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Research Article
Open Access Peer-reviewed

When Genetic Polymorphism Meets an Immune Checkpoint Inhibitor in Celiac Disease

Aaron Lerner , Carina Benzvi
International Journal of Celiac Disease. 2022, 10(1), 11-16. DOI: 10.12691/ijcd-10-1-7
Received July 22, 2022; Revised August 24, 2022; Accepted September 05, 2022

Abstract

Immune checkpoint inhibitors are increasingly used as adjuvant therapy in oncology; however, they have short and long-term side effects. A major one is the surge in autoimmune diseases. The number of those conditions is continuously increasing, and recently, celiac disease was added to the list. Since celiac disease is associated with CTLA-4 polymorphism and since the disease is underdiagnosed and since the patient is at risk for various cancers, upon anti-CTRA-4 immune therapy, the loss of function of the CTLA-4 protein can predispose them to overt celiac disease. The present review highlights some potential mechanisms for CTLA-4 dysfunction, putting the patients at risk of celiac disease induction.

Keywords: checkpoint inhibitor immunotherapy cancer CTLA-4 polymorphism celiac disease pathophysiology

1. Introduction

Immune checkpoint inhibitors (ICPis) represent a recently developed anti-cancer immunotherapy based on a very conserved immune regulation that modulates over stimulation 1, 2. In fact, the immune checkpoints are pivotal cross-controls of immune tolerance and homeostasis.

Immune hyperstimulation is associated with multiple infectious, inflammatory, and autoimmune diseases (ADs) and is an important avenue to fight cancer evolvement 3, 4, 5. The cross-talks between the antigen-presenting cell (APC) and the T cell are a crucial mechanism in immune homeostasis, operating through costimulatory molecules. The major players are represented by the cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and its receptors, the B7 1/2 and the programmed cell death protein 1 (PD-1) and its ligands, the programmed death-ligand 1/2 (PD-L1/2) (Figure 1). When activated, those regulatory pathways modulate immune overreaction, thus, protecting the host from immune dysregulation, loss of tolerance, and autoimmunity 4. However, this protective mechanism is a double-edged sword in cancer genesis since the cancer cells can escape the pathway designated to destroy them 5. In reality, invasive cancers can defend themselves by stimulating those checkpoint crossroads 6, 7. When blocked by monoclonal antibodies, the ICPis disrupt those costimulatory functionalities, resulting in anti-cancer immune overreaction, for the benefit of the affected patients 8. However, upon their introduction, toxicity and side effects are increasingly reported 9, 10, 11, 12. The present review will focus on the autoimmune reactions induced by those drugs, trying to explain the recently reported celiac disease-like condition post-ICPi therapy 13. The combined contribution of CTLA-4 genetic aberrations and the anti-CTLA-4 monotherapy on CTLA-4 dysfunction in celiac disease (CD) induction is highlighted.

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  • Figure 1. A schematic presentation of anti-CTLA-4 agents in action. (a) APCs, such as dendritic cells, present processed peptides to T cells on MHC molecules. Upon activation, T cells increasingly expresses CTLA-4. When it binds to B7-1/2, it initiates co-inhibition pathways that lead to T cell anergy. (b) Anti-CTLA-4 monoclonal antibodies block those inhibitory pathways resulting in effective anti-tumor T lymphocyte responses
1.1. CTLA-4 Polymorphism in Autoimmune Diseases

Being a protector of tolerance and an essential inhibitor of T-cell responses, CTLA-4 dysfunction is implicated as an auto immunogenic risk factor. In this sense, polymorphism of CTLA-4 is an important genetic marker associated with a risk of ADs development 14. Following are some ADs associated with CTLA-4 polymorphism (Table 1).

Following is a summary of polymorphic CTLA-4 and CD susceptibility.

1.2. CTLA-4 Polymorphism in Celiac Disease

A meta-analysis screened thirteen scientific reports on CTLA-4 polymorphic alleles involving 5072 CD patients, compared to 13462 controls, substantiated the association 35. CTLA-4 alleles were studied, spanning CT60 A/G, +49 A/G, -318 C/T polymorphisms. The authors concluded that only the CT60 A/G polymorphism conferred susceptibility to CD, and no association was found with the other polymorphic alleles, at least in Europeans 35.

