these results, we conclude that light regulation of the Calvin cycle in higher plants is not only via reductive activation of different proteins by the well-established ferredoxin/thioredoxin system, but in addition, by reversible dissociation of the PRK/CP12/GAPDH complex, mediated by NADP(H).
The yeast repressor Rme1p acts from distant binding sites to block transcription of the chromosomal IME1 gene. Rme1p can also repress the heterologous CYC1 promoter when Rme1p binding sites are placed 250-300 bp upstream of CYC1 transcriptional activator binding sites (UAS1 and UAS2). Here, in vivo footprinting studies indicate that Rme1p acts over this distance by preventing the binding of the CYC1 transcriptional activators to UAS1 and UAS2. Inhibition of activator binding by Rme1p has the same genetic requirements as repression: both depend upon sequences flanking the Rme1p binding sites and upon Rgr1p and Sin4p, two subunits of the RNA polymerase II-associated Mediator complex that are required for normal nucleosome density. Thus Rme1p may alter chromatin to prevent binding of transcriptional activators to distant DNA sequences.