The Goodpasture antigen and the pathogenic epitope

Basement membranes are specialized structures of the extracellular matrix found at the boundaries between cells and connective tissues. They play important roles in tissue and organ development and repair; in guiding cell migration and in signaling differentiation; and, in certain locations, such as in glomerulus, choroid plexus and alveolus, basement membranes control fluid exchange between the compartments they separate. In these three locations, the membrane appears to have arisen by the fusion of an endothelial and epithelial membrane. Interestingly these double-width basement membranes have been implicated in the autoimmune attack carried out by the GP antibodies (Figure 1).

A network of interacting collagen IV molecules

Choroid plexus

Lung

Kidney

Figure 1 Principal organs affected in Goodpasture's syndrome.

(Figures 2 and 3) in close association with laminm (not shown) contribute respectively the structural strength and the adhesiveness required to build a typical basement membrane. The proportion and subunit composition of some of the constituents, including collagen IV, greatly varies among basement membranes.

Collagen IV is a nonfibrillar collagen exclusively found in basement membranes, where it is also the major structural component. As in other collagens, it is a triple helix composed of three intertwined u chains (Figures 2 and 3). So far, six different but related a chains, al(IV)-a6(IV), have been characterized in collagen IV. The presence of noncol-lagenous sequences along each individual a(IV) chain causes imperfections in the resulting triple helix that prevent its molecular assembly into fibrils. Among

Choroid plexus

Lung

Kidney

Figure 1 Principal organs affected in Goodpasture's syndrome.

Figure 2 Diagram representing the localization and structural identification of the Goodpasture antigen from organ level to molecular level: (A) Cross-section of the kidney. (B) The functional unit of the kidney, the nephron. (C) The filtration unit of the nephron, the glomerulus. The blood enters the capillary tuft and the filtrate is forced out of the capillaries over the glomerular basement membrane into the surrounding Bowman's capsule. (D) Micrograph of the glomerular basement membrane (B) located between the fenestrated (f) endothelium (En) on the capillary (c) side and the epithelial foot processes (fp) on the urinary (U) side (Bowman's space). (E) Schematic drawing representing the collagen IV network of a basement membrane. Four collagen molecules are cross-linked through their N-terminal domains (7S) and two through their C-terminal domain (NC1). (F) Enlargement of a schematic collagen IV molecule in which the principal domains are indicated. (Figure courtesy of Charlotte Brunmark, originally presented in her doctoral dissertation Type IV collagen and renal disease'.)

Figure 2 Diagram representing the localization and structural identification of the Goodpasture antigen from organ level to molecular level: (A) Cross-section of the kidney. (B) The functional unit of the kidney, the nephron. (C) The filtration unit of the nephron, the glomerulus. The blood enters the capillary tuft and the filtrate is forced out of the capillaries over the glomerular basement membrane into the surrounding Bowman's capsule. (D) Micrograph of the glomerular basement membrane (B) located between the fenestrated (f) endothelium (En) on the capillary (c) side and the epithelial foot processes (fp) on the urinary (U) side (Bowman's space). (E) Schematic drawing representing the collagen IV network of a basement membrane. Four collagen molecules are cross-linked through their N-terminal domains (7S) and two through their C-terminal domain (NC1). (F) Enlargement of a schematic collagen IV molecule in which the principal domains are indicated. (Figure courtesy of Charlotte Brunmark, originally presented in her doctoral dissertation Type IV collagen and renal disease'.)

the noncollagenous sequences, the C-terminal region or NCI domain is the largest and conforms to a highly folded disulfide-rich region that guides, among other processes, the triple helix formation. In the basement membrane, two molecules of collagen IV interact through their NCI domains to yield a hexameric structure that can be released from the corresponding network by collagenase digestion (Figure 3). This hexamer is compacted by noncova-lent forces and by disulfide bonds and yields monomer and disulfide-related dimers under denaturing conditions. The CP epitope is hidden within the iso

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