Complement and autoimmunity

Abstract

The complement system is a component of the innate immune system. Its main function was initially believed to be limited to the recognition and elimination of pathogens through direct killing or stimulation of phagocytosis. However, in recent years, the immunoregulatory functions of the complement system were demonstrated and it was determined that the complement proteins play an important role in modulating adaptive immunity and in bridging innate and adaptive responses. When the delicate mechanisms that regulate this sophisticated enzymatic system are unbalanced, the complement system may cause damage, mediating tissue inflammation. Dysregulation of the complement system has been involved in the pathogenesis and clinical manifestations of several autoimmune diseases, such as systemic lupus erythematosus, vasculitides, Sjögren's syndrome, antiphospholipid syndrome, systemic sclerosis, dermatomyositis, and rheumatoid arthritis. Complement deficiencies have been associated with an increased risk to develop autoimmune disorders. Because of its functions, the complement system is an attractive therapeutic target for a wide range of diseases. Up to date, several compounds interfering with the complement cascade have been studied in experimental models for autoimmune diseases. The main therapeutic strategies are inhibition of complement activation components, inhibition of complement receptors, and inhibition of membrane attack complex. At present, none of the available agents was proven to be both safe and effective for treatment of autoimmune diseases in humans. Nonetheless, data from preclinical studies and initial clinical trials suggest that the modulation of the complement system could constitute a viable strategy for the treatment of autoimmune conditions in the decades to come.

Toward a Unified Biosignature for Tuberculosis

“…Involvement of the complement system is also observed in autoimmune diseases like SLE (Ballanti et al 2013), in which the disease is not triggered by a pathogen, but rather by a dysregulated chronic activation of the complement system. Complement activation in TB and similarities with SLE are also illustrated by the high enrichment of TB-induced genes in signatures associated with SLE (Maertzdorf et al 2011a).…”

Prospects for the design of new therapeutically significant protease inhibitors based on knottins and sunflower seed trypsin inhibitor (SFTI 1)

“…Однако при развитии патологических процессов часто нарушается протеазно-ингибиторный баланс в сторону повышения протеазной активности и может происходить выброс внутриклеточных протеаз в межклеточную жидкость [10]. Наиболее яркие примеры таких нарушений и их последствий -тромбоз кровеносных сосудов в результате усиленной активации тромбина (КФ 3.4.21.5) [11], повышенная активация системы комплемента (значительная часть которой представлена сериновыми протеазами), приводящая к развитию аутоиммунных заболеваний [12], активация матриптазой (КФ 3.4.21.109) инвазии опухолевых клеток в здоровые ткани и запуск этим ферментом процессов онкогенеза [13,14], развитие анафилаксии в результате выброса из гранул тучных клеток триптазы (КФ 3.4.21.59) и т.д. [15,16].…”

Complement-Targeted Therapies in Lupus

“…The complement system is a complex set of enzymes with activation occurring through three different pathways, the classical, the alternative, and the lection pathways [3,4]. All three converge at C3, but each has different roles in health and disease and each has different mechanisms of activation.…”