Epidermal Transglutaminase (TGase 3) Is the Autoantigen of Dermatitis Herpetiformis

Abstract

Gluten sensitivity typically presents as celiac disease, a common chronic small intestinal disorder. However, in certain individuals it is associated with dermatitis herpetiformis, a blistering skin disease characterized by granular IgA deposits in the papillary dermis. While tissue transglutaminase has been implicated as the major autoantigen of gluten sensitive disease, there has been no explanation as to why this condition appears in two distinct forms. Here we show that while sera from patients with either form of gluten sensitive disease react both with tissue transglutaminase and the related enzyme epidermal (type 3) transglutaminase, antibodies in patients having dermatitis herpetiformis show a markedly higher avidity for epidermal transglutaminase. Further, these patients have an antibody population specific for this enzyme. We also show that the IgA precipitates in the papillary dermis of patients with dermatitis herpetiformis, the defining signs of the disease, contain epidermal transglutaminase, but not tissue transglutaminase or keratinocyte transglutaminase. These findings demonstrate that epidermal transglutaminase, rather than tissue transglutaminase, is the dominant autoantigen in dermatitis herpetiformis and explain why skin symptoms appear in a proportion of patients having gluten sensitive disease.

Celiac Disease and Autoimmunity in the Gut and Elsewhere

“…Epidermal tissue transglutaminase (eTg) is considered one of the key target autoantigens; the intestinal inflammation occurring in CD may be associated with increased production of antibodies directed against eTg. [47,48] Lesions regress with oral Dapsone and compliance with a gluten free diet even in the absence of small bowel villous atrophy. [45] Recurrence of the lesions usually occurs with enteral or rectal challenge with gluten.…”

Transglutaminase 6 antibodies in gluten neuropathy

“…Deamidation of gluten peptides enhances binding with diseaserelevant HLAs and thereby enhances presentation, leading to the development of gluten-specific CD4 + T cells resulting in inflammation leading to the typical enteropathy [15]. Whilst TG2 has been shown to be the autoantigen in CD [16] and epidermal transglutaminase TG3 has been shown to be the autoantigen in DH [17], antibodies against TG6, a primarily brain expressed transglutaminase have been shown to be present in patients with GA [10,12]. In a previous study from our group and using the same methodology, 73% of patients with gluten ataxia were positive for TG6 antibodies [10].…”

Bioinformatics-Based Predictions of Peptide Binding to Disease-Associated HLA Proteins Suggest Explanation for Shared Autoimmunity

“…Theoretically, DH is caused by dermal deposition of circulating immune complexes containing both IgA and TGM3. 32,33 In contrast to these organ-specific diseases, connective tissue disorders, or systemic diseases, including systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and systemic sclerosis (SSc), involve multiple tissues and organs. [34][35][36] Mixed connective tissue disease (MCTD) is also a systemic autoimmune syndrome that is characterized by the presence of high titers of serum antibodies against small nuclear ribonuclear proteins (U-snRNPs), 37,38 in particular against U1 small nuclear RNP polypeptide (U1 snRNP).…”