The Second Study of Clinical and Immunological Findings in Anti-laminin 332-Type Mucous Membrane Pemphigoid Examined at Kurume University—Diagnosis Criteria Suggested by Summary of 133 Cases

Abstract

BackgroundRecently, we published an article retrospectively summarizing the results in 55 anti-laminin 332 (LM332)-type mucous membrane pemphigoid (MMP) cases examined at Kurume University, which were diagnosed by strict inclusion criteria, including positive reactivity in direct immunofluorescence and absence of antibodies to non-LM332 autoantigens. However, indirect immunofluorescence using 1M-NaCl-split normal human skin (ssIIF) is also valuable for diagnosis of anti-LM332-type MMP.MethodsIn this second study, we selected 133 anti-LM332-type MMP cases, which were diagnosed by our different inclusion criteria: (i) immunoglobulin G (IgG) deposition to basement membrane zone (BMZ) by direct immunofluorescence or IgG reactivity with dermal side of split skin by ssIIF, (ii) positivity for at least one of the three subunits of LM332 by immunoblotting of purified human LM332, and (iii) the presence of mucosal lesions. Clinical, histopathological, and immunological findings were summarized and analyzed statistically. Although these cases included the 55 previous cases, the more detailed study for larger scale of patients was conducted for further characterization.ResultsClinically, among the 133 patients, 89% and 43% patients had oral and ocular mucosal lesions, respectively, 71% had cutaneous lesions, and 17% had associated malignancies. Histopathologically, 93% patients showed subepidermal blisters. The sensitivities of ssIIF and direct immunofluorescence are similar but are significantly higher than indirect immunofluorescence using non-split human skin (both p < 0.001). In immunoblotting of purified LM332, patient IgG antibodies most frequently reacted with LMγ2 subunit (58%), followed by LMα3 (49%) and LMβ3 (36%). Thirty-four percent patients recognized additional non-LM332 autoantigens. Statistical analysis revealed that autoantibodies against non-LM332 autoantigens might stimulate the production of anti-LMγ2 antibodies.ConclusionsThis retrospective study further characterized in more detail the clinical and immunological features of 133 cases of anti-LM332-type MMP, in which the new diagnostic criteria without positive direct immunofluorescence reactivity were useful for the diagnosis. Higher frequency with anti-LMγ2 antibodies suggested more significant pathogenic role of this subunit. Additional autoantibodies to non-LM332 autoantigens detected in one-third of the patients may contribute to complexity in anti-LM332-type MMP, including the induction of anti-LMγ2 antibodies.

Case Report: Mucous Membrane Pemphigoid With IgG and IgA Anti-Laminin γ1 Antibodies and IgA Anti-Laminin α5 Antibodies

“…For diagnosis of autoimmune bullous diseases, there is a certain false negative rate of direct immunofluorescence, particularly for MMP. Actually, in our recently published paper, the positive rate of direct immunofluorescence in anti-LM332-type MMP was 89.8% (88 in 98 cases) ( 10 ).…”

Anti-Laminin 332-Type Mucous Membrane Pemphigoid

“…Among these mucosal sites, oral mucosa is affected most frequently, followed by ocular mucosa, with other mucosal sites involved less frequently [ 21 ]. In our latest study, which included 133 anti-LM332-type MMP patients, 89% had oral lesions, 43% had ocular lesions, 19% had pharyngeal lesions, 15% had laryngeal lesions, 11% had genital lesions, 6% had nasal lesions and 3% had esophageal lesions [ 22 ]. Compared with other types of MMP, the oral and ocular mucosae were involved more commonly and seriously in patients with anti-LM332-type MMP [ 23 ].…”

“…Moreover, oral destructions may result in airway obstruction, whereas the involvement of ocular mucosa usually includes scarring; these complications may lead to mortality and blindness, respectively [ 24 ]. The presence of skin lesions is not a necessary condition for the diagnosis of anti-LM332-type MMP, although more than 60% of patients present with skin involvement [ 12 , 22 , 24 , 25 ].…”

A Probing of the Issue of Detecting IgG, IgG4 and IgA Antibodies to Laminin 332 Epitopes in Mucous Membrane Pemphigoid: A Clinical-Laboratory Experience of a Single Central European University Dermatology Department

“…Ln-332, formerly known as kalinin, epiligrin, nicein and laminin-5, is a heterotrimer, which is the most important for the skin integrity. 3 Beyond the adhesion function, Ln-332 is associated with cell migration, tissue maturation, and wound repair. Ln-332 consists of the laminin chains (subunits) α3 (165 and 145 kDa), β3 (140 kDa) and γ2 (105 kDa).…”

“…Ln-332 consists of the laminin chains (subunits) α3 (165 and 145 kDa), β3 (140 kDa) and γ2 (105 kDa). 3 , 4 By analyzing the immune profile of MMP patients, it was reported that the IgG was mostly directed to the α3 subunit (86%), followed by the β2 subunit (46%) and the γ2 subunit (29%). 7 Huang et al 8 revealed the distinct roles of the three Ln-332 subunits (α3, β3 and γ2) in cell proliferation, migration, invasion and apoptosis.…”