Raised immunoglobulin E and idiopathic bronchiectasis

SummaryWe describe a series of 4 subjects with markedly raised immunoglobulin E levels in association with idiopathic bronchiectasis. This has not been described previously and appears to be a distinct entity from other conditions such as allergic bronchopulmonary aspergillosis

Th1 responsiveness to nephritogenic antigens determines susceptibility to crescentic glomerulonephritis in mice

Th1 responsiveness to nephritogenic antigens determines susceptibility to crescentic glomerulonephritis in mice. The pattern of glomerulonephritis (GN) developing in response to a planted antigen (sheep anti-mouse GBM globulin) was compared in two strains of mice which demonstrated either a predominant Th1 (C57BL/6) or Th2 (BALB/c) response to this antigen. GN was induced with a subnephritogenic i.v. dose of sheep anti-mouse GBM globulin in mice presensitized to sheep globulin. Sensitized C57BL/6 mice showed pronounced cutaneous delayed-type hypersensitivity (DTH) following the challenge with sheep globulin, low titers of circulating anti-sheep globulin antibody and high interferon γ (IFNγ) and low interleukin 4 (IL-4) production by splenic T cells, consistent with a predominant Th1 pattern of immune response. Sensitized BALB/c mice did not develop DTH following cutaneous challenge with sheep globulin, had higher circulating anti-sheep globulin antibody titers, and showed high IL-4 and low IFNγ production by splenic T cells compared with C57BL/6 mice, consistent with a predominant Th2 response. In C57BL/6 mice, GN developing in response to sheep globulin exhibited a severe crescentic pattern with prominent glomerular T cell and macrophage influx and fibrin deposition. In vivo depletion with a monoclonal anti-CD4 antibody demonstrated that this injury was T helper cell dependent. Treatment with monoclonal anti-mouse IFNγ antibody significantly reduced glomerular injury and crescent formation and attenuated the cutaneous DTH response. GN induced by the same protocol in BALB/c mice exhibited pronounced glomerular IgG and complement deposition. Crescent formation, fibrin deposition, and glomerular T cell and macrophage infiltration were significantly less than observed in C57BL/6 mice, and injury was not T cell dependent in the effector phase. These data suggest that the pattern of glomerular injury induced by a planted antigen can be determined by the balance of T helper cell subset activation. A Th1 response induces a severe crescentic pattern of GN, which like cutaneous DTH, is T helper cell and IFNγ dependent

Fibrin independent proinflammatory effects of tissuefactor in experimental crescentic glomerulonephritis

Fibrin independent proinflammatory effects of tissue factor in experimental crescentic glomerulonephritis.BackgroundTissue factor initiated glomerular fibrin deposition is an important mediator of injury in crescentic glomerulonephritis. Recent data have suggested noncoagulant roles for tissue factor in inflammation.MethodsTo test the hypothesis that in addition to its effects in initiating coagulation, tissue factor has proinflammatory effects in glomerulonephritis, rabbits given crescentic anti-glomerular basement membrane (GBM) antibody–induced glomerulonephritis were defibrinogenated with ancrod. One group of defibrinogenated rabbits was also given anti-tissue factor antibodies. Comparisons were made between these groups, as well as a third group that was neither defibrinogenated with ancrod nor given anti-tissue factor antibodies.ResultsDefibrinogenation alone abolished glomerular fibrin deposition, reduced crescent formation, and limited renal impairment (ancrod-treated, serum creatinine 274 ± 37 μmol/L; untreated 415 ± 51 μmol/L; P < 0.01). Tissue factor inhibition in defibrinogenated rabbits resulted in further protection of renal function (creatinine 140 ± 19 μmol/L, P < 0.01) and reduced proteinuria (0.4 ± 0.2g/day, untreated 2.6 ± 0.4 g/day, P <0.01), which was significantly increased by defibrinogenation alone (ancrod-treated, 5.6 ± 1.2 g/day). Anti-tissue factor antibodies (but not defibrinogenation alone) attenuated glomerular T-cell and macrophage recruitment, and major histocompatibility complex (MHC) class II expression.ConclusionThese results demonstrate important proinflammatory effects of tissue factor in crescentic glomerulonephritis that are fibrin independent and provide in vivo evidence for tissue factor's proinflammatory effects on MHC class II expression and leukocyte accumulation

Microbiologic follow-up study in adult bronchiectasis

SummaryThere is minimal published longitudinal data about pathogenic microorganisms in adults with bronchiectasis. Therefore a study was undertaken to assess the microbiologic profile over time in bronchiectasis.A prospective study of clinical and microbiologic outcomes was performed. Subjects were assessed by a respiratory physician and sputum sample were collected for analysis. Subjects were followed up and had repeat assessment performed.Eighty-nine subjects were followed up for a period of 5.7±3.6 years. On initial assessment the two most common pathogens isolated were Haemophilus influenzae (47%) and Pseudomonas aeruginosa (12%) whilst 21% had no pathogens isolated. On follow-up review results were similar (40% H. influenzae, 18% P. aeruginosa and 26% no pathogens). The prevalence of antibiotic resistance of isolates increased from 13% to 30%. Analysis of a series of H. influenzae isolates showed they were nearly all nontypeable and all were different subtypes. Subjects with no pathogens isolated from their sputum had the mildest disease, while subjects with P. aeruginosa had the most severe bronchiectasis.Many subjects with bronchiectasis are colonized with the same bacterium over an average follow-up of 5 years. Different pathogens are associated with different patterns of clinical disease

