Autoimmunity against type VII collagen in inflammatory bowel disease

Abstract

Autoimmunity against type VII collagen, an adhesion molecule of the extracellular matrix in epithelial basement membranes, is causing the rare organ-specific epidermolysis bullosa acquisita (EBA). An intriguing association between EBA and inflammatory bowel disease (IBD) has been extensively documented over the last decades, but, because of the very low incidence of EBA, received little attention from physicians involved in the care of patients with IBD. More recently, autoantibodies against type VII collagen have been detected in up to 68% of IBD patients. Although these findings suggest that chronic intestinal inflammation in IBD predisposes for autoimmunity against type VII collagen, their relevance for the pathogenesis of both IBD and EBA is still unclear. In this review article, the main features of the association between IBD and EBA are presented and pathomechanistic hypotheses as well as future lines of investigation in this area are discussed. Future research should provide new pathomechanistic insights and will likely facilitate the development of more specific and effective immunotherapeutic strategies for both conditions.

Fig 1

Molecular map of autoantigens of the dermal–epidermal junction. The adhesion of neighbouring keratinocytes is maintained via the extracellular portions of desmosomal cadherins, including desmoglein (Dsg) 1, desmoglein 3 and desmocollin (Dsc) 1, which are main targets of autoantibodies in pemphigus diseases. Their intracellular portions bind to desmosomal plaque proteins that mediate the interaction of desmosomes with keratin filaments. Keratin filaments also bind to bullous pemphigoid antigen 230 (BP230) and plectin, the main intracellular constituents of the hemidesmosomes. BP230 and plectin function as ligands for transmembrane hemidesomosomal proteins, type XVII collagen (BP180) and α₆β₄ integrin. These hemidesmosomal proteins are main autoantigens in pemphigoid diseases and may connect the hemidesmosomes to laminin (Ln) 332, which in addition to type IV collagen, is a major component of the lamina densa. Ln 332 is a known ligand for type VII collagen, the major constituent of the anchoring fibrils, which connect lamina densa to the collagen bundles of the upper dermis.

Fig 2

Clinical, histopathological and immunopathological features of EBA. (A) Ruptured blisters, erosions sometimes skin atrophy, scars, poikiloderma. (B) Histopathological examination of lesional biopsy reveals subepidermal blisters associated with various degrees of inflammatory infiltrates in the upper dermis (haematoxylin and eosin staining). Direct IF microscopy shows (C) IgG and (D) C3 deposits deposition in a linear pattern at the dermal–epidermal junction. (E) Circulating IgG autoantibodies binding to the dermal side of 1 M NaCl-split skin can be detected by indirect IF microscopy. (F) By immunblotting, similar to the monoclonal antibody against type VII collagen (LH7.2; left strip), autoantibodies from the serum of an EBA patient (middle strip) react with a recombinant form comprising the non-collagenous (NC) 1 and 2 domains of type VII collagen. In contrast, serum from a healthy donor (right strip) does not show reactivity with this substrate.

Fig 4

Key features of the immune responses in CD and EBA. The upper panel depicts the key immunopathological features within the small bowel/terminal ileum in active CD. The luminal presence of pathogenic bacteria/antigens (not depicted) and/or disruption of the epithelial barrier results in an activation (directly and through other APCs, like M cells and intestinal epithelial cells – IEC) and migration of dendritic cells (DC) to the mesenteric lymph nodes (MLN). Here, DC activate naïve T cells, which undergo differentiation, and then migrate to the effector site inducing pro-inflammatory responses that causes the characteristic tissue damage in IBD. Typically, these lesions are represented by granuloma without necrosis (composed of macrophages, giant and epitheloid cells) surrounded by inflammatory infiltrates, as well as additional epithelial injury (enterocyte and goblet cell destruction), which further amplifies the immune response and tissue injury. Type VII collagen, expressed in the basement membrane of the gut (blue arrowheads), is targeted by autoantibodies in a subgroup of patients with IBD. The lower panel depicts the characteristic blister formation within the basement membrane of the skin in EBA and autoimmunity against type VII collagen. Autoantibodies accumulate in tissues and bind to type VII collagen at the epithelial basement membrane. Binding of pathogenic autoantibodies triggers an inflammatory reaction, including fixation of complement and Fc-dependent activation of leucocytes. In addition to granulocytes, mast cells likely contribute to the antibody-induced inflammation at the dermal–epidermal junction. Activated granulocytes release reactive oxygen intermediates and proteases leading to epithelial damage and blister formation.

Fig 3

Diagnostic algorithm in EBA.