Literature Review Sample Work
The Involvement Of Anti-Endomysial Antibody And Il-15 In The Proliferation Of Intestinal Regulatory T Cells In Celiac Disease
Info: 2652 words Sample Literature Review
Published: 18th FEB 2023
Tagged: Medical
Review of Literature
A coordinated response combining both innate and adaptive immunity leads to celiac disease. The adaptive immune response to gluten has been thoroughly documented with peptide sequences displaying HLA-DQ2 or -DQ8 restrictive binding patterns across numerous gluten proteins. Stress and inflammation and non-classical MHC-I molecules like MICA increase enterocytes' surface expression in innate immunity. These molecules are recognised by intra-epithelial lymphocytes, which then engage with them to produce lymphokine-activated death cells. This recognition is made possible by the specific natural killer receptors expressed on their surface (Setty et al., 2008). The amount of published material on the topic is significant, and it covers a wide range of issues, including the aetiology, diagnosis, and treatment of the disease. In the current literature analysis, we tried to analyse the existing research on the topic and extrapolate information pertinent to the study.
Review articles
Cui et al., in their review article, claimed that celiac disease is an autoimmune illness with a rising prevalence that affects persons who carry the HLA-DQ2 or HLA-DQ8 allele and results in lifelong gluten intolerance. In addition to extra-intestinal pathologic situations, it also causes gastroenteropathy. According to their claims, innate immunity plays a significant role in the pathogenesis of CD. They indicated that in patients with a genetic predisposition to CD, the independent or combined activities of IL-15 and type one interferon could lead to the failure to tolerate oral gluten and intraepithelial lymphocyte activation. According to the authors, CD is an autoimmune illness with a rising frequency that requires a multidisciplinary approach for an accurate diagnosis and course of therapy (Cui et al., 2017).
Kaur et al. highlighted that in addition to the release of proinflammatory cytokines like IFN-c, an increase in the CD4+ T cell population that recognises gliadin is one of the hallmarks of celiac disease. IFN-c, which promotes intraepithelial lymphocyte activation and controls innate and adaptive immune responses, is created under the direction of IL-21. Stress-inducible molecules like MIC and HLA-E appear due to increased IL-15 levels. The aforementioned transmembrane receptors are activated and significantly contribute to the facilitation of tissue damage in a targeted manner when the enterocytes express IL-15 and hurt occurs to the stress-induced ligands for natural killer receptors (Kaur et al., 2017).
Parzanese et al. studied the connection between celiac disease and the immune system in a review study and concluded that systemic immunity is the problem that mediates celiac infection. This reveals the primary mechanism associated with CD and demonstrates how gluten-derived peptides cause an aberrant adaptive immune response. They found that prolamines composed of epitopes that are displayed by HLA-DQ2 or HLA-DQ8 cause a CD4+ T-lymphocyte response. In those genetically predisposed to CD, gliadin interacts with intestinal cells to erode the structural integrity of inter-enterocyte tight junctions (TJs). T-lymphocyte activation that is localised in the lamina propria is caused by the passage of gliadin peptides across the epithelial barrier. These cells then go through plasma cell development to create anti-gliadin and anti-tissue transglutaminase antibodies. According to the authors, a CD is distinguished by an increased density of CD8+ intraepithelial cells (Parzanese et al., 2017).
López Casado et al. examined the autoimmune basis of celiac illness. According to the scientists, a significant, proinflammatory, and pathogenic immune response to specific gluten components and the gut tissue results in structural abnormalities in CD. The pathophysiology of CD is thought to be mediated by TG2, modified gluten-producing pathogenic CD4+ T-cell response, and distinct B-cell response. TG2, a deamidating enzyme that stimulates the immune system by acting as a target antigen, amplifies the immunostimulatory effects of gluten. A literature study also looked at the function of autoantibodies in CD, concluding that autoantibodies to TG2 can be utilised to diagnose CD and have high specificity and sensitivity levels. Finally, the authors proposed that, along with the gluten-specific T-cell response, the generation of antibodies also occurs during the early stages of the disease since tissues in the intestine have deposits of anti-TG2 IgA even before the discovery of apparent CD (López Casado et al., 2018).
