The α5 Chain of Type IV Collagen Is the Target of IgG Autoantibodies in a Novel Autoimmune Disease with Subepidermal Blisters and Renal Insufficiency

Abstract

We describe a novel autoimmune disease characterized by severe subepidermal bullous eruptions and renal insufficiency with IgG autoantibodies directed against the NC1 domain of the ␣5(IV) collagen chain. In vivo deposits of IgG and C3 were found along the dermal-epidermal junction of skin lesions. The identity of the target antigen was determined by immunochemical analyses of candidate antigens using the patients' autoantibodies. The patients' IgG autoantibodies reacted with a 185-kDa polypeptide that was distinguished from the known autoantigens of the extracellular matrix including type XVII collagen, type VII collagen, or the ␣3, ␤3, and ␥2 chains of laminin 5. Preincubation of the serum with recombinant ␣5(IV)NC1 domain of type IV collagen abolished immunoreactivity with the 185-kDa antigen. The serum reacted specifically with the ␣5(IV)NC1, among the six NC1 domains of type IV collagen, by Western blot and enzyme-linked immunosorbent assay analyses. The patients' autoantibodies reacted with normal skin and renal glomerulus but not with skin and glomerulus of a patient with Alport syndrome in which the basement membranes are devoid of the ␣5(IV) collagen chain. This study provided for the first time unambiguous evidence for the ␣5(IV) collagen chain as the target antigen in a novel autoimmune disease characterized by skin and renal involvement.

Humoral Autoimmunity to Basement Membrane Antigens Is Regulated in C57BL/6 and MRL/MpJ Mice Transgenic for Anti-Laminin Ig Receptors

“…Structurally diverse soluble, matrix, and cell surface proteins and glycolipids distributed throughout the kidney incite injury in animals (reviewed in Ref. 1), whereas basement membrane proteins are the only confirmed Ag targets in human immune nephritis (2)(3)(4)(5). Basement membranes are highly organized molecular scaffolds that require proper assembly to correctly present their cell and cytokine binding domains (6).…”

“…The H chain V region was cloned from an anti-laminin IgG, mAb H50, derived from a systemic lupus erythematosus (SLE) 3 MRL/MpJ-Tnfrsf6 lpr (formerly, MRL/MpJ-Fas lpr ; hereafter, MRL/lpr) mouse with nephritis (24). It binds in vitro to murine laminin-1, including an epitope on the ␣1 chain expressed in adult glomerulus and renal tubular basement membranes, and forms renal immune deposits in vivo (24).…”

In vitro and in vivo models to investigate the pathomechanisms and novel treatments for pemphigoid diseases

“…In addition, few patients have a pemphigoid disease that is characterized by renal insufficiency and autoantibodies against the α5-chain of type IV collagen (α5(IV)COL). [7] In total, PD includes eight disorders, which are summarized in Table 1. [2,7] The investigation of PDs is important to improve our understanding of these life-threatening and difficult-to-treat diseases.…”

“…[7] In total, PD includes eight disorders, which are summarized in Table 1. [2,7] The investigation of PDs is important to improve our understanding of these life-threatening and difficult-to-treat diseases. For that reason, we use different in vivo and in vitro models for testing new therapeutics and for unravelling the pathomechanistic processes that finally induce blister formation.…”

Autotopes and Allotopes

“…Will the XLAS allotope be relatively accessible, like the ARAS allotope, or sequestered, like the Goodpasture autotope? Autoantibodies to ␣5(IV) NC1 in nonAlport patients are very rare but have been reported, and are associated with anti-GBM nephritis and subepidermal blisters (16). Perhaps ␣5(IV) NC1 is also a "Janus-faced antigen" that, like ␣3(IV) NC1, carries autotopes and allotopes.…”