Over the last decades, genetic associations of several CTLA-4 polymorphic alleles conferring susceptibility to CD have been described [32-41]. Moreso, over secretion of soluble CTLA-4 in CD and some other ADs overlapping CD were reported 36, 42, 43, 44. However, the ability to produce the soluble form and its relationship to the various CTLA-4 polymorphic alleles is not fully understood 36 and is unknown in CD. Intriguingly, most of the CTLA-4 molecule is located intracellularly, then it is transported transmembranely to be expressed on the cell surface, capable of rapid internalization. The expressed level and the circulating soluble CTLA-4 are regulated by dynamic recycling, endocytosis, controlled neo-synthetization, and multiple genetic factors 45. Any interference with CTLA-4 surface expression, regulation, and function might affect immune homeostasis, tolerance, and predispose autoimmunity, including CD. Finally, as a proof of concept, the anti-CTLA-4 specific ICPi are associated with CD induction 13, and even a fulminant CD case was most recently described post-ICPi therapy 46. It seems that the CTLA-4 loss of function is a major risk factor for CD development.

2. CTLA-4 polymorphism and the Anti-CTLA-4 therapy-induced Loss of Function

Based on the crucial role of the CTLA-4 protein in tolerance induction and as a protector in ADs prevention, its dysfunction to execute its homeostatic roles is important in regulating the balance between tolerance and autoimmunity. Many processes can impact its loss of function. Table 2 summarizes those possibilities.

At least two of those avenues can operate in CD induction, namely, CTLA-4 polymorphism and ICPi usage.

3. Potential Mechanisms in CTLA-4 Dysfunction in CD Induction

The topic of an additive or potentiating effect of the anti-CTLA-4 ICPi and the CTLA-4 polymorphism on the protein functionality in ADs was not elucidated so far. However, several potential mechanisms can be offered. Table 3 summarizes the potential modes of action of the anti-CTLA-4 ICPi and CTLA-4 polymorphism to compromise the dysfunction of the CTLA-4 protein that might operate in CD.

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  • Figure 2. A schematic presentation of celiac disease induction via CTLA-4 dysfunction. (A) Gluten is ingested and digested, reaching the gut lumen as gliadin peptides. (B) Gliadins are rich in glutamine and proline, and thus are a prime substrate for deamidation and cross-linking by luminal and mucosal transglutaminases, thus, turning those naïve molecules into immunogenic ones. Transglutaminase capacity to deamidated or transamidate, results in increased post-translation modified proteins (PTMP). Luminal digestive peptidases cannot further break down those bonds, hence, inducing gut inflammation, mucus disruption, and intestinal epithelial damage. (C) Gluten increases intestinal permeability by binding to epithelial CXCR3 receptors, resulting in zonulin release. Gliadin-transglutaminase transformed peptides can potentially infiltrate through the open junctions or trans-enterocytically into the lamina propria. A breach in the epithelial barrier exposes the highly immunoreactive sub-epithelium to luminal foreign antigens, stimulating the local immune system. (D) In the lamina propria, gliadin-transglutaminase cross-linked complexes induce pro-inflammatory cytokines. (E) Two types of DC are present, sub-epithelial DCs that send protrusions into the lumen and sense the gut microbiota, and the lamina propria DCs that migrate to lymph nodes, where they present antigens and activate T cells. (F) Immune checkpoint inhibitors block co-inhibitory pathways unleashing effector T cells and depleting regulatory T cells. CTLA-4 polymorphism, such as CT60, manifest itself in less soluble CTLA-4, which leads to a more aggressive response. (G) Uncontrolled activation and proliferation of cytotoxic T lymphocytes (CTLs) further aggravate barrier perturbation, secreting IFNγ and TNFα cytokines, leading to severe intestinal damage

In summary, multiple genetic and environmental factors might induce systemic or intestinal dysfunction of the CTLA-4 molecule. Most of them are hypothetical and not fully investigated in CD-associated ICPi therapy.

4. Conclusions

Checkpoint inhibitors have various enteric side effects and are associated with ADs induction. Recently CD-like condition was associated with their usage 13. The potential mechanism might operate in CD induction in patients with CTLA-4 polymorphic alleles, post-ICPi therapy, however, the incidence, pathophysiology, and outcome of the patients are far from being elucidated. The present review offers several potential mechanisms. It is hoped that those pathophysiological avenues will encourage the medical and scientific communities to investigate and clarify this enigma.

Abbreviations

ICPi- immune checkpoint inhibitors, CTLA-4-cytotoxic T-lymphocyte-associated protein 4, PD-1-programmed cell death protein 1, PD-L1-programmed death-ligand 1, IRAEs-immune-related adverse events, CD-celiac disease, AD-autoimmune disease.