Malamut et al., in a review study, examined the role of cytotoxic intraepithelial lymphocytes and IL-15 in inducing tissue damage in celiac disease through a review of prior literature. They said that if the start of CD requires gluten-specific CD4+ T cells, it is now clear that tissue damage also involves the activation of cytotoxic IELs with help from interleukin-15 (IL-15). A significant increase in IELs, especially CD8+ IELs with a TCR, is a hallmark of established celiac disease. The authors noted that interleukin-15 had been proven to influence CD significantly. This cytokine is produced by intestinal epithelial and dendritic cells, stimulating the growth of IEL and their cytotoxic action. As a result, they proposed that CD8+ T-IELs are shown to have increased granzyme B production as well as activating NK receptors NKG2D and CD94-NKG2C expression in an established CD. It was discovered that these cells could kill in vitro targets expressing the respective ligands for these receptors, MICA and HLA-E. This setup can still function when IL-15, MICA, and HLA-E expression increases in the duodenal epithelium during active CD. In terms of CD, it's likely that IL-2, IL-21, and Interleukin-15, which are produced by CD4+ T cells that specifically recognise gluten, are what induce IEL activation (Malamut et al., 2019).
Maiuri et al. reviewed the molecular characteristics of gliadin that contribute to CD pathophysiology. The antigenicity of CD is caused by a 33-amino-acid peptide (P55-87) and a fragment known as QLQPFPQPQLPY (P57-68), which are deamidated by the enzyme transglutaminase-2 (TGM2) and, upon starting their action, produce QLQPFPQPELPY and bind to MHC class II. CD only occurs in people with such HLA alleles who are genetically pre. In addition, P57-68 causes a small number of the same people to develop a pathogenic T helper 1 (TH1) response, which destroys intestinal epithelial cells through immune-mediated pathways. They claimed that these adjuvant signals shape the local milieu, enabling the subsequent reaction against the immunogenic peptide P57-68 (Maiuri et al., 2019).
Caio et al. examined and identified the significance of serology in treating celiac disease in a thorough evaluation of the literature on the condition. Genetic predisposition, gluten exposure, impaired intestinal barrier function, proinflammatory immune response brought on by gluten, variable adaptive immune response, and gut dysbiosis are the critical factors at play. They explained the significance of innate immunity in the onset of CD. They claimed that cytokines like interleukin (IL) 15 and interferon alfa could polarise dendritic cells and intraepithelial lymphocyte activity, which prepares the immune response. As EmA exhibits excellent specificity when evaluated in third-level laboratories by skilled workers, they concluded that EmA is the antibody test with the highest degree of diagnostic precision (Caio et al., 2019).
Case reports
A case of occupational exposure that caused a wheat-hypersensitive reaction that was both IgE-mediated and non-IgE-mediated was described by Pastorello et al. In CD, it has been discovered that intestinal lesions are caused by an interaction between CD4+ lamina propria T cells, which produce interferon c in response to gluten peptides presented by HLA-DQ2+ antigen-presenting cells, and IELs, which are triggered by IL-15 and NK receptors. IL-21 may boost the local Th1 response by restricting the activity of regulatory T cells. Finally, they concluded that IL-21 and IL-15 work synergistically to increase IEL activation and enterocyte cytotoxicity (Pastorello et al., 2015).
Histopathologic, Immunohistochemical and Serologic Studies
Ettersperger et al. conducted a study using 28 samples of human tissue and 28 pieces of murine tissue. They found that in both humans and mice, innate gastrointestinal IELs that express intracellular CD3 differentiate via an Id2 transcription factor (TF) independent pathway in response to signals from the TF NOTCH1, interleukin-15 (IL-15), and Granzyme B. It was observed that IL-15 induced Granzyme B, which cleaved NOTCH1 to a peptide with little transcriptional activity in NOTCH1-activated human hematopoietic progenitors. As a result, NOTCH1 target genes essential for T cell development and reprogramming precursors into innate cells with T cell markers were rendered inactive. They concluded that the dual T, ILC, and NK-marked innate-type IELs were thought to arise from hematopoietic progenitors in the gut epithelium via a particular mechanism of differentiation that requires NOTCH and IL-15 signals (Ettersperger et al., 2016).
