Cross-reactivity hypothesis for the onset of<unk>  in people with celiac disease In terms of pathology, the first signs of the condition may be observed within the dermis. The changes that may take place at this level may include edema, vascular dilatation, and cellular infiltration. It is common for lymphocytes and eosinophils to be seen. The bullae found in the skin affected by<unk>  are subepidermal and have rounded lateral borders. When looked at under the microscope, the skin affected by<unk>  presents a collection of neutrophils. They have an increased prevalence in the areas where the dermis is closest to the epidermis. Direct IMF studies of uninvolved skin show IgA in the dermal papillae and patchy granular IgA along the basement membrane. The jejunal mucosa may show partial villous atrophy, but the changes tend to be milder than in coeliac disease. Immunological studies revealed findings that are similar to those of coeliac disease in terms of autoantigens. The main autoantigen of<unk>  is epidermal transglutaminase (eTG), a cytosolic enzyme involved in cell envelope formation during keratinocyte differentiation. Various research studies have pointed out different potential factors that may play a larger or smaller role in the development of<unk> . 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<unk>  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<unk> . 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. 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).<unk>  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 cell's 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). Class A antibodies (IgA) deposit in the gut. Some may bind to the CD89 (FcαRI) receptor on macrophages (M1) via their Fc region (constant region). This will trigger endocytosis of the tTG-IgA complex, resulting in the activation of macrophages. Macrophages secrete more IL-8, propagating the neutrophil-mediated inflammatory response. The purportedly cross-reactive autoantibodies may migrate to the skin in<unk> . IgA deposits may form if the antibodies cross-react with epidermal transglutanimase (eTG). Some patients have eTG-specific antibodies instead of tTG-specific cross-reactive antibodies and the relationship between<unk>  and celiac disease in these patients is not fully understood. Macrophages may be stimulated to secrete IL-8 by the same process as is seen in the gut, causing neutrophils to accumulate at sites of high eTG concentrations in the dermal papillae of the skin. Neutrophils produce pus in the dermal papillae, generating characteristic blisters. IL-31 accumulation at the blisters may intensify itching sensations. Memory B and T cells may become activated in the absence of PAMPs and DAMPs during successive encounters with tTG-modified gliadin complexes or modified gliadin alone, respectively. Symptoms of<unk>  are often resolved if patients avoid a gluten-rich diet.
Dermatitis herpetiformis
Dermatitis
Blister beetle dermatitis
Scabies
Rodent mite dermatitis
Bed bug
Paederus dermatitis
Dermatitis repens