Author Contributions

AL- screened the literature, designed and wrote the manuscript, CB- screened the literature, edited, and revised the manuscript, designed the figure with BioRender.com permission. The two authors agreed to the published version of the manuscript.

Funding

This research received no external funding.

References

[1]  Nurieva, R.I., Liu, X. and Dong, C., “Yin-Yang of costimulation: crucial controls of immune tolerance and function”, Immunological reviews, 229 (1). 88-100. May 2009.
In article      View Article  PubMed 
 
[2]  Chen, L. and Flies, D.B., “Molecular mechanisms of T cell co-stimulation and co-inhibition”, Nature reviews. Immunology, 13 (4).227. April 2013.
In article      View Article  PubMed 
 
[3]  Dotan, A., Muller, S., Kanduc, D., David, P., Halpert, G. and Shoenfeld, Y., “The SARS-CoV-2 as an instrumental trigger of autoimmunity”, Autoimmunity reviews, 20 (4). April 2021.
In article      View Article  PubMed 
 
[4]  Balomenos, D. and Martínez-A, C., “Cell-cycle regulation in immunity, tolerance and autoimmunity”, Immunology today, 21 (11). 551-555. 2000.
In article      View Article 
 
[5]  Poto, R., Troiani, T., Criscuolo, G., Marone, G., Ciardiello, F., Tocchetti, C.G. and Varricchi, G., “Holistic Approach to Immune Checkpoint Inhibitor-Related Adverse Events”, Frontiers in immunology, 13 March 2022.
In article      View Article  PubMed 
 
[6]  Kumar, P., Bhattacharya, P. and Prabhakar, B.S., “A comprehensive review on the role of co-signaling receptors and Treg homeostasis in autoimmunity and tumor immunity”, Journal of Autoimmunity, 95 77-99. December 2018.
In article      View Article  PubMed 
 
[7]  Kumar, P., Saini, S. and Prabhakar, B.S., “Cancer immunotherapy with check point inhibitor can cause autoimmune adverse events due to loss of Treg homeostasis”, Seminars in Cancer Biology, 64 (December 2018). 29-35. 2020.
In article      View Article  PubMed 
 
[8]  Robert, C.,”A decade of immune-checkpoint inhibitors in cancer therapy”, Nature communications, 11 (1). December 2020.
In article      View Article  PubMed 
 
[9]  Wang, D.Y., Salem, J.E., Cohen, J. V., Chandra, S., Menzer, C., Ye, F., Zhao, S., Das, S., Beckermann, K.E., Ha, L., et al.,”Fatal Toxic Effects Associated With Immune Checkpoint Inhibitors: A Systematic Review and Meta-analysis”, JAMA oncology, 4 (12). 1721-1728. December 2018.
In article      View Article  PubMed 
 
[10]  Khan, S. and Gerber, D.E., “Autoimmunity, checkpoint inhibitor therapy and immune-related adverse events: A review”, Seminars in Cancer Biology, 64 (January). 93-101. 2020.
In article      View Article  PubMed 
 
[11]  Ben Zvi, C., Ehrenfeld, M. and Shoenfeld, Y., “[IMMUNOTHERAPY WITH CHECKPOINT INHIBITORS (ICPI) AND IMMUNE RELATED ADVERSE EVENTS (IRAE’S)].”, Harefuah, 159 (7). 508-515. July 2020 Available: https://www.ncbi.nlm.nih.gov/pubmed/32720769.
In article      
 
[12]  Orlova, R., Zhukova, N., Malkova, A. and Shoenfeld, Y., “Hypothesis for the development of immune-related adverse events in immune checkpoint inhibitors therapy”, Cancer treatment and research communications, 31 January 2022.
In article      View Article  PubMed 
 
[13]  Lerner, A. and Benzvi, C.,”Checkpoint Inhibitors and Induction of Celiac Disease-like Condition”, Biomedicines, 10 (3). March 2022.
In article      View Article  PubMed 
 
[14]  Fernández-Mestre, M., Sánchez, K., Balbás, O., Gendzekhzadze, K., Ogando, V., Cabrera, M. and Layrisse, Z., “Influence of CTLA-4 gene polymorphism in autoimmune and infectious diseases”, Human immunology, 70 (7). 532-535. July 2009.
In article      View Article  PubMed 
 
