Circulating pemphigus autoantibodies in healthy relatives of pemphigus patients: coincidental phenomenon with a risk of disease development?

Torzecka, Jolanta Dorota; Woźniak, Katarzyna; Kowaléwski, Cezary; Waszczykowska, Elżbieta; Sysa-Jędrzejowska, Anna; Pas, Hendrikus

doi:10.1007/s00403-007-0760-y

Cited by 41 publications

(34 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Examination of the related healthy control population may help to identify key elements or disturbances in immune function that are lacking in this group, but required for transition to a disease state in patients. Our demonstration of anti-Dsg autoAbs in these individuals is in line with the findings of other groups who have shown that relatives of patients with pemphigus can exhibit positive Dsg3 titers and positive immunofluorescence results (47,48). However, to our knowledge, we are the first to demonstrate that healthy relatives of patients with PV also possess autoreactivity toward additional non-Dsg antigens that are also targeted by patients.…”

Section: Discussionsupporting

confidence: 91%

“…Recent studies demonstrating the presence of abundant autoAbs in healthy individuals have challenged this view, suggesting that these "natural" autoAbs may play a role in immune homeostasis (40)(41)(42)(43)(44)(45)(46). The detection of Abs directed against Dsg1 and -3 in healthy controls related to patients with PV (47,48) suggests that shared genetic (and possibly environmental) factors may contribute to the development of autoreactivity, if not autoimmune disease. To investigate further, in the next analysis, we included control subjects who were first-or second-degree blood relatives of patients with PV (n = 20).…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Multiplexed autoantigen microarrays identify HLA as a key driver of anti-desmoglein and -non-desmoglein reactivities in pemphigus

Sajda

Hazelton

Patel

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Patients with pemphigus vulgaris (PV) harbor antibodies reactive against self-antigens expressed at the surface of keratinocytes, primarily desmoglein (Dsg) 3 and, to a lesser extent, Dsg1. Conventionally, only antibodies targeting these molecules have been thought to contribute to disease pathogenesis. This notion has been challenged by a growing pool of evidence that suggests that antibodies toward additional targets may play a role in disease. The aims of this study were to (i) establish high-throughput protein microarray technology as a method to investigate traditional and putative autoantibodies (autoAbs) in PV and (ii) use multiplexed protein array technology to define the scope and specificity of the autoAb response in PV. Our analysis demonstrated significant IgG reactivity in patients with PV toward the muscarinic acetylcholine receptor subtypes 3, 4, and 5 as well as thyroid peroxidase. Furthermore, we found that healthy first-and second-degree relatives of patients with PV express autoAbs toward desmoglein and non-Dsg targets. Our analysis also identified genetic elements, particularly HLA, as key drivers of autoAb expression. Finally, we show that patients with PV exhibit significantly reduced IgM reactivity toward disease-associated antigens relative to controls. The use of protein microarrays to profile the autoAb response in PV advanced the current understanding of disease and provided insight into the complex relationship between genetics and disease development.pemphigus | autoantibody | protein microarray P emphigus vulgaris (PV) is a blistering autoimmune skin disease characterized by the presence of autoantibodies (autoAbs) directed against keratinocyte surface antigens (1, 2). Although early immunofluorescence studies demonstrated the presence of autoAbs in patient sera that bound to the surface of keratinocytes, a direct role of autoAbs in disease pathogenesis was not established until purified patient IgG (PVIgG) was shown to elicit blister formation upon passive transfer in mice (3). The main targets of these autoAbs were identified as Desmoglein (Dsg) 3 and 1, cadherin proteins that constitute key components of desmosomes, protein complexes responsible for maintaining cell-cell adhesion (4-7). Later experiments in which patient sera depleted of anti-Dsg3 Abs failed to produce blisters when passively transferred to mice (8) seemingly cemented the notion that these autoAbs alone were responsible for blister formation. As a result, subsequent research in the field has focused primarily on autoAbs directed against Dsgs.The assertion that anti-Dsg autoAbs alone are pathogenic was first challenged when PVIgG, lacking any anti-Dsg1 autoAbs, produced blisters when passively transferred into Dsg3-null mice (9). Additionally, several studies have shown that anti-Dsg Ab titers do not necessarily correlate with disease activity, and a subset of patients with PV do not harbor any detectable anti-Dsg Abs (10-14). The presence of pathogenic autoAbs directed against non-Dsg targets could account for th...

