Pemphigus Vulgaris (PV), Pemphigus Foliaceus (PF) and Bullous Pemphigoid (BP) are a group of rare organ-specific diseases that affect skin and mucous membranes. Each subtype of pemphigus has its own anti-Desmogleins (Dsgs) autoantibodies profile: Dsg1 is the auto-antigen in PF whereas Dsg3 is the in PV.
We identified 2 PF patients with positive levels of anti-Dsg3 Abs and also 4 healthy blood donors with high levels of anti-Dsg1 Abs and anti-Dsg3 Abs.
The purpose of this study was to examine epitopes recognized by anti-Dsg1/anti-Dsg3 Abs and to identify potential autoreactive HLAII-restricted helper T cell epitopes shared among Dsg1+/Dsg3+ subjects that could explain the simultaneous occurrence of these auto-Abs.
On IIF, only one PF patients had antibodies to the keratinocyte surface. Interestingly, the ELISA for BP180 was also positive in 2 healthy blood donors. IP-IB analysis showed immunoreactivity to more than one EC domain of Dsg1 and towards the C-terminal EC5 domain of Dsg3. MHC II gene analysis demonstrated that all healthy blood donors had at least one protective allele associated to PF.
We confirm in this study that the onset and course of this disease depend on a variable interaction between predisposing and inducing genetic, environmental, hormonal, and immunological factors.
PF: Pemphigus Foliaceus;
PV: Pemphigus Vulgaris;
BP: Bullous Pemphigoid,
HLA: Human Leucocyte Antigen
Autoimmune mucocutaneous blistering diseases such as Pemphigus Vulgaris (PV), Pemphigus Foliaceus (PF), Bullous Pemphigoid (BP), and Mucous Membrane Pemphigoid (MMP), are a group of rare organ-specific diseases that affect skin and multiple mucous membranes [1,3]. There is increasing evidence that the clinical phenotype is strongly related to the antibody profile. Desmogleins (Dsgs) are the target antigens in pemphigus [3,4]. Each subtype has its own anti-Dsg autoantibodies profile: Dsg1 is the auto-antigen in PF whereas Dsg3 is the autoantigen in PV .
In discordance with the above, we identified a group of 2 PF patients with positive levels of anti-Dsg3 Abs and also 4 healthy blood donors with positive levels of both anti-Dsg1 Abs and anti-Dsg3 Abs (Table 1). Indeed, it has been well documented that autoimmune diseases may coexist in the same patient, either sequentially or concurrently [5-7]. Anti-Dsg3 autoantibodies are detected in the sera of a small number of PF patients (<7%) . Moreover, it has been reported that multiple keratinocyte cadherins such as Dsg1, Dsg2, Dsg3, Dsg4, Dsc1, Dsc2, Dsc3, and E-cadherin, are recognized by healthy controls in endemic area as well as PF patients [9,10]. Multiple factors, including those of immunological, genetic, endocrine and environmental origin, contribute to the above condition. The phenomenon of epitope spreading can be used to explain this coexistence or this shift. Epitope spreading is a phenomenon in which immune responses can spread over the disease course to recognize epitopes that are different from the original target . If it occurs in the same molecule, this is termed “intramolecular epitope spreading” [12,13]. When responses begin to target epitopes on other proteins, this is termed “intermolecular epitope spreading” [14,15].
The purpose of this study was to examine first the epitopes of anti-Dsg1 and anti-Dsg3 Abs from patients and healthy subjects in order to investigate whether there is any difference in Abs binding sites between groups and secondly to identify potential autoreactive HLA II-restricted helper T cell epitopes shared among Dsg1+/Dsg3+ subjects that could explain the simultaneous occurrence of these auto-Abs. Indeed, it has been reported that both qualitative and quantitative genetic variation of MHC class II molecules may influence susceptibility to endemic pemphigus foliaceus .
|IIF||ELISA||1st Haplotype||2nd Haplotype|
|Group I: Healthy blood donors|
|Group II: PF patients|
Table 1: Characterization of healthy blood donors and Pemphigus Foliaceus (PF) patients with antibodies to PF, Pemphigus Vulgaris (PV) and Bullous Pemphigoid (BP).