[15]  Ulker, M., Yazisiz, V., Sallakci, N., Avci, A.B., Sanlioglu, S., Yegin, O. and Terzioglu, E., “CTLA-4 gene polymorphism of exon 1(+49 A/G) in Turkish systemic lupus erythematosus patients”, International journal of immunogenetics, 36 (4). 245-250. August 2009.
In article      View Article  PubMed 
 
[16]  Du, L., Yang, P., Hou, S., Zhou, H. and Kijlstra, A., “No association of CTLA-4 polymorphisms with susceptibility to Behçet disease”, British Journal of Ophthalmology, 93 (10). 1378-1381. October 2009.
In article      View Article  PubMed 
 
[17]  Gouda, N.S., Fawzy, M.S. and Toraih, E.A., “Impact of cytotoxic T-lymphocyte-associated protein 4 codon 17 variant and expression on vitiligo risk”, Journal of clinical laboratory analysis, 35 (6). June 2021.
In article      View Article  PubMed 
 
[18]  Abida, O., Bahloul, E., Ben Jmaa, M., Sellami, K., Zouidi, F., Fakhfakh, R., Mahfoudh, N., Turki, H. and Masmoudi, H., “Chromosome 2q33genetic polymorphisms in Tunisian endemic pemphigus foliaceus”, Molecular genetics & genomic medicine, 8 (11). November 2020.
In article      View Article  PubMed 
 
[19]  Xu, W., Ren, M., Ghosh, S., Qian, K., Luo, Z., Zhang, A., Zhang, C. and Cui, J., “Defects of CTLA-4 Are Associated with Regulatory T Cells in Myasthenia Gravis Implicated by Intravenous Immunoglobulin Therapy”, Mediators of inflammation, 2020.
In article      View Article  PubMed 
 
[20]  Khalid Kheiralla, K.E.,”CTLA-4 (+49A/G) Polymorphism in Type 1 Diabetes Children of Sudanese Population”, Global medical genetics, 8 (1). 011-018. March 2021.
In article      View Article  PubMed 
 
[21]  Borysewicz-Sańczyk, H., Sawicka, B., Wawrusiewicz-Kurylonek, N., Głowińska-Olszewska, B., Kadłubiska, A., Gościk, J., Szadkowska, A., Łosiewicz, A., Młynarski, W., Kretowski, A., et al., “Genetic Association Study of IL2RA, IFIH1, and CTLA-4 Polymorphisms With Autoimmune Thyroid Diseases and Type 1 Diabetes”, Frontiers in pediatrics, 8 August 2020.
In article      View Article  PubMed 
 
[22]  Du, P., Ma, X. and Wang, C., “Associations of CTLA4 Gene Polymorphisms with Graves’ Ophthalmopathy: A Meta-Analysis”, International journal of genomics, 2014.
In article      View Article  PubMed 
 
[23]  Louthrenoo, W., Kasitanon, N., Wongthanee, A., Kuwata, S. and Takeuchi, F., “CTLA-4 polymorphisms in Thai patients with rheumatoid arthritis, systemic lupus erythematosus, and systemic sclerosis”, International journal of rheumatic diseases, 24 (11). 1378-1385. November 20219.
In article      View Article  PubMed 
 
[24]  Agarwal, K., Czaja, A.J., Jones, D.E.J. and Donaldson, P.T., “Cytotoxic T lymphocyte antigen-4 (CTLA-4) gene polymorphisms and susceptibility to type 1 autoimmune hepatitis”, Hepatology (Baltimore, Md.), 31 (1). 49-53. 2000.
In article      View Article  PubMed 
 
[25]  Favorova, O.O., Favorov, A. V., Boiko, A.N., Andreewski, T. V., Sudomoina, M.A., Alekseenkov, A.D., Kulakova, O.G., Gusev, E.I., Parmigiani, G. and Ochs, M.F., “Three allele combinations associated with multiple sclerosis”, BMC medical genetics, 7 July 2006.
In article      View Article  PubMed 
 
[26]  Yu, L., Shao, M., Zhou, T., Xie, H., Wang, F., Kong, J., Xu, S., Shuai, Z. and Pan, F., “Association of CTLA-4 (+49 A/G) polymorphism with susceptibility to autoimmune diseases: A meta-analysis with trial sequential analysis”, International immunopharmacology, 96 July 2021.
In article      View Article  PubMed 
 
[27]  Eskandari-Nasab, E., Tahmasebi, A. and Hashemi, M., “Meta-analysis: the relationship between CTLA-4 +49 A/G polymorphism and primary biliary cirrhosis and type I autoimmune hepatitis”, Immunological investigations, 44 (4). 331-348. May 2015.
In article      View Article  PubMed 
 