Meisel et al. article analysed The increased susceptibility to colitis associated with overexpressed IL-15in IECs, according to research using human intestinal and mouse tissue samples to examine whether IL-15-induced intestinal dysbiosis could be the cause of IBD. This research used a chemically induced colitis model to determine this. This study suggests that the effects of IL-15 overexpression on butyrate-producing bacteria and luminal butyrate concentration cause intestinal and extraintestinal immunological issues. Additionally, they predicted that antibodies that neutralise IL-15 and prevent the signalling that it causes could be used therapeutically to treat autoimmune diseases (Meisel et al., 2017).
Vicari et al. reported that a humanised anti-IL-15 antibody was found and described by the authors of a mouse study that involved the discovery and classification of a different humanised anti-IL-15 antibody and its significance in the treatment of CD of refractory nature and eosinophilic esophagitis. It was proposed that IL-15's physiological functions—acting as a warning indication in tissue-resident T cell regulation and causing the destruction of intestinal tissue—allow it to play a significant role in the pleiotropic effects of CD. The study suggested an intriguing direction for further research (Vicari et al., 2017).
Hu et al., in an article, investigated the IL-15's part in IEL's differentiation, and survival was examined using mouse research, cutting-edge live cell imaging tools, and in vitro investigations. They discovered that IL-15 is vital in the proliferation, survival, cytolytic activity, and stimulation of IEL motility. The inhibition of the IL-2Rb signalling pathway, which functions by limiting these cells within the LIS, was observed to impede the function of IEL surveillance. Furthermore, the data they gathered demonstrated that IL-15 enhances the effectiveness of IEL surveillance of the epithelial villi and further clarified the crucial process that local cytokine production plays in the migratory behaviour of IEL (Hu et al., 2018).
Systematic Review and Meta-Analysis
Singh et al., in a study, investigated that the disease entity known as CD has recently posed a significant threat to public health. Patients were classified as seropositive for CD in this investigation if they had either a tissue transglutaminase antibody (Ab) or an anti-endomysial antibody. Since antigliadin antibody is no longer part of the diagnostic strategy for CD, studies that only used it for CD diagnosis were disregarded throughout the systematic review. The presence of one or more of the following criteria led to the final diagnosis of celiac disease (CD) in the patient: test positive for at least one serologic test; biopsy of the small intestine shows changes in the histology of Marsh grade 2 or more; in the absence of serological evidence in a study, a CD was considered to be diagnosed in the presence of histologic changes of modified Marsh grade 2 or higher on biopsies and imprecision of the diagnosis. The authors estimated the prevalence of CD to be 1.4% based on seropositivity and 0.7% based on biopsy data (Singh et al., 2018).
Conclusion
One of the most prevalent autoimmune disorders known to the medical community is celiac disease, which has generated a lot of research over the years. More sensitive and targeted diagnostic methods for the illness have been created due to recent improvements in histopathologic and serological analyses and a deeper comprehension of the pathophysiology involved. Even though prior research has enhanced academics' and clinicians' awareness of the illness, several parts of the disease, such as the therapeutic features, seronegative phenotype, refractory disease, and genetic aspects of CD, still require research. Therefore, future research should concentrate on the abovementioned areas to improve CD patients' prognosis and quality of life.
