Laminin 332 Mucous Membrane Pemphigoid 

Background​

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• MMP mediated by antibodies to laminin 332 usually presents with multisite mucosal lesions. Anti-laminin 332 MMP lesions tend to scar and can result in serious complications depending on the mucosal surface affected. Scarring of ocular mucosa can result in symblepharon, disruption of the tear film, entropion, and/or corneal opacities, all of which may lead to blindness. Other irreversible, severe complications are esophageal, anal stenosis, and urethral strictures. An additional complication of anti-laminin 332 MMP is increased relative risk of solid epithelial malignancies, mainly adenocarcinoma affecting the gastrointestinal, genital mucosa and lungs (Balestri, 2016).  

• Laminin-332 (other names: laminin-5, epiligrin) is an integral component of the skin and mucosa and is located in the epithelial basement membrane zone (Florea, 2008).  Laminin-332 is secreted by keratinocytes and is a heterodimer composed of alpha 3, beta 3, and gamma 2 chains. It plays an important role in integrity of the skin and mucosal membranes by dermal -epidermal adhesion through other cell anchoring proteins such as integrins, syndecans, BP180, type XVII collagen) and type VII collagen. Other important functions of laminin -332 include cell regeneration and repair (Kirtschig, 1995). Laminin 332 was identified as the main target of antigen complex of autoantibodies in patients with MMP by Domloge-Hultsch et al. in 1992. Since then, the role of pathogenesis of antibodies to laminin 332 mediating a specific subset of MMP has been well characterized utilizing the mouse models (Heppe, 2017; Lazarova, 1996). Patients with anti-laminin-332 mucous membrane pemphigoid show autoantibodies specific to α3, β3 or γ2 subunits of laminin 332 (Heppe, 2017; Lazarova, 1996).  

• The most common clinical site of involvement in MMP is the oral mucosa (80–90%). Other mucosal surfaces are less involved with ocular (50%), genital (15%), the anal (10%), pharynx, esophagus and larynx (<10%) (16). In the oral cavity, gingiva is the most commonly affected (70% of oral MMP cases), followed by the buccal mucosa (60%), the palate (27%), and the tongue and lips (13%) (Amber, 2017). 

• Clinically, patients with anti-laminin 332 MMP cannot be differentiated from patients with MMP with autoantibodies against the other main target antigen, BP180, although pharyngeal involvement was reported to occur less frequently in the latter patients. Patients with anti-laminin 332 MMP cannot be differentiated from other variants of MMP based on clinical appearance and can only be distinguished by serological testing. Identification of MMP patients with laminin 332-specific antibodies are essential since 25%–30% of these patients might have a malignancy (Goletz, 2019). 

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Diagnostic Testing

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• The diagnostic work-up, prompted by a high index of suspicion, relies on different laboratory tests, including histopathological analysis, detection of tissue-bound immunoreactants by DIF as well as of serum autoantibodies by IIF and ELISA. Diagnosis of MMP is confirmed by the detection of in vivo bound IgG and/or IgA and C3 deposits at the epithelial basement membrane by DIF microscopy of the perilesional mucosa or skin and the detection of circulating autoantibodies against the epithelial basement membrane antigens by various methods.  The rather low clinical MMP activity is paralleled by a relatively low autoantibody reactivity in peripheral blood of the patients. Not unexpectedly, in up to 50% of MMP patients, no autoantibodies are detected by IIF on salt-split skin. Target specific autoantibody tests are available for most but not all known antigens involved in MMP. In roughly two thirds of the MMP patients, IgG and/or IgA autoantibodies target collagen XVII/BP180, while approximately one third show autoantibodies to laminin 332. These cases in the IIF usually show dermal binding of immunoreactants at the epithelial basement membrane (Goletz, 2019). The IIF assay using laminin 332 transfected cells is helpful for confirmation of this form of MMP. The IIF assay offered at Beutner Laboratories has a sensitivity of 84% and a specificity of 99%. 

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Laminin 332 Mucous Membrane Pemphigoid (MMP) Tests