Interleukin-4 deficiency enhances Th1 responses and crescentic glomerulonephritis in mice

Interleukin-4 deficiency enhances Th1 responses and crescentic glomerulonephritis in mice. Evidence suggests that crescentic glomerulonephritis (GN) is due to T helper cell 1 (Th1) directed delayed-type hypersensitivity (DTH)-like injury. As endogenous interleukin (IL)-4, (the pivotal cytokine in Th2 responses) may attenuate Th1 responses in this disease, we compared the development of crescentic GN, induced by a planted antigen, in mice genetically deficient in IL-4 (IL-4−/−) with disease in normal mice (IL-4+/+). IL-4−/− mice developed more severe GN with increased renal impairment (CCr 35 ± 7 μl/min vs. 133 ± 14 μl/min, P < 0.002) and crescent formation (55.7 ± 8.4% vs. 4.9 ± 1.2%, P < 0.002). This was associated with increased glomerular fibrin deposition, glomerular CD4+ T cell infiltration and macrophage recruitment. Systemically, IL-4−/− mice showed an increased antigen specific Th1 response indicated by increased skin DTH, and increased IgG3 and IgG2b. Decreased IgG1 levels indicated a reduced Th2 response. These results demonstrate a protective role for endogenous IL-4 in crescentic GN. They show that IL-4 deficiency promotes crescentic glomerular injury and amplifies local and systemic Th1 responses. They support the hypothesis that crescent formation results from Th1 immune responses to antigens in the glomerulus

Ageing enhances cellular immunity to myeloperoxidase and experimental anti-myeloperoxidase glomerulonephritis

OBJECTIVES: Anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis is an autoimmune disease characterised by small blood vessel inflammation, commonly affecting the kidneys and respiratory tract. It is unclear why the incidence of this condition increases with age. Previous studies in a passive antibody transfer system in aged mice have implicated innate effectors. To test the hypothesis that autoimmunity to myeloperoxidase, an autoantigen responsible for ANCA-associated vasculitis, increases with age, anti-myeloperoxidase autoimmunity was studied in murine models of active autoimmunity and disease induced by cellular immunity. METHODS: Young (8 weeks) and aged (either 15 or 22 month) mice were immunised with whole proteins or peptides from ovalbumin, as a model foreign antigen, or myeloperoxidase protein or peptides. Mice were subjected to a model of active anti-myeloperoxidase glomerulonephritis. Cellular and humoral immune responses and tissue inflammation were assessed. RESULTS: While cellular immunity to ovalbumin was diminished in aged mice, cellular autoimmunity to myeloperoxidase and its immunodominant CD4+ and CD8+ T cell epitopes was increased after immunization with either MPO peptides or whole MPO protein, assessed by peptide and antigen specific production of the pro-inflammatory cytokines interferon-γ and interleukin-17A. MPO-ANCA titres were not increased in aged mice compared with young mice. In experimental anti-MPO glomerulonephritis, cell mediated injury was increased, likely due to CD4+ and CD8+ T cells, innate immunity and the increased vulnerability of aged kidneys. CONCLUSION: Heightened cellular immunity to MPO develops with ageing in mice and may contribute to the increased incidence and severity of ANCA-associated vasculitis in older people

HLA and kidney disease: from associations to mechanisms

Since the first association between HLA and diseases of native kidneys was described almost 50 years ago, technological and conceptual advances in HLA biology and typing, together with better case ascertainment, have led to an improved understanding of HLA associations with a variety of renal diseases. A substantial body of evidence now supports the existence of HLA genetic associations in the field of renal disease beyond the role of HLA in allogeneic responses in transplant recipients. Allomorphs of HLA have emerged as important risk factors in most immune-mediated renal diseases, which, together with other genetic and environmental factors, lead to loss of tolerance and autoimmune-mediated renal inflammation. HLA associations have also been described for renal diseases that are less traditionally seen as autoimmune or immune-mediated. Here, we review essential concepts in HLA biology and the association of HLA with diseases of the native kidneys, and describe the current understanding of the epistatic and mechanistic bases of HLA-associated kidney disease. Greater understanding of the relationship between HLA and kidney function has the potential not only to further the understanding of immune renal disease at a fundamental level but also to lead to the development and application of more effective, specific and less toxic therapies for kidney diseases

Restoring speech following total removal of the larynx by a learned transformation from sensor data to acoustics

Total removal of the larynx may be required to treat laryngeal cancer: speech is lost. This article shows that it may be possible to restore speech by sensing movement of the remaining speech articulators and use machine learning algorithms to derive a transformation to convert this sensor data into an acoustic signal. The resulting “silent speech,” which may be delivered in real time, is intelligible and sounds natural. The identity of the speaker is recognisable. The sensing technique involves attaching small, unobtrusive magnets to the lips and tongue and monitoring changes in the magnetic field induced by their movement