Complement C1s as a diagnostic marker and therapeutic target: Progress and propective

Abstract

The molecules of the complement system connect the effectors of innate and adaptive immunity and play critical roles in maintaining homeostasis. Among them, the C1 complex, composed of C1q, C1r, and C1s (C1qr2s2), is the initiator of the classical complement activation pathway. While deficiency of C1s is associated with early-onset systemic lupus erythematosus and increased susceptibility to bacteria infections, the gain-of- function variants of C1r and C1s may lead to periodontal Ehlers Danlos syndrome. As C1s is activated under various pathological conditions and associated with inflammation, autoimmunity, and cancer development, it is becoming an informative biomarker for the diagnosis and treatment of a variety of diseases. Thus, more sensitive and convenient methods for assessing the level as well as activity of C1s in clinic samples are highly desirable. Meanwhile, a number of small molecules, peptides, and monoclonal antibodies targeting C1s have been developed. Some of them are being evaluated in clinical trials and one of the antibodies has been approved by US FDA for the treatment of cold agglutinin disease, an autoimmune hemolytic anemia. In this review, we will summarize the biological properties of C1s, its association with development and diagnosis of diseases, and recent progress in developing drugs targeting C1s. These progress illustrate that the C1s molecule is an effective biomarker and promising drug target.

Degradation of collagen I by activated C1s in periodontal Ehlers-Danlos Syndrome

“…However, complement analysis in pEDS patients does not usually show any abnormalities ( 4 ), and beyond activation of the complement components C4 and C2, C1s has been shown to act on wide range of cellular protein and regulatory pathways ( 12 ). There is no evidence that C4 is indeed the main target of activated C1s outside the C1 complex in vivo , and uncontrolled production of aC1s may have various complement-independent effects depending on the molecular availability of other substrates.…”

“…A number of studies have suggested a variety of biological functions of C1s beyond its role in complement activation ( 12 ). In 1990, Yamaguchi and colleagues reported that aC1s may proteolytically cleave collagens I and II in an in vitro assay ( 13 ).…”

Integrated analysis to identify the prognostic and immunotherapeutic roles of coagulation-associated gene signature in clear cell renal cell carcinoma

“…Studies have shown that abnormal activation of C1S contributes to the development of autoimmune and infectious diseases. In addition, the overexpression of C1S may be a new escape mechanism to promote tumor progress (54). CASP4, as a gene related to cell apoptosis, is differentially expressed in a variety of tumors, and can be used to predict the prognosis of tumor patients (55,56).…”

HMGB1 cleavage by complement C1s and its potent anti-inflammatory product

“…This study therefore focuses on how free complement C1s protease cleaves HMGB1 and how this could impact HMGB1 inflammatory cytokine signaling. This is interesting because activated C1s is found in some specific disease contexts such as SLE (48) but also in other autoimmune and cancer disease contexts (49)(50)(51). At present, it is not known if this pathological activated C1s is in a free form or not, but it likely escapes from the functional control of C1q and C1-INH.…”