Title: T-Cell Response in Dermatitis Herpetiformis: May Epidermal Transglutaminase Play a Role in Predicting Clinical Relapse?
Emiliano Antiga,1 ORCID 0000-0001-7787-4433, Roberto Maglie,1 ORCID 0000-0002-5106-4042,
Paolo Fabbri,1 ORCID 0000-0003-4606-9655
1Department of Health Sciences, Section of Dermatology, University of Florence, Florence, Italy
Corresponding Author: Emiliano Antiga, MD, PhD Department of Health Sciences Section of Dermatology University of Florence Viale Michelangiolo 41 50125 Florence, Italy Phone: +390556939664 email: emiliano.antiga@unifi.it
Short title: T-Cell Response in Dermatitis Herpetiformis
Abbreviations:
CD: celiac disease; DH: dermatitis herpetiformis; ELISpot: enzyme linked immunospot; eTG: epidermal transglutaminase; IL: interleukin; IFN: interferon; PBMCs: peripheral blood
We read with interest the paper by Kalliokoski et al (Kalliokoski et al., 2020), investigating whether peripheral blood mononuclear cells (PBMCs) collected from patients with dermatitis herpetiformis (DH) undergoing a three-day oral gluten challenge react to gluten-derived gliadin in the enzyme linked immunospot (ELISpot) assay similarly to those of patients with celiac disease (CD).
Interestingly, the Authors found that upon stimulation with tissue transglutaminase (tTG)-gliadin or either of the gliadin peptides, 7 of the 15 (47%) patients with DH and 15 of the 18 (83%) patients with CD were considered responders in the interferon (IFN)- ELISpot assay.
The Authors hypothesized that the percentage of responding patients with DH was significantly lower than that of patients with CD, possibly because of the significantly longer duration of gluten-free diet for patients with DH before the challenge. This is an intriguing hypothesis, suggesting that the immune tolerance can be restored just avoiding the environmental trigger (gluten) for a
reasonably long period of time.
However, another explanation is possible for this different rate of responders. In fact, as it was previously demonstrated, in patients with DH the immune response is oriented towards a T helper 2 (Th2)-type pathway. Th2-related markers like interleukin (IL)-4 and IL-5 are overexpressed both in the skin (Caproni et al., 1998) and in the serum of patients with DH (Caproni et al., 2002; Makino et al., 2017). By contrast, it is well known that celiac disease is associated with a Th1 (and Th17)-oriented autoimmune response, with a primary role for IFN- (Castellanos-Rubio A et al., 2009). Therefore, it is not unexpected that a IFN-gamma ELISpot assay would have produced higher percentages of positive CD patients than DH ones; by contrast, a IL-4 ELISpot assay would have been a more appropriate tool to investigate the reactivity of DH-derived PBMCs.
Moreover, epidermal TG (eTG) is now considered as the main autoantigen of DH and anti-eTG antibodies are found in both DH and CD (Antiga et al., 2019). Accordingly, to assess whether an ELISpot assay could predict clinical relapse in patients with DH, the use of eTG as the autoantigen and the detection of IL-4 expression as the sign of PBMCs activation should be added to increase
sensitivity and reliability to the IFN-gamma ELISPOT assay performed with tTG and gluten-derived peptides.
Conflict of Interest Statement: None.
Acknowledgments: None.
Author Contributions Statement:
EA: Conceptualization, Writing – original draft, Writing – review & editing RM: Conceptualization, Writing – review & editing
PF: Conceptualization, Supervision, Writing – review & editing
References
Antiga E, Maglie R, Quintarelli L, Verdelli A, Bonciani D, Bonciolini V, et al. Dermatitis
Herpetiformis: Novel Perspectives. Front Immunol 2019;10:1290. doi: 10.3389/fimmu.2019.01290. Caproni M, Feliciani C, Fuligni A, Salvatore E, Atani L, Bianchi B, et al. Th2-like cytokine activity in dermatitis herpetiformis. Br J Dermatol 1998;138:242-7.
Caproni M, Cardinali C, D'Agata A, Selvaggi W, Fabbri P. Serum eosinophil cationic protein, myeloperoxidase, tryptase, eotaxin and Th2-L-like cytokines in Dermatitis herpetiformis. Int Arch Allergy Immunol 2002;128:67-72.
Castellanos-Rubio A, Santin I, Irastorza I, Castaño L, Carlos Vitoria J, Ramon Bilbao J. TH17 (and TH1) signatures of intestinal biopsies of CD patients in response to gliadin. Autoimmunity
Kalliokoski S, Mansikka E, de Kauwe A, Huhtala H, Saavalainen P, Kurppa K, et al. Gliadin-Induced Ex Vivo T-Cell Response in Dermatitis Herpetiformis: A Predictor of Clinical Relapse on Gluten Challenge? J Invest Dermatol 2020;140:1867-1869.e2. doi: 10.1016/j.jid.2019.12.038. Makino T, Yoshihisa Y, Mizawa M, Tsutsui K, Nishijima C, Inaoki M, et al. Increased Serum Levels of Th2-type Cytokines and Eotaxin in Fibrillar-type Dermatitis Herpetiformis. Acta Derm Venereol 2017;97:642-643.
