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Biochemical Markers in Ophthalmology
Published in Ching-Yu Cheng, Tien Yin Wong, Ophthalmic Epidemiology, 2022
Abdus Samad Ansari, Pirro G. Hysi
Like any other statistical method, the power of the GWAS improves as the sample sizes increase. Successive attempts at identifying DNA polymorphisms affecting susceptibility to AMD have, at the time of writing, culminated in a study of 16,144 patients and 17,832 controls from 27 international centers participating in the International Age-related Macular Degeneration Genomics Consortium (IAMDGC) [18]. The IAMDGC study identified 52 SNPs in 34 genomic regions (or “locus”, plural “loci”) associated with altered susceptibility to AMD. In addition to the CFH genomic locus, strong associations have also been identified elsewhere, such as at loci near the ARMS2-HTRA1 genes and near the complement factor B (CFB) gene. These two SNPs alone explain more than half of the AMD genetic predisposition. Together, all 52 genomic markers are used to make predictions of AMD risk at birth (area under the curve [AUC] = 0.74–76) [18].
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
Fat Distribution and Diabetes Mellitus
Published in Emmanuel C. Opara, Sam Dagogo-Jack, Nutrition and Diabetes, 2019
Danae A. Delivanis, Michael D. Jensen
Adipose tissue is also an endocrine organ that secretes numerous adipokines. Some, such as leptin, help control energy balance. Others, including the cytokines TNF-α, IL-6, and IL-1β, are thought to modulate systemic inflammation. Another adipose hormone, adiponectin, is thought to reduce insulin resistance, while adipose-derived complement and complement-related proteins (adipsin and complement factor B) are proposed to modulate immunity.117,118
Retinal findings in glomerulonephritis
Published in Clinical and Experimental Optometry, 2022
Heather G Mack, Deborah J Colville, Phillip Harraka, Judith Anne Savige, Alessandro Invernizzi, Samantha Fraser-Bell
The most interesting therapies are APL-2 (pegcetacoplan), eculizumab and IONIS-FB-LRx. Each of these is in advanced clinical trials for both AMD and renal disease. APL-2, a PEGylated peptide administered by intravitreal injection, is an inhibitor of C3, and all downstream complement functions. It appeared to reduce geographic atrophy growth rate in a phase 2 study132 but was associated with the development of choroidal neovascularisation in a dose dependent fashion.133 A phase 3 study is underway for GA, and a phase 2 study is underway to assess its effectiveness in C3G recurring post kidney transplant (NCT04572854). Eculizumab is a humanised murine monoclonal antibody delivered by intravenous infusion, blocking the complement cascade at the level of C5 (both C5a and C5b), while C3 remains activated. It has been used off-label for treatment of dense deposit disease and C3 glomerulonephropathy23; multiple clinical trials are underway assessing its role in kidney transplant rejection. IONIS_FB_LRx is an inhibitor of complement factor B (CFB) administered by subcutaneous injection. A phase 3 study is underway for GA, and a phase 2 study to evaluate effectiveness in primary IgA Nephropathy (NCT04014335).134
Antisense Oligonucleotide Therapy for Ophthalmic Conditions
Published in Seminars in Ophthalmology, 2021
Kevin Ferenchak, Iris Deitch, Rachel Huckfeldt
The association between the alternative complement pathway and both wet and dry age-related macular degeneration (AMD) has been established in the literature and may make this pathway a target for AONs.54,55 In animal models, choroidal neovascularization (CNV) could be reduced by blocking complement factor B and thus reducing alternate complement pathway activity .55 Reducing inflammation mediated by the alternate complement pathway has been associated with slower progression of geographic atrophy (GA) in the randomized phase II trial for pegcetacoplan, an complement C3 inhibitory peptide.56 The phase II trial for lampalizumab, a monoclonal antibody against complement factor D demonstrated a significant reduction in the rate of expansion of GA although these results could not be reproduced in phase 3 trials.57,58 A phase II trial for a novel AON targeting complement factor B for patients with GA from AMD began in March 2019 under ClinicalTrials.gov no. 03815825.
Complement system network in cell physiology and in human diseases
Published in International Reviews of Immunology, 2021
Roberta Romano, Giuliana Giardino, Emilia Cirillo, Rosaria Prencipe, Claudio Pignata
The dysfunctional regulation of alternative complement pathway due to Factor H or I deficiency or C3 unresponsiveness to inhibition leads to the development of the atypical form of Hemolytic Uremic Syndrome. Usually caused, in its typical form, by Shiga-toxin producing Escherichia coli, atypical Hemolytic Uremic Syndrome is a thrombotic microangiopathy disease affecting mainly kidneys, in which deposits of C5b-C9 damage glomerular endothelium. Thereafter, intravascular hemolysis and platelets activation result in the formation of microthrombi [48]. Atypical forms account for 5 to 20% of cases of Hemolytic Uremic Syndrome and may be either due to mutations in one of more genes coding for regulatory or cascade proteins (loss of function mutations in CFH, CFI or gain of function mutations in CFB and C3) [49,50] or due to autoantibodies to factor H, detected in 5-13% of European atypical Hemolytic Uremic Syndrome patients. In such patients, genetic and autoantibodies testing are essential: the detection of anti-factor H autoantibodies may suggest the use of immunosuppressive drugs combined with plasma exchange, as therapeutic approach [51] as opposed to sero-negative atypical Hemolytic Uremic Syndrome forms in which the standard treatment choice is a humanized monoclonal antibody, Eculizumab, that binds the terminal complement component C5, as below described [51].