SLE: Novel Postulates for Therapeutic Options
Genetic deficiency in C1q is a strong susceptibility factor for systemic lupus erythematosus (SLE). There are two major hypotheses that potentially explain the role of C1q in SLE. The first postulates that C1q deficiency abrogates apoptotic cell clearance, leading to persistently high loads of poten...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2020-10-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2020.583853/full |
| _version_ | 1819206884168564736 |
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| author | Kinga K. Hosszu Alisa Valentino Ellinor I. Peerschke Berhane Ghebrehiwet |
| author_facet | Kinga K. Hosszu Alisa Valentino Ellinor I. Peerschke Berhane Ghebrehiwet |
| author_sort | Kinga K. Hosszu |
| collection | DOAJ |
| description | Genetic deficiency in C1q is a strong susceptibility factor for systemic lupus erythematosus (SLE). There are two major hypotheses that potentially explain the role of C1q in SLE. The first postulates that C1q deficiency abrogates apoptotic cell clearance, leading to persistently high loads of potentially immunogenic self-antigens that trigger autoimmune responses. While C1q undoubtedly plays an important role in apoptotic clearance, an essential biological process such as removal of self- waste is so critical for host survival that multiple ligand-receptor combinations do fortunately exist to ensure that proper disposal of apoptotic debris is accomplished even in the absence of C1q. The second hypothesis is based on the observation that locally synthesized C1q plays a critical role in regulating the earliest stages of monocyte to dendritic cell (DC) differentiation and function. Indeed, circulating C1q has been shown to keep monocytes in a pre-dendritic state by silencing key molecular players and ensuring that unwarranted DC-driven immune responses do not occur. Monocytes are also able to display macromolecular C1 on their surface, representing a novel mechanism for the recognition of circulating “danger.” Translation of this danger signal in turn, provides the requisite “license” to trigger a differentiation pathway that leads to adaptive immune response. Based on this evidence, the second hypothesis proposes that deficiency in C1q dysregulates monocyte-to-DC differentiation and causes inefficient or defective maintenance of self-tolerance. The fact that C1q receptors (cC1qR and gC1qR) are also expressed on the surface of both monocytes and DCs, suggests that C1q/C1qR may regulate DC differentiation and function through specific cell-signaling pathways. While their primary ligand is C1q, C1qRs can also independently recognize a vast array of plasma proteins as well as pathogen-associated molecular ligands, indicating that these molecules may collaborate in antigen recognition and processing, and thus regulate DC-differentiation. This review will therefore focus on the role of C1q and C1qRs in SLE and explore the gC1qR/C1q axis as a potential target for therapy. |
| first_indexed | 2024-12-23T05:14:41Z |
| format | Article |
| id | doaj.art-5a22f3eac8e54fb38584e634dcea26c7 |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-23T05:14:41Z |
| publishDate | 2020-10-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-5a22f3eac8e54fb38584e634dcea26c72022-12-21T17:58:52ZengFrontiers Media S.A.Frontiers in Immunology1664-32242020-10-011110.3389/fimmu.2020.583853583853SLE: Novel Postulates for Therapeutic OptionsKinga K. Hosszu0Alisa Valentino1Ellinor I. Peerschke2Berhane Ghebrehiwet3Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, United StatesDepartment of Lab Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, United StatesDepartment of Lab Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, United StatesThe Department of Medicine, Stony Brook University, Stony Brook, NY, United StatesGenetic deficiency in C1q is a strong susceptibility factor for systemic lupus erythematosus (SLE). There are two major hypotheses that potentially explain the role of C1q in SLE. The first postulates that C1q deficiency abrogates apoptotic cell clearance, leading to persistently high loads of potentially immunogenic self-antigens that trigger autoimmune responses. While C1q undoubtedly plays an important role in apoptotic clearance, an essential biological process such as removal of self- waste is so critical for host survival that multiple ligand-receptor combinations do fortunately exist to ensure that proper disposal of apoptotic debris is accomplished even in the absence of C1q. The second hypothesis is based on the observation that locally synthesized C1q plays a critical role in regulating the earliest stages of monocyte to dendritic cell (DC) differentiation and function. Indeed, circulating C1q has been shown to keep monocytes in a pre-dendritic state by silencing key molecular players and ensuring that unwarranted DC-driven immune responses do not occur. Monocytes are also able to display macromolecular C1 on their surface, representing a novel mechanism for the recognition of circulating “danger.” Translation of this danger signal in turn, provides the requisite “license” to trigger a differentiation pathway that leads to adaptive immune response. Based on this evidence, the second hypothesis proposes that deficiency in C1q dysregulates monocyte-to-DC differentiation and causes inefficient or defective maintenance of self-tolerance. The fact that C1q receptors (cC1qR and gC1qR) are also expressed on the surface of both monocytes and DCs, suggests that C1q/C1qR may regulate DC differentiation and function through specific cell-signaling pathways. While their primary ligand is C1q, C1qRs can also independently recognize a vast array of plasma proteins as well as pathogen-associated molecular ligands, indicating that these molecules may collaborate in antigen recognition and processing, and thus regulate DC-differentiation. This review will therefore focus on the role of C1q and C1qRs in SLE and explore the gC1qR/C1q axis as a potential target for therapy.https://www.frontiersin.org/article/10.3389/fimmu.2020.583853/fullc1qgC1qRcC1qRcomplementSLEnovel hypothesis |
| spellingShingle | Kinga K. Hosszu Alisa Valentino Ellinor I. Peerschke Berhane Ghebrehiwet SLE: Novel Postulates for Therapeutic Options Frontiers in Immunology c1q gC1qR cC1qR complement SLE novel hypothesis |
| title | SLE: Novel Postulates for Therapeutic Options |
| title_full | SLE: Novel Postulates for Therapeutic Options |
| title_fullStr | SLE: Novel Postulates for Therapeutic Options |
| title_full_unstemmed | SLE: Novel Postulates for Therapeutic Options |
| title_short | SLE: Novel Postulates for Therapeutic Options |
| title_sort | sle novel postulates for therapeutic options |
| topic | c1q gC1qR cC1qR complement SLE novel hypothesis |
| url | https://www.frontiersin.org/article/10.3389/fimmu.2020.583853/full |
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