The paradoxical roles of C1q and C3 in autoimmunity

Scott, Diane; Botto, Marina

doi:10.1016/j.imbio.2015.05.001

Cited by 39 publications

(32 citation statements)

References 108 publications

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“…Conversely, the C1 complex, or genes that make up the C1 complex, such as C1qa, can act independently of C3 through a variety of different interactions (reviewed in ref. 71). The C1 complex can bind receptors that affect immune cell differentiation and polarization (71) or compete with binding of opsonins (including C3) to phagocytic receptors and interfere with efficient phagocytosis (72,73).…”

Section: Discussionmentioning

confidence: 99%

“…71). The C1 complex can bind receptors that affect immune cell differentiation and polarization (71) or compete with binding of opsonins (including C3) to phagocytic receptors and interfere with efficient phagocytosis (72,73). The C1q subunit, comprising C1qa, C1qb, and C1qc, has a collagen-like domain that can stabilize immune complex formation in the basement membrane (74).…”

Section: Discussionmentioning

confidence: 99%

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Early immune responses are independent of RGC dysfunction in glaucoma with complement component C3 being protective

Harder

Braine

Williams

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

103

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Various immune response pathways are altered during early, predegenerative stages of glaucoma; however, whether the early immune responses occur secondarily to or independently of neuronal dysfunction is unclear. To investigate this relationship, we used the Wld s allele, which protects from axon dysfunction. We demonstrate that DBA/2J.Wld s mice develop high intraocular pressure (IOP) but are protected from retinal ganglion cell (RGC) dysfunction and neuroglial changes that otherwise occur early in DBA/2J glaucoma. Despite this, immune pathways are still altered in DBA/2J.Wld s mice. This suggests that immune changes are not secondary to RGC dysfunction or altered neuroglial interactions, but may be directly induced by the increased strain imposed by high IOP. One early immune response following IOP elevation is up-regulation of complement C3 in astrocytes of DBA/2J and DBA/ 2J.Wld s mice. Unexpectedly, because the disruption of other complement components, such as C1Q, is protective in glaucoma, C3 deficiency significantly increased the number of DBA/2J eyes with nerve damage and RGC loss at an early time point after IOP elevation. Transcriptional profiling of C3-deficient cultured astrocytes implicated EGFR signaling as a hub in C3-dependent responses. Treatment with AG1478, an EGFR inhibitor, also significantly increased the number of DBA/2J eyes with glaucoma at the same early time point. These findings suggest that C3 protects from early glaucomatous damage, a process that may involve EGFR signaling and other immune responses in the optic nerve head. Therefore, therapies that target specific components of the complement cascade, rather than global inhibition, may be more applicable for treating human glaucoma.G laucoma is a common disorder characterized by the loss of retinal ganglion cells (RGCs) and degeneration of the optic nerve (1-3). Intraocular pressure (IOP) elevation is a major risk factor for developing glaucoma (4). Harmful IOP leads to changes in immune response pathways in nonneuronal cells, such as astrocytes and microglia/monocytes (5-9). Similar changes occur in many neurodegenerative diseases, including Parkinson's disease (10), Alzheimer's disease (11), and Huntington's disease (12). In glaucoma, immune responses are known to occur at predegenerative stages (5, 8), but key questions remain unanswered (2, 13-15). It is not known whether the earliest immune responses are protective or damaging, or which events irreversibly damage the optic nerve. Moreover, it is not known whether the immune responses are secondary to RGC dysfunction or occur independently, possibly as a more direct result of IOP elevation.In glaucoma, an early insult to RGC axons occurs where they exit the eye in the optic nerve head (ONH) (16)(17)(18)(19)(20). Modeling shows that an increase in IOP inside the eye leads to increased strain in this critical region (21,22). To understand the molecular responses occurring during glaucoma, gene expression profiles of human lamina astrocytes and ONH tissue from animal models hav...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Early immune responses are independent of RGC dysfunction in glaucoma with complement component C3 being protective

Harder

Braine

Williams

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

103

View full text Add to dashboard Cite

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“…Interestingly, and despite a prominent role for C3 opsonization in ‘waste disposal’ (that is, clearance of debris and apoptotic cells), C3 deficiencies are not strongly associated with autoimmune disease. These paradoxical roles of C1q and C3 have been explained by the observation that, whereas C1q primarily facilitates phagocytic uptake, C3 opsonins also mediate intracellular trafficking of apoptotic cargoes and enhance endocytic processing of antigens that are required for generating potentially adverse T-cell responses 9 .…”

