Letter: Acetylcholine receptor antibodies in patients with pemphigus vulgaris: Correlation with disease extent at the time of diagnosis and during follow-up
Andrés Tirado-Sánchez1,2 MD MSc, Denisse Vázquez-González2 MD, Rosa María Ponce-Olivera2 MD MSc, Héctor Eduardo López-Lozano2 MD
Dermatology Online Journal 18 (5): 14

1. Instituto Mexicano del Seguro Social, Mexico
2. Servicio de Dermatología, Hospital General de México, Mexico


Abstract

Several studies have tried to determine the relationship between autoantibodies against the acetylcholine receptor and the development of pemphigus vulgaris. In this study, we observed that antibody levels against the acetylcholine receptor are mildly elevated in pemphigus vulgaris (PV), and significantly correlate with disease severity on the initial diagnosis and during follow up. However, it is not clear if these antibodies are just an epiphenomenon or a potential trigger of the known pathogenic process in PV.


Pemphigus is a group of human autoimmune blistering diseases characterized by autoantibodies against desmogleins (Dsg), resulting in loss of epidermal cell-to-cell adhesion (acantholysis). This process is directly related to antiDsg antibody levels, particularly antiDsg3 [1]. In recent years, new immunological targets in pemphigus vulgaris (PV) have been described (e.g., cholinergic receptors) [2]. Human keratinocytes (KC) synthesize, store, release, and degrade acetylcholine. Cholinergic receptors (AChR), expressed by KC, are detected in sites where pemphigus IgG accumulates and acantholysis occurs [3] suggesting their involvement in regulating cell-to-cell adhesion.

The aim of this study was to determine the relationship between autoantibodies against both Dsg3 and AChR in comparison with the extent of skin lesions in PV at the time of diagnosis and during follow-up.


Figure 1

The study comprised patients with PV with a recent diagnosis, which was made according to clinical (flaccid blisters with Nikolsky sign), histological (suprabasal blister with acantholytic cells), and immunologic criteria (IgG deposits between epidermal cell unions by direct immunofluorescence), without evidence for myasthenia or thymus pathology. ELISA was performed to detect IgG antibodies against Dsg3 (MBL Co., Nagoya, Japan; cut-off values ≥ 20UI/mL) and against muscarinic AChR M3 (Uscn Life Science Inc. Wuhan, China; cut-off values ≥ 2 nmol/L).

Disease extent was determined by body surface area (BSA) affected (the palm without fingers is equal to 1% of BSA). Serum samples were analyzed at the time of diagnosis (all patients started with prednisone 1 mg/kg/day without adjuvant) and at weeks two, four, and six during the follow-up. The study was approved by our Institutional Review Board and written informed consent of the patients was obtained prior to the study.

Variables were analyzed with χ² or the exact test of Fisher (categorical) and with the U Mann Whitney test (numerical). Pearson's correlation test was used to correlate disease extent and autoantibody titers. A P-value of < 0.05 was considered significant. Analyses were performed using SPSS (ver. 17 for Windows, Chicago, Ill).

We included 31 patients with PV. Demographic, clinical, and immunologic characteristics of the sample are shown in Table 1. During the initial phase of the study, we found a positive correlation of antiDsg3 and antiAChR antibodies with disease extent (R = 0.782, P = .007 and R = 0.777, P = .008 respectively); moreover, this correlation was constantly observed during the follow-up period (R = 0.687, P = 0.004 and R = 0.728, P = 0.001 respectively). Both results were independent of gender. These results are in accordance with Grando et al. [4], who showed that cholinomimetic drugs can modulate pemphigus IgG-induced acantholysis in vitro. These authors also consider KC AChR as important therapeutic targets directly related to disease severity. Nguyen et al. [5], propose that cutaneous activity in PV is mediated in part by antiAChR antibodies that weaken intercellular adhesions between KC, via inactivation of the AChR-mediated physiologic control of cadherin expression and/or function. This causes dyshesion, cell detachment, and rounding up, or acantholysis. In addition, antibodies to adhesion molecules prevent the formation of new desmosomes by blocking the extracellular domains of desmosomal cadherins that mediate homophilic adhesion. On the other hand, previous observations showed that activation of KC AChR reverses acantholysis in vitro, and cholinergic agonists have been shown to be effective in controlling PV erosions [5], related to the blockade of the muscarinic antiAChR antibodies and also activation of these receptors [6]. One of the efforts of this study was to demonstrate that antibody levels significantly correlate with disease severity at initial diagnosis and during follow up. However, it is not clear if antiAChR are just an epiphenomenon or a potential trigger of the known pathogenic process in PV.

The study suggests the utility of both antiDsg3 and antiAChR antibodies for initial diagnosis and during follow up. However, caution needs to be taken to monitor disease activity and/or response to therapy.

References

1. Venugopal SS, Murrell DF. Diagnosis and clinical features of pemphigus vulgaris. Dermatol Clin 2011; 29(3): 373-80. [PubMed]

2. Grando SA. Pemphigus in the XXI century: new life to an old story. Autoimmunity 2006; 39(7): 521-30. [PubMed]

3. Grando SA, Zelickson BD, Kist DA, Weinshenker D, Bigliardi PL, Wendelschafer-Crabb G, Kennedy WR, Dahl MV. Keratinocyte muscarinic acetylcholine receptors: immunolocalization and partial characterization. J Invest Dermatol 1995; 104(1): 95-100. [PubMed]

4. Grando SA, Dahl MV. Activation of keratinocyte muscarinic acetylcholine receptors reverses pemphigus acantholysis. J Eur Acad Dermatol Venereol 1993; 2: 72-86.

5. Nguyen VT, Lee TX, Ndoye A, Shultz LD, Pittelkow MR, Dahl MV, Lynch PJ, Grando SA. The pathophysiological significance of nondesmoglein targets of pemphigus autoimmunity. Development of antibodies against keratinocyte cholinergic receptors in patients with pemphigus vulgaris and pemphigus foliaceus. Arch Dermatol 1998; 134(8): 971-80. [PubMed]

6. Kalantari-Dehaghi M, Molina DM, Farhadieh M, Morrow WJ, Liang X, Felgner PL, Grando SA. New targets of pemphigus vulgaris antibodies identified by protein array technology. Exp Dermatol 2011; 20(2): 154-6. [PubMed]

© 2012 Dermatology Online Journal

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Title:

Acetylcholine receptor antibodies in patients with pemphigus vulgaris: Correlation with disease extent at the time of diagnosis and during follow-up

Journal Issue:

Dermatology Online Journal, 18(5)

Author:

Tirado-Sánchez, Andrés;
Vázquez-González, Denisse;
Ponce-Olivera, Rosa María;
López-Lozano, Héctor Eduardo

Publication Date:

2012

Publication Info:

Dermatology Online Journal, UC Davis

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