Collagen IV in Normal Skin and in Pathological Processes

Abstract

Context: Type IV collagen is a type of collagen found primarily in the skin within the basement membrane zone. The type IV collagen C4 domain at the C-terminus is not removed in post-translational processing, and the fibers are thus link head-to-head, rather than in a parallel fashion. Also, type IV collagen lacks a glycine in every third amino-acid residue necessary for the tight collagen helix. Thus, the overall collagen-IV conformation is structurally more pliable and kinked, relative to other collagen subtypes. These structural features allow collagen IV to form sheets, which is the primary structural form found in the cutaneous basal lamina. There are six human genes associated with collagen IV, specifically COL4A1, COL4A2, COL4A3, COL4A4, COL4A5 and COL4A6. The aim of this review is to highlight the significance of this protein in normal skin, and in selected diseases.

Results: The alpha 3 protein constituent of type IV collagen is thought to be the antigen implicated in Goodpasture's syndrome, wherein the immune system attacks the basement membranes of the renal glomeruli and pulmonary alveoli. In addition, mutations to the genes coding for type IV collagen lead to the Alport syndrome. Furthermore, autoantibodies directed against denatured human type IV collagen have been described in rheumatoid arthritis, scleroderma, and SLE. Structural studies of collagen IV have been utilized to differentiate between subepidermal blistering diseases, including bullous pemphigoid, acquired epidermolysis bullosa, anti-epiligrin cicatricial pemphigoid, and bullous lupus erythematosus. Collagen IV is also of importance in wound healing and in embryogenesis.

Conclusions: Pathological studies have demonstrated that minor structural differences in collagen IV can lead to distinct, clinically different diseases.

Keywords: Alport syndrome; Basement membrane zone; Collagen-type IV; Goodpasture's syndrome; Subepidermal blistering diseases.

Figure 1

Examples of staining of collagen type IV antibody in the skin by direct immunofluorescence (DIF) (a,b,c,e, and h) and by immunohistochemistry (IHC) (d,f,g,i) under normal conditions, as well as in a patient with lupus erythematosus. All staining was performed as previously documented.[–31] We utilized an antibody to collagen IV from Invitrogen (Carlsbad, California, USA). 1 a and b, Double positive DIF staining of the BMZ ‘lupus band’ in a lupus patient using an FITC conjugated antibody to human IgG, overlapping with the staining of Texas red conjugated collagen IV, resulting in orange staining (white arrows). The blood vessels also stained positive with the antibody to collagen IV (red staining; yellow arrows). c. Positive DIF staining of the cutaneous BMZ using the antibody to collagen IV alone (red staining; white arrow at the BMZ, yellow arrow showing positivity on a dermal blood vessel). d. Positive IHC staining for collagen IV antibodies around a nerve (brown staining; red arrow), blood vessels (green arrow), and eccrine sweat gland ducts (black arrows). e. Positive DIF staining of a sweat gland coil BMZ, utilizing Texas red conjugated collagen IV (red staining). The nuclei of the cells were counterstained with Dapi (blue staining; yellow arrow). f. Positive IHC staining of eccrine glands for collagen IV (brown staining; red arrow). g. Positive IHC staining of eccrine gland ducts (brown staining; red arrow) and of small blood vessels (green arrow). h. Positive DIF staining of skin blood vessels utilizing Texas red conjugated collagen IV (red staining, yellow arrow). The nuclei of the cells were counterstained with Dapi (blue). i. Positive IHC staining for collagen IV antibody on a large blood vessel in a subcutaneous adipose tissue septum (brown staining; red arrow)