ABSTRACT
Evaluating the activity of the complement system under conditions of altered thyroid hormone levels might help elucidate the role of complement in triggering autoimmune processes. Here, we investigated alternative pathway (AP) activity in male Wistar rats (180 ± 10 g) after altering their thyroid hormone levels by treatment with triiodothyronine (T3), propylthiouracil (PTU) or thyroidectomy. T3 and thyroxine (T4) levels were determined by chemiluminescence assays. Hemolytic assays were performed to evaluate the lytic activity of the AP. Factor B activity was evaluated using factor B-deficient serum. An anti-human factor B antibody was used to measure factor B levels in serum by radial immunodiffusion. T3 measurements in thyroidectomized animals or animals treated with PTU demonstrated a significant reduction in hormone levels compared to control. The results showed a reduction in AP lytic activity in rats treated with increasing amounts of T3 (1, 10, or 50 µg). Factor B activity was also decreased in the sera of hyperthyroid rats treated with 1 to 50 µg T3. Additionally, treating rats with 25 µg T3 significantly increased factor B levels in their sera (P < 0.01). In contrast, increased factor B concentration and activity (32 percent) were observed in hypothyroid rats. We conclude that alterations in thyroid hormone levels affect the activity of the AP and factor B, which may in turn affect the roles of AP and factor B in antibody production.
Subject(s)
Animals , Male , Rats , Antithyroid Agents/pharmacology , Complement Factor B/metabolism , Complement Pathway, Alternative/drug effects , Propylthiouracil/pharmacology , Thyroxine/blood , Triiodothyronine/blood , Complement Pathway, Alternative/physiology , Hyperthyroidism/blood , Hyperthyroidism/chemically induced , Hyperthyroidism/immunology , Hypothyroidism/blood , Hypothyroidism/chemically induced , Hypothyroidism/immunology , Luminescent Measurements , Rats, Wistar , ThyroidectomyABSTRACT
Emerging treatments for dry age-related macular degeneration (AMD) and geographi c atrophy focus on two strategies that target components involved in physiopathological pathways: prevention of photoreceptors and retinal pigment epithelium loss (neuroprotection induction, oxidative damage prevention, and visual cycle modification) and suppression of inflammation. Neuroprotective drugs, such as ciliary neurotrophic factor, brimonidine tartrate, tandospirone, and anti-amyloid β antibodies, aim to prevent apoptosis of retinal cells. Oxidative stress and depletion of essential micronutrients are targeted by the Age-Related Eye Disease Study (AREDS) formulation. Visual cycle modulators reduce the activity of the photoreceptors and retinal accumulation of toxic fluorophores and lipofuscin. Eyes with dry age-related macular degeneration present chronic inflammation and potential treatments include corticosteroid and complement inhibition. We review the current concepts and rationale of dry age-related macular degeneration treatment that will most likely include a combination of drugs targeting different pathways involved in the development and progression of age-related macular degeneration.
Os novos tratamentos para a forma seca da degeneração macular relacionada à idade (DMRI) e da atrofia geográfica têm sido baseados em duas estratégias que abordam componentes envolvidos nos mecanismos fisiopatológicos da doença: prevenção da perda de fotorreceptores e células do epitélio pigmentado da retina (indução de neuroproteção, diminuição do dano oxidativo e modificação do ciclo visual) e supressão da inflamação. As drogas neuroprotetoras visam evitar a apoptose das células retinianas, como o fator neurotrófico ciliar, o tartarato de brimonidina, a tandosporina e anticorpos antiamiloide β. A redução do dano oxidativo e a complementação de micronutrientes essenciais são os objetivos da fórmula AREDS. Os modificadores do ciclo visual reduzem a atividade dos fotorreceptores e o acúmulo de fluoróforos tóxicos e lipofuscina na retina. Olhos com a forma seca da degeneração macular relacionada à idade apresentam inflamação crônica e os novos tratamentos incluem corticosteroides e inibidores do sistema complemento. Neste artigo, revisamos o estágio atual do tratamento da forma seca da degeneração macular relacionada à idade que provavelmente será feito através da combinação de drogas que agem em diferentes componentes envolvidos no aparecimento e na progressão da degeneração macular relacionada à idade.
Subject(s)
Animals , Humans , Macular Degeneration/drug therapy , Clinical Trials as Topic , Complement Pathway, Alternative/drug effectsABSTRACT
La interacción de complejos inmunes (CI) con receptores para el fragmento Fc de IgG (RFcgama) expresados en leucocitos pone en marcha mecanismos efectores y regulatorios de suma relevancia en el curso de la respuesta inmune. En trabajos anteriores, empleando la citotoxicidad celular dependiente de anticuerpos (ADCC) como expresión funcional de los RFcy, hemos demostrado que las células monocucleares periféricas humanas (CMPH), previamente bloqueadas en CI, recuperan la capacidad de mediar la ADCC a través de la activación de la vía alternativa del complemento (VAC). El objetivo de este trabajo fue analizar los mecanismos de recuperación funcional de los RFcgama cuando éstos han sido bloqueados por CI no fijadores de complemento (C). A tal fin, la IgG usada para preparar los CI se trató con carbodiimida (CDI), procedimiento que modifica su capacidad para fijar C, sin alterar mayormente su sitio de combinación con el antígeno, ni su habilidad para unirse a los RFcgama. Los resultados obtenidos demostraron que el C sólo es eficiente para revertir el bloqueo de la ADCC por CI, cuando éstos son capaces de fijar C