References
Caio, G., Volta, U., Sapone, A., Leffler, D. A., De Giorgio, R., Catassi, C., & Fasano, A. (2019). Celiac disease: a comprehensive current review. BMC Medicine, 17(1), 142. https://doi.org/10.1186/s12916-019-1380-z
Cui, C., Basen, T., Philipp, A. T., Yusin, J., & Krishnaswamy, G. (2017). Celiac disease and nonceliac gluten sensitivity. Annals of Allergy, Asthma & Immunology : Official Publication of the American College of Allergy, Asthma, & Immunology, 118(4), 389–393. https://doi.org/10.1016/j.anai.2017.01.008
Ettersperger, J., Montcuquet, N., Malamut, G., Guegan, N., Lopez-Lastra, S., Gayraud, S., Reimann, C., Vidal, E., Cagnard, N., Villarese, P., Andre-Schmutz, I., Gomes Domingues, R., Godinho-Silva, C., Veiga-Fernandes, H., Lhermitte, L., Asnafi, V., Macintyre, E., Cellier, C., Beldjord, K., … Meresse, B. (2016). Interleukin-15-Dependent T-Cell-like Innate Intraepithelial Lymphocytes Develop in the Intestine and Transform into Lymphomas in Celiac Disease. Immunity, 45(3), 610–625. https://doi.org/10.1016/j.immuni.2016.07.018
Green, P. H. R., Lebwohl, B., & Greywoode, R. (2015). Celiac disease. Journal of Allergy and Clinical Immunology, 135(5), 1099–1106. https://doi.org/10.1016/j.jaci.2015.01.044
Hu, M. D., Ethridge, A. D., Lipstein, R., Kumar, S., Wang, Y., Jabri, B., Turner, J. R., & Edelblum, K. L. (2018). Epithelial IL-15 Is a Critical Regulator of γδ Intraepithelial Lymphocyte Motility within the Intestinal Mucosa. Journal of Immunology (Baltimore, Md. : 1950), 201(2), 747–756. https://doi.org/10.4049/jimmunol.1701603
Kaur, A., Shimoni, O., & Wallach, M. (2017). Celiac disease: from etiological factors to evolving diagnostic approaches. Journal of Gastroenterology, 52(9), 1001–1012. https://doi.org/10.1007/s00535-017-1357-7
López Casado, M. Á., Lorite, P., Ponce de León, C., Palomeque, T., & Torres, M. I. (2018). Celiac Disease Autoimmunity. Archivum Immunologiae et Therapiae Experimentalis, 66(6), 423–430. https://doi.org/10.1007/s00005-018-0520-z
Maiuri, L., Villella, V. R., Piacentini, M., Raia, V., & Kroemer, G. (2019). Defective proteostasis in celiac disease as a new therapeutic target. Cell Death & Disease, 10(2), 114. https://doi.org/10.1038/s41419-019-1392-9
Malamut, G., Cording, S., & Cerf-Bensussan, N. (2019). Recent advances in celiac disease and refractory celiac disease. F1000Research, 8. https://doi.org/10.12688/f1000research.18701.1
Meisel, M., Mayassi, T., Fehlner-Peach, H., Koval, J. C., O’Brien, S. L., Hinterleitner, R., Lesko, K., Kim, S., Bouziat, R., Chen, L., Weber, C. R., Mazmanian, S. K., Jabri, B., & Antonopoulos, D. A. (2017). Interleukin-15 promotes intestinal dysbiosis with butyrate deficiency associated with increased susceptibility to colitis. The ISME Journal, 11(1), 15–30. https://doi.org/10.1038/ismej.2016.114
Parzanese, I., Qehajaj, D., Patrinicola, F., Aralica, M., Chiriva-Internati, M., Stifter, S., Elli, L., & Grizzi, F. (2017). Celiac disease: From pathophysiology to treatment. World Journal of Gastrointestinal Pathophysiology, 8(2), 27–38. https://doi.org/10.4291/wjgp.v8.i2.27
Pastorello, E. A., Aversano, M. G., Mascheri, A., Farioli, L., Losappio, L. M., Mirone, C., Preziosi, D., & Scibilia, J. (2015). Celiac Disease in a Patient with Baker’s Asthma and Wheat Allergy Due to Tri a 14. Case Reports in Clinical Medicine, 04(07), 253–256. https://doi.org/10.4236/crcm.2015.47050
Setty, M., Hormaza, L., & Guandalini, S. (2008). Celiac disease: risk assessment, diagnosis, and monitoring. Molecular Diagnosis & Therapy, 12, 289–298. https://link.springer.com/article/10.1007/BF03256294
Singh, P., Arora, A., Strand, T. A., Leffler, D. A., Catassi, C., Green, P. H., Kelly, C. P., Ahuja, V., & Makharia, G. K. (2018). Global Prevalence of Celiac Disease: Systematic Review and Meta-analysis. Clinical Gastroenterology and Hepatology, 16(6), 823-836.e2. https://doi.org/10.1016/j.cgh.2017.06.037
Vicari, A. P., Schoepfer, A. M., Meresse, B., Goffin, L., Léger, O., Josserand, S., Guégan, N., Yousefi, S., Straumann, A., Cerf-Bensussan, N., Simon, H.-U., & Chvatchko, Y. (2017). Discovery and characterization of a novel humanized anti-IL-15 antibody and its relevance for the treatment of refractory celiac disease and eosinophilic esophagitis. MAbs, 9(6), 927–944. https://doi.org/10.1080/19420862.2017.1332553
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