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Gene Therapy for Lung Cancer
Published in Kenneth L. Brigham, Gene Therapy for Diseases of the Lung, 2020
Choon Taek Lee, David P. Carbone
Tumor necrosis factor has direct cytolytic effects on tumor cells and attracts and augments the tumoricidal activity of macrophages (33). Systemic administration of TNF, however, was too toxic to achieve significant in vivo antitumor effects. Local production of TNF-α by retroviral transduction into the TNF-insensitive tumor cell line (J558L) drastically suppressed tumorigenicity in a syngenic animal, even though it did not appreciably affect growth in vitro (34). Administration of an anti-type 3 complement factor receptor to block the migration of inflammatory cells abolished the antitumor effects of TNF-α, which suggested the involvement of an inflammatory mechanism including the activation of macrophages (34). The antitumor effect of TNF-α was also proven in human lung cancer cell lines even though most human tumor cells are resistant to TNF-α. Insertion of human TNF-α cDNA into several human lung cancer cells resulted in decreased tumorigenicity in nude mice (35). Furthermore, injection of a mixture of 50% gene-modified and 50% parental cells also showed decreased tumor formation. These data suggest that local production of TNF-α can induce antitumor effects on human lung cancer cell growth, and every tumor cell need not be gene-modified to produce local antitumor effects.
The nervous system and the eye
Published in C. Simon Herrington, Muir's Textbook of Pathology, 2020
James A.R. Nicoll, William Stewart, Fiona Roberts
Age-related macular degeneration (ARMD) is the most important cause of untreatable visual loss in the ageing Western population. The pathogenesis is poorly understood but recent studies have implicated local inflammation and activation of complement among the processes involved. In particular, a specific polymorphism (Y402H) in the gene encoding complement factor H is strongly associated with disease susceptibility. The disease results in atrophy of photoreceptors at the macula and is accompanied by degenerative changes in the retinal pigment epithelium (RPE) (dry ARMD). This degeneration in the RPE may be complicated by haemorrhage and fibrosis (wet ARMD; disciform degeneration). The overlying photoreceptor tissue is destroyed with loss of central vision. Early disciform degeneration may now be successfully treated by intraocular injection of anti-VEGF antibodies.
Gonadotropins and Sex Hormones
Published in Istvan Berczi, Pituitary Function and Immunity, 2019
Women were found to have significantly higher IgM serum levels than men, both as adults and children older than 6 years. Although the mean IgG level was found to be markedly higher and the mean IgA concentration was slightly higher in blacks than in whites, in the younger adults of both races mean IgM values were markedly higher in females than in males.49,50 Concentrations of either complement components were determined in sera of 419 healthy children aged 1 to 19 years. A significant correlation between concentration and age for all components (Clq, cls, C4, C3, C5, factor B, properdin, and C1 inhibitor) was observed for girls. However, in boys a significant correlation was present only for Clq, C1, C3, C5, and properdin.51 The polymorphism of complement factor B was analyzed in six different mouse strains. Females of each strain had only three bands compared with the four or five found in males. However, no differences were found in the serum level between males and females.52
Severe acute kidney injury following Sri Lankan Hypnale spp. envenoming is associated with thrombotic microangiopathy
Published in Clinical Toxicology, 2021
Eranga S. Wijewickrama, Lalindra V. Gooneratne, Ariaranee Gnanathasan, Indika Gawarammana, Mangala Gunatilake, Geoffrey K. Isbister
The pathophysiology of TMA and its association with AKI in snakebites is poorly understood. Thrombotic thrombocytopaenic purpura (TTP) and haemolytic uraemic syndrome (HUS) are the prototype diseases associated with TMA [27]. TTP is caused by the reduction in the amount or the function of ADAMTS13, which is an enzyme, required to cleave the giant multimers of von Willebrand Factor (vWF). Increase in the circulating multimers of vWF lead to excessive platelet adhesion in arterioles and capillaries leading to thrombi formation. The disease is characterized by fever, neurological dysfunction and acute kidney injury in addition to MAHA and thrombocytopenia. The classic form of HUS follows a diarrhoeal illness due to Shiga toxin producing serotypes of E. coli or Shigella species and is associated with normal ADAMTS13 activity. Shiga toxin triggers a cascade of signalling events resulting in loss of anti-adhesive, anti-inflammatory and thromboresistant properties of glomerular endothelial cells leading to platelet adhesion and thrombus formation causing TMA [28]. In the atypical form of HUS (aHUS), which may or not be associated with diarrhoea, the endothelial cell damage and subsequent glomerular microthrombi formation is caused by dysregulation of the alternative complement pathway leading to excessive activation of the terminal complement pathway [29]. Complement abnormalities have been detected in about 50% of patients with aHUS including loss of function mutations in membrane co-factor protein, complement factor H, complement factor I and autoantibodies to factors H and I.
Renal microvascular lesions in lupus nephritis
Published in Renal Failure, 2020
Ying Ding, Ying Tan, Zhen Qu, Feng Yu
IgG is considered to be the predominant antibody constituting the ICDs in LN [32]. It was thought that the pathology underlying this type of vasculopathy was similar to those that mediate glomerular and tubulo-interstitial immune deposits formation. However, Satoskar et al. found that in a total of 40 arterial/arteriolar IgG-positive patients, the IgG subclass pattern was discordant in 27 biopsies, with stronger IgG subclass staining in the vascular walls of six patients. This indicated that the IgG subclass may not just represent the same circulating ICs distributed within the different compartments of the kidney. They also found that the staining for each of the IgG subclasses showed better correlation with C1q than with C3 in the glomeruli, tubular basement membrane (TBM), and vasculature, which supported the role of classical complement pathway activation in the development of tissue injury in LN [33]. The ICs in the vascular endothelium trigger an inflammatory response, which involves activation of the complement cascade and subsequent destruction of the vascular basal membranes and inflammatory cell infiltrates. The deficiency or dysfunction of some complement regulators, such as complement factor H (CFH), would induce the immunological attack or lose the protection from the injury [34].
CFH Y402H polymorphism in Italian patients with age-related macular degeneration, retinitis pigmentosa, and Stargardt disease
Published in Ophthalmic Genetics, 2018
Andrea Sodi, Ilaria Passerini, Daniela Bacherini, Luca Boni, Simona Palchetti, Vittoria Murro, Orsola Caporossi, Dario Pasquale Mucciolo, Fabrizio Franco, Lorenzo Vannozzi, Francesca Torricelli, Elisabetta Pelo, Stanislao Rizzo, Gianni Virgili
The complement system is an essential part of innate immunity and also plays a central role in modulating the adaptive immune response (19). However, inappropriate complement function may lead to various human diseases (20–23) and has been involved in the pathogenesis of AMD (24–27). Among the variants of the genes encoding complement pathway proteins, the CFH Y402H polymorphism (rs1061170) is considered to be one of the most significant genetic factors associated with an increased risk of AMD (28–41), even though the strength of the association with AMD may be lower in specific ethnic groups (42,43). In fact, Complement Factor H (CFH) is the main inhibitor of the complement alternative pathway and the impairment of its function may be associated with an increased activation of complement function with a final proinflammatory effect.