[28]  Ismail, N.A., Toraih, E.A., Ameen, H.M., Gomaa, A.H.A. and Marie, R.E.S.M., “Association of Rs231775 Genetic Variant of Cytotoxic T-lymphocyte Associated Protein 4 with Alopecia Areata Disease in Males: A Case-Control Study”, Immunological investigations, 50 (8). 977-986. 2021.
In article      View Article  PubMed 
 
[29]  Zhang, M., Ni, J., Xu, W.D., Wen, P.F., Qiu, L.J., Wang, X.S., Pan, H.F. and Ye, D.Q., “Association of CTLA-4 variants with susceptibility to inflammatory bowel disease: a meta-analysis”, Human immunology, 75 (3). 227-233. March 2014.
In article      View Article  PubMed 
 
[30]  Pastuszak-Lewandoska, D., Sewerynek, E., Domańska, D., Gładyś, A., Skrzypczak, R. and Brzeziańska, E., “CTLA-4 gene polymorphisms and their influence on predisposition to autoimmune thyroid diseases (Graves’ disease and Hashimoto’s thyroiditis)”, Archives of medical science: AMS, 8 (3). 415-421. June 2012.
In article      View Article  PubMed 
 
[31]  Carr, E.J., Niederer, H.A., Williams, J., Harper, L., Watts, R.A., Lyons, P.A. and Smith, K.G.C., “Confirmation of the genetic association of CTLA4 and PTPN22 with ANCA-associated vasculitis”, BMC Medical Genetics, 10 December 2009.
In article      View Article  PubMed 
 
[32]  Holopainen, P., Arvas, M., Sistonen, P., Mustalahti, K., Collin, P., Mäki, M. and Partanen, J., “CD28/CTLA4 gene region on chromosome 2q33 confers genetic susceptibility to celiac disease. A linkage and family-based association study”, Tissue antigens, 53 (5). 470-475. 1999.
In article      View Article  PubMed 
 
[33]  Naluai, Å.T., Nilsson, S., Samuelsson, L., Gudjónsdóttir, A.H., Ascher, H., Ek, J., Hallberg, B., Kristiansson, B., Martinsson, T., Nerman, O., et al., “The CTLA4/CD28 gene region on chromosome 2q33 confers susceptibility to celiac disease in a way possibly distinct from that of type 1 diabetes and other chronic inflammatory disorders”, Tissue antigens, 56 (4). 350-355. 2000.
In article      View Article  PubMed 
 
[34]  Popat, S., Hearle, N., Hogberg, L., Braegger, C.P., O’Donoghue, D., Falth-Magnusson, K., Holmes, G.K.T., Howdle, P.D., Jenkins, H., Johnston, S., et al., “Variation in the CTLA4/CD28 gene region confers an increased risk of coeliac disease”, Annals of human genetics, 66 (Pt 2). 125-137. March 2002.
In article      View Article  PubMed 
 
[35]  Song, G.G., Kim, J.H., Kim, Y.H. and Lee, Y.H., “Association between CTLA-4 polymorphisms and susceptibility to Celiac disease: a meta-analysis”, Human immunology, 74 (9).1214-1218. September 2013.
In article      View Article  PubMed 
 
[36]  Pesce, G., Auricchio, R., Bagnasco, M. and Saverino, D., “Oversecretion of soluble CTLA-4 in various autoimmune diseases overlapping celiac disease”, Genetic testing and molecular biomarkers, 18 (1). 8-11. January 2014.
In article      View Article  PubMed 
 
[37]  King, A.L., Moodie, S.J., Fraser, J.S., Curtis, D., Reid, E., Dearlove, A.M., Ellis, H.J. and Ciclitira, P.J., “CTLA-4/CD28 gene region is associated with genetic susceptibility to coeliac disease in UK families”, Journal of medical genetics, 39 (1). 51-54. 2002.
In article      View Article  PubMed 
 
[38]  van Belzen, M.J., Mulder, C.J.J., Zhernakova, A., Pearson, P.L., Houwen, R.H.J. and Wijmenga, C., “CTLA4 +49 A/G and CT60 polymorphisms in Dutch coeliac disease patients”, European journal of human genetics: EJHG, 12 (9). 782-785. September 2004.
In article      View Article  PubMed 
 
