C3d-Targeted factor H inhibits tissue complement in disease models and reduces glomerular injury without affecting circulating complement.

Complement-mediated diseases can be treated using systemic inhibitors. However, complement components are abundant in circulation, affecting systemic inhibitors' exposure and efficacy. Furthermore, because of complement's essential role in immunity, systemic treatments raise infection risk in patients. To address these challenges, we developed antibody fusion proteins combining the alternative-pathway complement inhibitor factor H (fH1-5) with an anti-C3d monoclonal antibody (C3d-mAb-2fH). Because C3d is deposited at sites of complement activity, this molecule localizes to tissue complement while minimizing circulating complement engagement. These fusion proteins bind to deposited complement in diseased human skin sections and localize to activated complement in a primate skin injury model. We further explored the pharmacology of C3d-mAb-2fH proteins in rodent models with robust tissue complement activation. Doses of C3d-mAb-2fH >1 mg/kg achieved >75% tissue complement inhibition in mouse and rat injury models while avoiding circulating complement blockade. Glomerular-specific complement inhibition reduced proteinuria and preserved podocyte foot-process architecture in rat membranous nephropathy, indicating disease-modifying efficacy. These data indicate that targeting local tissue complement results in durable and efficacious complement blockade in skin and kidney while avoiding systemic inhibition, suggesting broad applicability of this approach in treating a range of complement-mediated diseases.

The relevance of complement in pemphigoid diseases: A critical appraisal.

Pemphigoid diseases are autoimmune chronic inflammatory skin diseases, which are characterized by blistering of the skin and/or mucous membranes, and circulating and tissue-bound autoantibodies. The well-established pathomechanisms comprise autoantibodies targeting various structural proteins located at the dermal-epidermal junction, leading to complement factor binding and activation. Several effector cells are thus attracted and activated, which in turn inflict characteristic tissue damage and subepidermal blistering. Moreover, the detection of linear complement deposits in the skin is a diagnostic hallmark of all pemphigoid diseases. However, recent studies showed that blistering might also occur independently of complement. This review reassesses the importance of complement in pemphigoid diseases based on current research by contrasting and contextualizing data from in vitro, murine and human studies.

Multiple Modes of Action Mediate the Therapeutic Effect of Intravenous IgG in Experimental Epidermolysis Bullosa Acquisita.

Substitution of IgG in antibody deficiency or application of high-dose intravenous IgG in patients with autoimmunity is a well-established treatment. However, data on the mode of action of intravenous IgG are controversial and may differ for distinct diseases. In this study, we investigated the impact and molecular mechanism of high-dose IgG (hd-IgG) treatment in murine autoantibody‒induced skin inflammation, namely, epidermolysis bullosa acquisita. Epidermolysis bullosa acquisita is caused by antibodies directed against type VII collagen and is mediated by complement activation, the release of ROS, and proteases by myeloid cells. In murine experimental epidermolysis bullosa acquisita, the disease can be induced by injection of anti‒type VII collagen IgG. In this study, we substantiate that treatment with hd-IgG improves clinical disease manifestation. Mechanistically, hd-IgG reduced the amount of anti‒type VII collagen in the skin and sera, which is indicative of an FcRn-dependent mode of action. Furthermore, in a nonreceptor-mediated fashion, hd-IgG showed antioxidative properties by scavenging extracellular ROS. Hd-IgG also impaired complement activation and served as a substrate for proteases, both key events during epidermolysis bullosa acquisita pathogenesis. Collectively, the nonreceptor-mediated anti-inflammatory properties of hd-IgG may explain the therapeutic benefit of intravenous IgG treatment in skin autoimmunity.

Homozygous HOXB1 loss-of-function mutation in a large family with hereditary congenital facial paresis.

Hereditary congenital facial paresis (HCFP) belongs to the congenital cranial dysinnervation disorders. HCFP is characterized by the isolated dysfunction of the seventh cranial nerve and can be associated with hearing loss, strabismus, and orofacial anomalies. Möbius syndrome shares facial palsy with HCFP, but is additionally characterized by limited abduction of the eye(s). Genetic heterogeneity has been documented for HCFP as one locus mapped to chromosome 3q21-q22 (HCFP1) and a second to 10q21.3-q22.1 (HCFP2). The only known causative gene for HCFP is HOXB1 (17q21; HCFP3), encoding a homeodomain-containing transcription factor of the HOX gene family, which are master regulators of early developmental processes. The previously reported HOXB1 mutations change arginine 207 to another residue in the homeodomain and alter binding capacity of HOXB1 for transcriptional co-regulators and DNA. We performed whole exome sequencing in HCFP-affected individuals of a large consanguineous Moroccan family. The homozygous nonsense variant c.66C>G/p.(Tyr22*) in HOXB1 was identified in the four patients with HCFP and ear malformations, while healthy family members carried the mutation in the heterozygous state. This is the first disease-associated HOXB1 mutation with a likely loss-of-function effect suggesting that all HOXB1 variants reported so far also have severe impact on activity of this transcriptional regulator. © 2016 Wiley Periodicals, Inc.