show abstract

Section: Discussionsupporting

confidence: 91%

Section: Resultsmentioning

confidence: 99%

Multiplexed autoantigen microarrays identify HLA as a key driver of anti-desmoglein and -non-desmoglein reactivities in pemphigus

Sajda

Hazelton

Patel

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…It was reported that Dsg3-reactive T cells could be isolated from healthy individuals with PV-associated HLA alleles (11). In addition, low level of anti-Dsg3 Ab was detected in healthy relatives of PV patients (28,29). In a BCR transgenic model, a Dsg3-specific B cell escaped from tolerance mechanism (30).…”

Section: Discussionmentioning

confidence: 99%

A Single Helper T Cell Clone Is Sufficient to Commit Polyclonal Naive B Cells to Produce Pathogenic IgG in Experimental Pemphigus Vulgaris

Takahashi¹,

Kuwana

Amagai³

2009

The Journal of Immunology

View full text Add to dashboard Cite

The development of naive B cells into IgG-producing memory B cells requires cognate T cell-B cell interaction in Ag-specific immune responses. It is unknown whether a single T cell clone is sufficient or whether multiple clones are necessary to induce polyclonal IgG production in vivo. We addressed this issue using a mouse model of pemphigus vulgaris, a fatal autoimmune blistering skin disease caused by IgG autoantibodies against desmoglein (Dsg) 3. We previously isolated several Dsg3-reactive T cell clones from Dsg3−/− mice. Among these, two pathogenic T cell clones induced anti-Dsg3 IgG production and the development of a pemphigus phenotype when adoptively transferred with unprimed B cells from Dsg3−/− mice. IgG Abs harvested from recipient mice reacted with at least three parts of the extracellular domain of Dsg3, as determined using domain-swapped Dsg3/Dsg1 molecules. The anti-Dsg3 IgGs included at least two subclasses among IgG1, IgG2a, IgG2b, and IgG3 in each mouse. The anti-Dsg3 IgG induced by Dsg3-reactive T cell clones with primed B cells from Dsg3−/− mice also showed reactivity against different parts of the molecule, with a similar epitope distribution. Together, these results indicate that a single potent Dsg3-reactive T cell is sufficient to commit polyclonal naive B cells to produce pathogenic anti-Dsg3 IgG Abs and induce the PV phenotype. These findings provide an important framework for examining immunological mechanisms in Ab-mediated autoimmune diseases.

show abstract

“…In both PV and PF, patients with active disease demonstrate DSG-reactive IgG4 and IgG1, while patients in remission and some healthy relatives of pemphigus patients can demonstrate only anti-DSG IgG1 [27,28,37,72,73]. Probably IgG2 and IgG3 anti-DSG abs have not been associated with pemphigus [7,74]. Moreover, an IgG4-specific ELISA was shown to have greater sensitivity and specificity than a total IgG anti-DSG ELISA in detecting active stage of some kind of PF, suggesting a more significant clinical association of pathogenic abs with IgG4 rather than with other IgG subclass in this patient.…”

Section: Discussionmentioning

confidence: 99%

Clinical immunology Immunoglobulin G4 is prevailing over immunoglobulin G1 in autoimmunity of pemphigus and bullous pemphigoid: analysis of tissue-bound antibodies in active diseases

Gornowicz‐Porowska¹,

Pietkiewicz²,

Bowszyc‐Dmochowska³

et al. 2013

cejoi

View full text Add to dashboard Cite

Circulating pemphigus autoantibodies in healthy relatives of pemphigus patients: coincidental phenomenon with a risk of disease development?

Cited by 41 publications

References 18 publications

Multiplexed autoantigen microarrays identify HLA as a key driver of anti-desmoglein and -non-desmoglein reactivities in pemphigus

Multiplexed autoantigen microarrays identify HLA as a key driver of anti-desmoglein and -non-desmoglein reactivities in pemphigus

A Single Helper T Cell Clone Is Sufficient to Commit Polyclonal Naive B Cells to Produce Pathogenic IgG in Experimental Pemphigus Vulgaris

Clinical immunology Immunoglobulin G4 is prevailing over immunoglobulin G1 in autoimmunity of pemphigus and bullous pemphigoid: analysis of tissue-bound antibodies in active diseases

Contact Info

Product

Resources

About