[39]  Hunt, K.A., McGovern, D.P.B., Kumar, P.J., Ghosh, S., Travis, S.P.L., Walters, J.R.F., Jewell, D.P., Playford, R.J. and van Heel, D.A.,”A common CTLA4 haplotype associated with coeliac disease”, European journal of human genetics: EJHG, 13 (4). 440-444. April 2005.
In article      View Article  PubMed 
 
[40]  Brophy, K., Ryan, A.W., Thornton, J.M., Abuzakouk, M., Fitzgerald, A.P., McLoughlin, R.M., O’Morain, C., Kennedy, N.P., Stevens, F.M., Feighery, C., et al., “Haplotypes in the CTLA4 region are associated with coeliac disease in the Irish population”, Genes and immunity, 7 (1). 19-26. January 2006.
In article      View Article  PubMed 
 
[41]  King, A.L., Moodie, S.J., Fraser, J.S., Curtis, D., Reid, E., Dearlove, A.M. and Ciclitira, P.J., “Coeliac disease: investigation of proposed causal variants in the CTLA4 gene region”, European journal of immunogenetics: official journal of the British Society for Histocompatibility and Immunogenetics, 30 (6). 427-432. December 2003.
In article      View Article  PubMed 
 
[42]  Simone, R., Brizzolara, R., Chiappori, A., Milintenda-Floriani, F., Natale, C., Greco, L., Schiavo, M., Bagnasco, M., Pesce, G. and Saverino, D.,”A functional soluble form of CTLA-4 is present in the serum of celiac patients and correlates with mucosal injury”, International immunology, 21 (9). 1037-1045. 2009.
In article      View Article  PubMed 
 
[43]  Alfadhli, S., “Overexpression and secretion of the soluble CTLA-4 splice variant in various autoimmune diseases and in cases with overlapping autoimmunity”, Genetic testing and molecular biomarkers, 17 (4). 336-341. April 2013.
In article      View Article  PubMed 
 
[44]  Saverino, D., Simone, R., Bagnasco, M. and Pesce, G., “The soluble CTLA-4 receptor and its role in autoimmune diseases: An update”, Autoimmunity Highlights, 1 (2). 73-81. November 2010.
In article      View Article  PubMed 
 
[45]  Schneider, H. and Rudd, C.E., “Diverse mechanisms regulate the surface expression of immunotherapeutic target ctla-4”, Frontiers in immunology, 5 (DEC). 2014.
In article      View Article 
 
[46]  Falade, A.S., Reynolds, K.L., Zubiri, L., Deshpande, V., Fintelmann, F.J., Dougan, M. and Mooradian, M.J., “Case Report: Fulminant Celiac Disease With Combination Immune Checkpoint Therapy”, Frontiers in immunology, 13 April 2022.
In article      View Article  PubMed 
 
[47]  Watari, K., Konnai, S., Maekawa, N., Okagawa, T., Suzuki, Y., Murata, S. and Ohashi, K., “Immune inhibitory function of bovine CTLA-4 and the effects of its blockade in IFN-γ production”, BMC veterinary research, 15 (1). October 2019.
In article      View Article  PubMed 
 
[48]  Leblanc, J., Hoibian, S., Boucraut, A., Ratone, J.P., Stoffaes, L., Dano, D., Louvel-Perrot, D., Chanez, B., Chretien, A.S., Madroszyk, A., et al., “Celiac Disease After Administration of Immune Checkpoint Inhibitors: A Case Report”, Frontiers in immunology, 12 December 2021.
In article      View Article  PubMed 
 
[49]  Badran, Y.R., Shih, A., Leet, D., Mooradian, M.J., Coromilas, A., Chen, J., Kem, M., Zheng, H., Borowsky, J., Misdraji, J., et al., “Immune checkpoint inhibitor-associated celiac disease”, Journal for immunotherapy of cancer, 8 (1). June 2020.
In article      View Article  PubMed 
 
[50]  Liu, X., Shi, Y., Zhang, D., Zhou, Q., Liu, J., Chen, M., Xu, Y., Zhao, J., Zhong, W. and Wang, M., “Risk factors for immune-related adverse events: what have we learned and what lies ahead?”, Biomarker research, 9 (1). December 2021.
In article      View Article  PubMed 
 
[51]  De Moel, E.C., Rozeman, E.A., Kapiteijn, E.H., Verdegaal, E.M.E., Grummels, A., Bakker, J.A., Huizinga, T.W.J., Haanen, J.B., Toes, R.E.M. and Van Der Woude, D., “Autoantibody Development under Treatment with Immune-Checkpoint Inhibitors”, Cancer immunology research, 7 (1). 6-11. January 2019.
In article      View Article  PubMed 
 
