## 4 Discussion
In MMP, IgA antibodies have been found to react with a number of antigens, some of which proved to be different from those recognized by IgG, including a 45-kDa keratin, which was recognized only by IgA antibodies described in ocular cicatricial pemphigoid [21,22]. [PERSON] et al., in a retrospective study of 67 patients with MMP, found circulating IgA in 61.2%, in all cases binding the roof of the salt-split skin. Moreover, unlike the present results, patients with combined IgG and IgA-anti-BMZ reactivity had a more severe and persistent disease than those lacking IgA autoantibodies [23]. In the oral cavity, [PERSON] et al. found that in a cohort of 28 consecutive patients with MMP predominantly affecting the gingiva, the IgA of three sera (11%) reacted with BPAg2 and three (11%) reacted with BPAg1, but the frequency of positive immunoblotting among patients with exclusive oral lesions and MMP patients not restricted to the oral cavity was not significant [24]. Unlike [PERSON], [PERSON] et al. failed to confirm the importance of IgA antibodies as a prognostic indicator and found that the IgA antibodies in a cohort of 28 MMP patients were directed to BPAg1 alone [25]. Interestingly, [PERSON] et al. reported that the persistence of IgA-secreting plasmablasts/plasma cells could be responsible for unresponsiveness to treatment in refractory mucous membrane pemphigoid [26]. The antigenic specificity of IgA in MMP is not clearly understood, and whether or not IgA plays a pathogenetic role remains unclear. Noteworthily, many studies include, in the same analysis, MMP patients with oral and other sites involved, but differences may be involved among clinical phenotypes. For example, reactivity to the \(\alpha\)6 subunit in the ocular MMP sera was found in only 23.3% for IgG and 18.6% for IgA, although the presence of anti-\(\alpha\)684 integrin antibodies in MMP must be validated by independent laboratories [27]. In addition, [PERSON] et al. found that in MMP, ocular disease was inversely associated with oral involvement, suggesting site-preferred targeted antigens [28]. Speculatively, IgA could recognize different epitopes and might be responsible for the persistence of the inflammatory process, but their role in determining clinical severity might be exerted in sites different from the oral cavity. In future studies, it could be interesting to investigate IgA reactivity to different antigens in OMMP and their potential relationship with clinical severity and the risk of spreading to high-risk sites such as ocular mucous membranes. [PERSON] et al., in a large cohort of 78 Italian patients with MMP, found that BP180 reactivity presented a significant inverse association with disease severity. More in detail, [PERSON] et al. conducted a well-designed study investigating the serological profiles of a large cohort of MMP patients using the most well-established diagnostic procedure, such as ELISA based on BP180, BP230, and Col VII and immunoblotting on affinity-purified laminin 332. Clinical severity was measured using the Setterfield score, a score similar to ODSS but extended to regions beyond the oral cavity such as the skin, ocular mucosaae, genital area, nasopharynx region, larynx, and esophagus. It emerged that besides the inverse relationship between BP180 reactivity and clinical severity, BP180 positivity was also related to oral and cutaneous localization of the lesions. By contrast, Col VII-positive patients presented a mixed form with the involvement of multiple mucosal sites, also showing a significant association with severity score [9]. Such apparent contradiction may be explained by the inclusion of patients with ocular, cutaneous, or mixed forms of MMP where other target antigens are at play. Indeed, in a recent study, [PERSON] et al. [10] found that BP180 NC16a ELISA reactivity was associated with the clinical phenotype mainly characterized by only oral mucosal lesions. The authors concluded that BP180 NC16a autoantibody might be useful as a serum marker to predict low-risk OMMP.