TG6 Auto-Antibodies in Dermatitis Herpetiformis

Abstract

Dermatitis herpetiformis (DH) is an extraintestinal manifestation of gluten sensitivity, in which an autoimmune response is directed against transglutaminase 3 (TG3), an epidermal transglutaminase. TG2 is the autoantigen in celiac disease (CD), defined by the presence of enteropathy, and TG6 is the autoantigen in neurological manifestations of gluten sensitivity. The interplay between B cell responses to these 3 transglutaminases in developing the clinical spectrum of disease manifestations is not completely understood. Also, the individual or combined diagnostic and predictive value of the respective autoantibodies is not fully explored. We examined the prevalence of TG6 antibodies in a cohort of patients with DH. TG6 positivity was found in 13/33 (39%), with IgA detected in 11 patients, IgG in 3, and both in 1. This was significantly higher compared to what is seen in the classic CD cases (14%) in a Finnish population. TG6 positive baseline samples constituted 60% of DH patients with no enteropathy (n = 10), as opposed to 17% positivity in those with overt enteropathy (n = 12; Marsh IIIB). Repeat testing after adherence to a gluten-free diet for 1 year showed reduced titers for TG6 antibodies in 11/13 (85%), whereby 7 patients were now TG6 antibody-negative. Four patients seroconverted and tested positive for TG6 antibodies at one year, due to the ongoing exposure to gluten. We report another patient who presented with neurological manifestations (encephalopathy) leading to the diagnosis of CD, who was intermittently adhering to a gluten-free diet. Serological testing at baseline showed him to be positive for antibodies to all 3 transglutaminases. Eleven years later, he developed DH. He also subsequently developed ataxia and peripheral neuropathy. Although TG3 and TG6 autoantibodies are linked to certain disease manifestations, TG2, TG3, and TG6 autoantibodies can be present across the spectrum of GRD patients and might develop years before onset of symptoms of extraintestinal manifestations. This is consistent with gluten-dependent adaptive immunity being a necessary but not sufficient pretext to organ-specific damage. TG6 antibodies appear to develop more frequently in patients where tolerance to gluten was broken but, either there was no development of the molecular state driving the tissue destruction at the level of the gut, or perhaps more likely, there was more resistance to developing this phenotype.

Missing Insight Into T and B Cell Responses in Dermatitis Herpetiformis

“…This is supported by the fact that DH generally tends to develop later than CeD and that CeD can progress into DH, particularly if dietary adherence is not optimal ( 67 ). In addition, CeD and DH patients have also been shown to develop antibodies against another closely related transglutaminase, TG6 ( 30 , 36 , 68 ). It is also noteworthy that such a pathogenic process may be exacerbated by a number of intrinsic and extrinsic factors.…”

Antibody Responses to Transglutaminase 3 in Dermatitis Herpetiformis: Lessons from Celiac Disease

“…The process is illustrated in Figure 2 . This type of mechanism is perhaps better known as the hapten-carrier effect, where allergy or autoimmune disease towards haptens develops as a result of complexes formed between carrier proteins and small molecule antigens [ 37 ]. The possibility of TG2-specific B cells presenting gliadin to T cells and thereafter receiving the appropriate signals for proliferation and class switching would indeed give a plausible explanation to the dilemma presented earlier.…”

Type 2 Transglutaminase in Coeliac Disease: A Key Player in Pathogenesis, Diagnosis and Therapy

“…CD-associated neuropathy affects about 40% of CD patients and includes cerebellar ataxia (named gluten ataxia), cognitive impairment, headache, and neuropsychiatric disorders [ 75 ]. Unexpectedly, anti-TG6 antibodies are also very common in DH patients [ 76 ].…”