C3 Glomerulopathy and Therapeutic Potential of C5 Complement Inhibitors

C3 glomerulopathy is a disease including both dense deposit disease and C3 glomerulonephritis has an estimated prevalence of 2 to 3 per million. Originally, these pathologies were defined as glomerular pathology characterized by accumulation of C3 with absent or scanty immunoglobulin deposition. The keystone defect in both of these pathologies is the unregulated hyperactivity of alternative complement pathway. Specifically, in C3 glomerulopathy patients, there exists a prolongation of C3 cleavage which causes the uncontrolled alternative pathway activation. Many treatments have been investigated for treating C3 glomerulopathy to little or no avail, including calcineurin inhibitors, plasmapharesis, and anti-CD20 monoclonal antibodies. The next logical step is exploring the efficacy of anti-C5 monoclonal antibody therapy in C3 glomerulopathies to target the specific pathophysiology of this particular disease. Eculizumab is an anti-C5 monoclonal antibody that blocks the terminal step of complement activation. This drug has proven to be an effective treatment in other nephrologic pathologies that are caused by complement dysregulation. Here in this paper we discuss and present various case studies and clinical trials available that experiment with Eculizumab in patients with either dense deposit disease or C3 glomerulonephritis. In most of these patients, treatment with Eculizumab has demonstrated clinical and biochemical improvements in kidney function. These results provide encouraging evidence that suggest Eculizumab as a promising therapy for patients with C3 glomerulopathy and warrant that more extensive clinical trials can be designed as a next step.

High-throughput RNA sequencing reveals the anti-inflammatory mechanism of baicalin on Propionibacterium acnes-induced acne in rabbits

Objective:Propionibacterium acnes(P.acnes)plays an important role in the development of acne,an inflammatory skin disease with a high-incidence.In this study,we used high-throughput RNA sequencing(RNA-seq)to reveal the anti-inflammatory mechanism of baicalin on P.acnes-induced acne in rabbits.Methods:The Kligman method was used to induce acne in the ears of New Zealand rabbits.The effect of baicalin on the acne model was evaluated by the number of acne lesions and hematoxylin and eosin(H&E)staining of acne tissues.Enzyme-linked immunoabsorbent assay was used to measure the protein expression levels of tumor necrosis factor a(TNFA),interleukin-1 b(IL1B),IL6,and IL8 in the serum of rabbits.RNA-seq was performed to investigate the mechanism of anti-inflammatory activities of baicalin on acne.Immunohistochemical analysis and Western blot were used to validate the expression levels of related proteins in acne tissues.Results:Baicalin treatment significantly reduced the number of acne lesions and lesions of the ear as well as levels of serum inflammatory cytokines.RNA-seq data showed that baicalin treatment globally suppressed inflammation,especially the TNF signaling pathway and Staphylococcus aureus infection pathway,in the rabbit acne model.Conclusion: Baicalin effectively ameliorates P. acnes-induced acne in rabbits by suppressingthe inflammatory response in rabbits.

Reclassification of membranoproliferative glomerulonephritis:Identification of a new GN:C3GN

This review revises the reclassification of the mem-branoproliferative glomerulonephritis （MPGN） after the consensus conference that by 2015 reclassified all the glomerulonephritis basing on etiology and patho-genesis, instead of the histomorphological aspects. After reclassification, two types of MPGN are to date recognized： The immunocomplexes mediated MPGN and the complement mediated MPGN. The latter type is more extensively described in the review either because several of these entities are completely new or because the improved knowledge of the complement cascade allowed for new diagnostic and therapeutic approaches. Overall the complement mediated MPGN are related to acquired or genetic cause. The presence of circulating auto antibodies is the principal acquired cause. Genetic wide association studies and family studies allowed to recognize genetic mutations of different types as causes of the complement dysregulation. The complement cascade is a complex phenomenon and activating factors and regulating factors should be distinguished. Genetic mutations causing abnormalities either in activating or in regulating factors have been described. The diagnosis of the complement mediated MPGN requires a complete study of all these different complement factors. As a consequence, new therapeutic approaches are becoming available. Indeed, in addition to a nonspecifc treatment and to the immunosuppression that has the aim to block the auto antibodies production, the specific inhibition of complement activation is relatively new and may act either blocking the C5 convertase or the C3 convertase. The drugs acting on C3 convertase are still in different phases of clinical development and might represent drugs for the future. Overall the authors consider that one of the principal problems in fnding new types of drugs are both the rarity of the disease and the consequent poor interest in the marketing and the lack of large international cooperative studies.