[52]  Kristiansen, O.P., Larsen, Z.M. and Pociot, F., “CTLA-4 in autoimmune diseases--a general susceptibility gene to autoimmunity?”, Genes and immunity, 1 (3). 170-184. 2000.
In article      View Article  PubMed 
 
[53]  Tison, A., Quéré, G., Misery, L., Funck-Brentano, E., Danlos, F.X., Routier, E., Robert, C., Loriot, Y., Lambotte, O., Bonniaud, B., et al., “Safety and Efficacy of Immune Checkpoint Inhibitors in Patients With Cancer and Preexisting Autoimmune Disease: A Nationwide, Multicenter Cohort Study”, Arthritis & rheumatology (Hoboken, N.J.), 71 (12). 2100-2111. December 2019.
In article      View Article  PubMed 
 
[54]  Vanderlugt, C.L. and Miller, S.D., “Epitope spreading in immune-mediated diseases: implications for immunotherapy”, Nature reviews. Immunology, 2 (2). 85-95. 2002.
In article      View Article  PubMed 
 
[55]  Kwek, S.S., Dao, V., Roy, R., Hou, Y., Alajajian, D., Simko, J.P., Small, E.J. and Fong, L., “Diversity of antigen-specific responses induced in vivo with CTLA-4 blockade in prostate cancer patients”, Journal of immunology (Baltimore, Md. 1950), 189 (7). 3759-3766. October 2012.
In article      View Article  PubMed 
 
[56]  Vojdani, A., Lerner, A. and Vojdani, E., “Cross-Reactivity and Sequence Homology between Al-Pha-Synuclein and Food Products: A Step Further for Parkinson’s Disease Synucleinopathy”, Cells, 10 (5).1111. May 2021.
In article      View Article  PubMed 
 
[57]  Vojdani, A., Monro, J., Lanzisera, F. and Sadeghi, H., “Serological cross-reactivity between viruses and their contribution to autoimmunity”, Autoimmunity reviews, 20 (7). July 2021.
In article      View Article  PubMed 
 
[58]  Lerner, A. and Benzvi, C., “Let Food Be Thy Medicine’: Gluten and Potential Role in Neurodegeneration”, Cells, 10 (4). 2021.
In article      View Article  PubMed 
 
[59]  Lerner, A., Aminov, R. and Matthias, T., “Transglutaminases in Dysbiosis As Potential Environmental Drivers of Autoimmunity”, Frontiers in microbiology, 8 (JAN). January 2017.
In article      View Article 
 
[60]  Bascuñán, K.A., Araya, M., Roncoroni, L., Doneda, L. and Elli, L., “Dietary Gluten as a Conditioning Factor of the Gut Microbiota in Celiac Disease”, Advances in nutrition (Bethesda, Md.), 11 (1). 160-174. January 2020.
In article      View Article  PubMed 
 
[61]  VIVARELLI, S., FALZONE, L., LEONARDI, G.C., SALMERI, M. and LIBRA, M., “Novel insights on gut microbiota manipulation and immune checkpoint inhibition in cancer (Review)”, International journal of oncology, 59 (3). September 2021.
In article      View Article  PubMed 
 
[62]  Zhang, M.L. and Deshpande, V., “Histopathology of Gastrointestinal Immune-related Adverse Events: A Practical Review for the Practicing Pathologist”, The American journal of surgical pathology, 46 (1). E15-E26. January 2022.
In article      View Article  PubMed 
 
[63]  Zhang, M.L., Neyaz, A., Patil, D., Chen, J., Dougan, M. and Deshpande, V., “Immune-related adverse events in the gastrointestinal tract: diagnostic utility of upper gastrointestinal biopsies”, Histopathology, 76 (2). 233-243. January 2020.
In article      View Article  PubMed 
 
[64]  Mendo, R., Figueiredo, P. and Mascarenhas, L., “Checkpoint Inhibitor-Induced Gastroduodenitis: An Unusual Manifestation”, GE Portuguese journal of gastroenterology, 28 (2). 150-152. February 2021.
In article      View Article  PubMed 
 
[65]  Gadhok, R., Paulon, E., Tai, C., Olushola, T., Barragry, J., Rahman, F., Di Caro, S. and Mehta, S., “Gastrointestinal consequences of cancer treatment: evaluation of 10 years’ experience at a tertiary UK centre”, Frontline gastroenterology, 12 (6). 2020.
In article      View Article  PubMed 
 