Section: Complex Involvement In Clinical Disordersmentioning

confidence: 99%

“…Rather, complement exerts much broader functions in immune surveillance and homeostasis 1 . For example, complement assists in the clearance of immune complexes, cellular debris, and apoptotic cells and has been associated with early development and tissue repair 1,6–9 . Such a broad involvement in physiological processes can only be achieved through close communication of the complement system with other regulatory systems.…”

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confidence: 99%

Complement in disease: a defence system turning offensive

2016

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Although the complement system is primarily perceived as a host defence system, a more versatile, yet potentially more harmful side of this innate immune pathway as an inflammatory mediator also exists. The activities that define the ability of the complement system to control microbial threats and eliminate cellular debris — such as sensing molecular danger patterns, generating immediate effectors, and extensively coordinating with other defence pathways — can quickly turn complement from a defence system to an aggressor that drives immune and inflammatory diseases. These host-offensive actions become more pronounced with age and are exacerbated by a variety of genetic factors and autoimmune responses. Complement can also be activated inappropriately, for example in response to biomaterials or transplants. A wealth of research over the past two decades has led to an increasingly finely tuned understanding of complement activation, identified tipping points between physiological and pathological behaviour, and revealed avenues for therapeutic intervention. This Review summarizes our current view of the key activating, regulatory, and effector mechanisms of the complement system, highlighting important crosstalk connections, and, with an emphasis on kidney disease and transplantation, discusses the involvement of complement in clinical conditions and promising therapeutic approaches.

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confidence: 99%

THU0256 Complement C3 Exacerbates TLR7-Mediated Skin Inflammation but Not Systemic Autoimmunity

et al. 2016

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TO THE EDITORThe complement system is pivotal in protection against pathogens, but it also plays important roles in bridging innate and adaptive immune responses (Scott and Botto, 2016) and in modulating local and systemic inflammation (Markiewski and Lambris, 2007). Activation of complement occurs through three different pathways (classical, alternative, and lectin), converges at C3 cleavage, and culminates in the formation of the membrane attack complex. The anaphylatoxic fragments, C3a and C5a, generated during the proteolytic cascade, recruit immune cells that can promote the removal of debris and pathogens, but they can also cause tissue damage (Markiewski and Lambris, 2007). The main source of complement is the liver. However, locally produced complement, particularly C3, can modulate inflammation in a variety of organs. There is also evidence that complement components are produced not only by immune cells such as macrophages and dendritic cells but also by nonimmune cells, which can contribute to local complement synthesis. In the skin, keratinocytes are a potential source of C3 (Pasch et al., 2000). A role for C3 in the skin has been identified in UV-induced immune tolerance (Hammerberg et al., 1998) and in the protection against Tcellemediated inflammation (Purwar et al., 2011). Furthermore, locally produced C3 contributes to the inflammatory responses accompanying wound healing (Rafail et al., 2014), an effect mediated mainly through C5a/C5aR interactions. The latter also play an important role in influencing the skin microbiome (Chehoud et al., 2013). In keeping with these observations in animal models, complement has been shown to have a role in the pathogenesis of many human skin diseases, including psoriasis (Kotnik, 2011).Psoriasis is an inflammatory skin disease characterized by epidermal hyperplasia, infiltration of immune cells, and secretion of inflammatory cytokines (Tortola et al., 2012). The anaphylatoxic fragments, C3a and C5a, have been found in corneal scale extracts from psoriatic lesions (Takematsu et al., 1986). The C5a from these lesions has been shown to chemoattract monocyte-derived dendritic cells (Mrowietz et al., 2001), indicating that complement may contribute to the inflammatory process in this disease. In the inducible AP-1edependent psoriasis-like mouse model, the S100A8-S100A9 complex that promotes skin inflammation has been shown to up-regulate C3 expression (Schonthaler et al., 2013). Psoriasis-like dermatitis can be induced by topical application of the toll-like receptor 7 agonist imiquimod (IMQ) (van der Fits et al., 2009) in the form of Aldara cream (3M Pharmaceuticals, St Paul, MN) (Walter et al., 2013). Here, we explore the role of complement in IMQ-mediated psoriasiform dermatitis.We first tested whether cutaneous IMQ treatment induces local C3 synthesis (experimental methods are provided as Supplementary Materials online) and found a progressive increase in C3 mRNA in the skin with repeated IMQ applications ( Figure 1a, and see Supplementary Figure S1a that the ...

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The paradoxical roles of C1q and C3 in autoimmunity

Cited by 39 publications

References 108 publications

Early immune responses are independent of RGC dysfunction in glaucoma with complement component C3 being protective

Early immune responses are independent of RGC dysfunction in glaucoma with complement component C3 being protective

Complement in disease: a defence system turning offensive

THU0256 Complement C3 Exacerbates TLR7-Mediated Skin Inflammation but Not Systemic Autoimmunity

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