Therefore, co-infection with microbes that carry PAMPs may be necessary for the initial onset of symptoms in gluten sensitivity, but would not be necessary for successive encounters with gluten due to the production of memory B and memory T cells (discussed below). Dermatitis herpetiformis may be characterised based on inflammation in the skin and gut. Inflammation in the gut is similar to, and linked to, celiac disease. tTG is treated as an autoantigen, especially in people with certain HLA-DQ2 and HLA-DQ8 alleles and other gene variants that cause atopy. tTG is up-regulated after gluten absorption. cDCs endocytose tTG-modified gliadin complexes or modified gliadin alone but they only present gliadin to CD4+ T cells on pMHC-II complexes. These T cells become activated and polarised into type I helper T (Th1) cells. Th1 cells reactive towards gliadin have been discovered, but none against tTG. A naive B cell sequesters tTG-modified gliadin complexes from the surface of cDCs in the lymph nodes (LNs) before they become endocytosed by the cDCs. The B cell receptor (membrane bound antibody; BCR) is specific to the tTG portion of the complex. The B cell endocytoses the complex and presents the modified gliadin to the activated Th1 cells T cell receptor (TCR) via pMHC-II in a process known as epitope spreading. Thus, the B cell presents the foreign peptide (modified gliadin) but produces antibodies specific for the self-antigen (tTG). Once the B cell becomes activated, it differentiates into plasma cells that secrete autoantibodies against tTG, which may be cross-reactive with epidermal transglutanimase (eTG).
The fact that eTG has been found in precipitates of skin-bound IgA from skin affected by this condition has been used to conclude that dermatitis herpetiformis may be caused by a deposition of both IgA and eTG within the dermis. It is estimated that these deposits may resorb after ten years of following a gluten-free diet. Moreover, it is suggested that this condition is closely linked to genetics. This theory is based on the arguments that individuals with a family history of gluten sensitivity who still consume foods containing gluten are more likely to develop the condition as a result of the formation of antibodies to gluten. These antibodies cross-react with eTG, and IgA/eTG complexes deposit within the papillary dermis to cause the lesions of dermatitis herpetiformis. These IgA deposits may disappear after long-term (up to ten years) avoidance of dietary gluten.Gliadin proteins in gluten are absorbed by the gut and enter the lamina propria where they need to be deamidated by tissue transglutaminase (tTG). tTG modifies gliadin into a more immunogenic peptide. Classical dendritic cells (cDCs) endocytose the immunogenic peptide and if their pattern recognition receptors (PRRs) are stimulated by pathogen-associated molecular patterns (PAMPs) or danger-associated molecular pattern (DAMPs), the danger signal will influence them to secrete IL-8 (CXCL8) in the lamina propria, recruiting neutrophils. Neutrophil recruitment results in a very rapid onset of inflammation.