Based on the specificity of the targeted antigens, several clinically and immune serologically distinct autoimmune bullous skin disorders have been characterized. Pemphigus and pemphigoid are an autoimmune blistering disorder with a complex etiology involving an interplay of genetic as well as environmental factors, most of which remain unknown. Pemphigus and pemphigoid are considered to be prototypic bullous disorders based on their well- defined immune response-mediated pathogenesis [27-29]. In PF, PV and BP, autoreactive CD4+T lymphocytes that are probably essential in initiating the autoimmune response recognize different epitopes of the extracellular portions of Dsg1, Dsg3 and BP180, respectively. Activation of autoreactive T cells in PF, PV and BP is restricted by distinct HLA class II alleles that are prevalent in individuals with these disorders. Autoreactive T cells are not only found in patients but have also been detected in healthy individuals . In healthy individuals, a subset of autoreactive T cells with high regulatory function was also identified suggesting that the occurrence of autoimmune bullous disorders may be linked to a dysfunction of Tregs. Dsg3- and BP180-reactive T cells produce Th2 cytokines such as IL-4, IL-5, and IL-13 and facilitating immunoglobulin class switching from non-pathogenic (IgG1) to pathogenic (IgG4) autoantibodies, which are specially seen in active stages of these disorders.
Zakka et al., studied the relationship between target antigens and Major Histocompatibility Complex (MHC) class II genes in producing two pathogenic antibodies simultaneously . Using computer models, they present the hypothesis that two autoantibodies are produced simultaneously due may be to the phenomena of epitope spreading through four possible scenarios. (i) One antigen molecule may contain at least two epitopes that have a certain point of similarity or overlapping sequence and can activate two different T cells and consequently stimulate two different B cells when presented by two different MHC II genes that may result in the simultaneous presence of two separate pathogenic autoantibodies. (ii) Antigen Presenting Cells (APC) may internalize two separate antigens, and then activate two different T cells that are specific to any one of these antigens. (iii) Two antigens may cluster in a single macromolecule complex, all of which are internalized by a single APC. This APC then activates two different T cells, making each specific for one subset of the macromolecule. The T cells would then solicit B cells and result in the production of two different autoantibodies. (vi) An autoimmune disease may cause tissue damage and inflammation in the surrounding tissue. This exposes the immune system to a previously sequestered epitope. This epitope becomes internalized by an APC, presented to a T cell that enlists B cells and produces a second antibody.
It has been also suggested that quantitative as well as qualitative variation of HLA class II molecules have an effect on the risk of an individual developing PF [16,32].
Flores et al., reported in 2012 that multiple, perhaps cross reactive, keratinocyte cadherins are recognized by Fogo Selvagem patients; the Brazilian endemic form of Pemphigus; and endemic controls. Authors suggested the relevance of the environment surrounding the patients and the endemic controls as a source of sensitizing antigen(s) that lead to the production of these autoantibodies through three possible explanations . (i) The putative environmental antigen(s) may share cross-reactive epitopes with all the keratinocyte cadherins, thus triggering independent populations of autoantibodies with specificities to each of the keratinocyte cadherin. (ii) One or all of the environmentally-elicited anti-keratinocyte cadherin autoantibodies recognize crossreactive epitopes due to structural homologies among these keratinocyte cadherins. (iii) Finally, once an initial autoantibody response is triggered against one of these cadherins (primary response), this response may be followed by autoantibody responses against other keratinocyte cadherins by the epitope spreading mechanism.
This study demonstrates that the associations result from the effect of genetically controlled levels of candidate’s genes such as HLA II and production of autoantibodies are necessary for developing an autoimmune disease. The HLA DRB1* and DQB1* alleles influence susceptibility to pemphigus or pemphigoid and may contribute to severity and type of disease but cooperation of environmental, hormonal, and immunological factors and background are crucial to induce and activate any of these diseases.
Citation: Toumi A, Abida O, Masmoudi H (2017) Antibodies against Desmoglein 1, Desmoglein 3 and BP180 in Healthy Tunisians Blood Donors without Immunopathological Phenotype. J Clin Dermatol Ther 4: 024.
Copyright: © 2017 Hatem Masmoudi, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.