Intracellular complement − the complosome − in immune cell regulation

Abstract

The complement system was defined over a century ago based on its ability to "complement" the antibody-mediated and cell-mediated immune responses against pathogens. Today our understanding of this ancient part of innate immunity has changed substantially and we know now that complement plays an undisputed pivotal role in the regulation of both innate and adaptive immunity. The complement system consists of over 50 blood-circulating, cell-surface expressed and intracellular proteins. It is key in the recognition and elimination of invading pathogens, also in the removal of self-derived danger such as apoptotic cells, and it supports innate immune responses and the initiation of the general inflammatory reactions. The long prevailing classic view of complement was that of a serum-operative danger sensor and first line of defence system, however, recent experimental and clinical evidences have demonstrated that "local" tissue and surprisingly intracellular complement (the complosome) activation impacts on normal cell physiology. This review will focus on novel aspects of intracellular complement activation and its unexpected roles in basic cell processes such as metabolism. We also discuss what the existence of the complosome potentially means for how the host handles intracellular pathogens such as viruses.

Modulation of three key innate immune pathways for the most common retinal degenerative diseases

“…Locally produced complements are known to play an important role in tissue homeostasis, and thus, dysfunction or dysregulation of the system may contribute to various diseases. Recent studies have shown that the complement system can also be activated inside the cell, and intracellular complement activation is known to be involved in many important cellular functions, including intracellular pathogen recognition/elimination, cytokine production, and metabolism (Arbore et al, ; Kolev & Kemper, ; Liszewski et al, ).…”

Novel mechanisms and functions of complement

“…Besides the classic components (C1-C9) of the cascade, the integrated complement system overall contains some 50 proteins. These form an elaborate network of fluid-phase, cell surface-associated, and intracellular proteins, which function as pattern-recognition molecules, proteases/convertases, regulators, and signaling receptors, collectively mediating immune surveillance and tissue homeostasis 2,3 .…”

“…Complement components can be secreted locally by tissue-resident and infiltrating cells, while emerging evidence suggests the existence of an intracellular complement system with novel homeostatic and immune functions 2 . New insights into the mechanisms and locations of complement activation have revealed a new layer of complexity in the biology of complement and its impact on health and disease 7,8 .…”

Acetylcholine receptor antibody–mediated animal models of myasthenia gravis and the role of complement

“…Therefore, complement deficiency influences cellular immune mechanisms. 31 Despite the presence of AChR-specific antibodies, neuromuscular junctions showed an absence of C3 or MAC deposits when EAMG was induced in C3-deficient mice. C5 is a critical component in the development of EAMG.…”

“…Both C3‐ and C4‐deficient animals demonstrate a reduced AChR IgG2b level and reduced B cell expression in the nonimmunized state, which remains low with EAMG induction. Therefore, complement deficiency influences cellular immune mechanisms . Despite the presence of AChR‐specific antibodies, neuromuscular junctions showed an absence of C3 or MAC deposits when EAMG was induced in C3‐deficient mice.…”