Linkage of pemphigus vulgaris antibody to the major histocompatibility complex in healthy relatives of patients.

Ar, Ahmed; Mohimen, A; Ej, Yunis; Nm, Mirza; Kumar, Vishwajeet; Eh, Beutner; Alper, C. A.

doi:10.1084/jem.177.2.419

Cited by 90 publications

(59 citation statements)

References 23 publications

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“…However, the nature of these genetic factors differs for different antibody responses. For example, inheritance of the ability to mount an autoantibody response to epidermal cadherin in healthy relatives of patients with pemphigus vulgaris is linked to HLA [41]. Similarly, HLA-DR and DQ genes control the autoimmune response to DNA topoisomerase I in systemic sclerosis [42].…”

Section: Discussionmentioning

confidence: 99%

Thyroid peroxidase autoantibody epitopic ‘fingerprints’ in juvenile Hashimoto’s thyroiditis: evidence for conservation over time and in families

Jaume

Burek

Hoffman

et al. 1996

Clinical and Experimental Immunology

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SUMMARYIn Hashimoto's thyroiditis, the humoral component is manifest by autoantibodies to thyroid peroxidase (TPO). Epitopic 'fingerprinting' of polyclonal serum TPO autoantibodies has been facilitated by the molecular cloning and expression as Fab of a repertoire of human TPO autoantibody genes. To investigate whether TPO autoantibody fingerprints are (i) stable over long periods of time ( 15 years), and (ii) inherited, we studied a cohort of nine patients with juvenile Hashimoto's thyroiditis and 21 first degree relatives of four of these patients. Fingerprints were determined by competition between four selected Fab and serum autoantibodies for binding to 125 I-TPO. Regardless of titre, the TPO epitopic profile was stable in 10/12 individuals whose TPO autoantibody levels were sufficient for analysis on two or three occasions over 12-15 years. Although the TPO epitopic fingerprint profiles in two families raised the possibility of inheritance, overall the data from all four families did not reveal an obvious pattern of genetic control. In no family was the TPO epitopic fingerprint associated with HLA A, B or DR. In conclusion, TPO autoantibody epitopic fingerprints are frequently conserved over many years. Studies on additional families are necessary to establish whether or not the epitopic profiles of TPO autoantibodies are inherited.

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Section: Discussionmentioning

confidence: 99%

Thyroid peroxidase autoantibody epitopic ‘fingerprints’ in juvenile Hashimoto’s thyroiditis: evidence for conservation over time and in families

Jaume

Burek

Hoffman

et al. 1996

Clinical and Experimental Immunology

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“…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

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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.

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“…Pemphigus vulgaris (PV) is caused by autoAb against the extracellular domain (ECD) of desmoglein 3 (Dsg3), while pemphigus foliaceus, a clinically less severe disorder, is caused by autoAb against the ECD of Dsg1 (1,3). AutoAb production in PV is polyclonal, and most autoAb are of the IgG4 subclass in pemphigus patients with active disease (4), while patients with chronic disease have autoAb of the IgG1 and IgG4 subtypes, and healthy relatives of PV patients and healthy carriers of PV-prevalent HLA class II alleles appear to have low levels of Dsg3-reactive IgG1 (4,5).…”

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confidence: 99%

Dichotomy of Autoreactive Th1 and Th2 Cell Responses to Desmoglein 3 in Patients with Pemphigus Vulgaris (PV) and Healthy Carriers of PV-Associated HLA Class II Alleles

Veldman

Stauber²,

Waßmuth³

et al. 2003

The Journal of Immunology

115

120

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Pemphigus vulgaris (PV) is the most severe autoimmune bullous skin disorder and is primarily associated with circulating autoantibodies (autoAb) against desmoglein 3 (Dsg3). In light of recent evidence that autoreactive T cells are critical for the induction and regulation of Ab production, the goal of this study was to characterize and quantitate autoreactive T cells in patients with PV and healthy controls. Peripheral Dsg3-reactive Th cells from 28 patients with acute-onset, chronic active, and remittent PV were quantitated by MACS secretion assay. Dsg3-reactive Th2 cells were detected at similar frequencies in all studied PV patients, while the number of autoreactive Th1 cells exceeded those of Th2 cells in chronic active PV. In contrast, healthy carriers of the PV-associated HLA class II alleles, DRB1*0402 and DQB1*0503, exhibited exclusively Dsg3-reactive Th1 cell responses, while healthy carriers of other HLA class II alleles did not. Moreover, the presence of IgG1 and IgG4 against Dsg3 was directly related to the ratio of Dsg3-reactive Th1/Th2 cells. T cell recognition of Dsg3 was restricted by HLA-DRB1*0402 and DQB1*0503 in PV patients and Dsg3-responsive healthy donors. These observations strongly suggest 1) that the appearance of Dsg3-reactive Th2 cells is restricted to patients with PV; 2) that specific HLA class II alleles that are prevalent in PV are critical for T cell recognition of Dsg3 in PV patients and Dsg3-responsive healthy donors; and 3) that autoAb production is associated with both Th1 and Th2 cells.

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Linkage of pemphigus vulgaris antibody to the major histocompatibility complex in healthy relatives of patients.

Cited by 90 publications

References 23 publications

Thyroid peroxidase autoantibody epitopic ‘fingerprints’ in juvenile Hashimoto’s thyroiditis: evidence for conservation over time and in families

Thyroid peroxidase autoantibody epitopic ‘fingerprints’ in juvenile Hashimoto’s thyroiditis: evidence for conservation over time and in families

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

Dichotomy of Autoreactive Th1 and Th2 Cell Responses to Desmoglein 3 in Patients with Pemphigus Vulgaris (PV) and Healthy Carriers of PV-Associated HLA Class II Alleles

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