[66]  Chatzileontiadou, D.S.M., Sloane, H., Nguyen, A.T., Gras, S. and Grant, E.J., “The Many Faces of CD4 + T Cells: Immunological and Structural Characteristics”, International journal of molecular sciences, 22 (1).1-27. January 2020.
In article      View Article  PubMed 
 
[67]  Cook, L., Munier, C.M.L., Seddiki, N., van Bockel, D., Ontiveros, N., Hardy, M.Y., Gillies, J.K., Levings, M.K., Reid, H.H., Petersen, J., et al., “Circulating gluten-specific FOXP3 + CD39 + regulatory T cells have impaired suppressive function in patients with celiac disease”, The Journal of allergy and clinical immunology, 140 (6). 1592-1603. e8. December 2017.
In article      View Article  PubMed 
 
[68]  Valk, E., Rudd, C.E. and Schneider, H., “CTLA-4 trafficking and surface expression”, Trends in immunology, 29 (6). 272-279. June 2008.
In article      View Article  PubMed 
 

Published with license by Science and Education Publishing, Copyright © 2022 Aaron Lerner and Carina Benzvi

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Aaron Lerner, Carina Benzvi. When Genetic Polymorphism Meets an Immune Checkpoint Inhibitor in Celiac Disease. International Journal of Celiac Disease. Vol. 10, No. 1, 2022, pp 11-16. https://pubs.sciepub.com/ijcd/10/1/7
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Lerner, Aaron, and Carina Benzvi. "When Genetic Polymorphism Meets an Immune Checkpoint Inhibitor in Celiac Disease." International Journal of Celiac Disease 10.1 (2022): 11-16.
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Lerner, A. , & Benzvi, C. (2022). When Genetic Polymorphism Meets an Immune Checkpoint Inhibitor in Celiac Disease. International Journal of Celiac Disease, 10(1), 11-16.
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Lerner, Aaron, and Carina Benzvi. "When Genetic Polymorphism Meets an Immune Checkpoint Inhibitor in Celiac Disease." International Journal of Celiac Disease 10, no. 1 (2022): 11-16.
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  • Figure 1. A schematic presentation of anti-CTLA-4 agents in action. (a) APCs, such as dendritic cells, present processed peptides to T cells on MHC molecules. Upon activation, T cells increasingly expresses CTLA-4. When it binds to B7-1/2, it initiates co-inhibition pathways that lead to T cell anergy. (b) Anti-CTLA-4 monoclonal antibodies block those inhibitory pathways resulting in effective anti-tumor T lymphocyte responses
  • Figure 2. A schematic presentation of celiac disease induction via CTLA-4 dysfunction. (A) Gluten is ingested and digested, reaching the gut lumen as gliadin peptides. (B) Gliadins are rich in glutamine and proline, and thus are a prime substrate for deamidation and cross-linking by luminal and mucosal transglutaminases, thus, turning those naïve molecules into immunogenic ones. Transglutaminase capacity to deamidated or transamidate, results in increased post-translation modified proteins (PTMP). Luminal digestive peptidases cannot further break down those bonds, hence, inducing gut inflammation, mucus disruption, and intestinal epithelial damage. (C) Gluten increases intestinal permeability by binding to epithelial CXCR3 receptors, resulting in zonulin release. Gliadin-transglutaminase transformed peptides can potentially infiltrate through the open junctions or trans-enterocytically into the lamina propria. A breach in the epithelial barrier exposes the highly immunoreactive sub-epithelium to luminal foreign antigens, stimulating the local immune system. (D) In the lamina propria, gliadin-transglutaminase cross-linked complexes induce pro-inflammatory cytokines. (E) Two types of DC are present, sub-epithelial DCs that send protrusions into the lumen and sense the gut microbiota, and the lamina propria DCs that migrate to lymph nodes, where they present antigens and activate T cells. (F) Immune checkpoint inhibitors block co-inhibitory pathways unleashing effector T cells and depleting regulatory T cells. CTLA-4 polymorphism, such as CT60, manifest itself in less soluble CTLA-4, which leads to a more aggressive response. (G) Uncontrolled activation and proliferation of cytotoxic T lymphocytes (CTLs) further aggravate barrier perturbation, secreting IFNγ and TNFα cytokines, leading to severe intestinal damage
[1]  Nurieva, R.I., Liu, X. and Dong, C., “Yin-Yang of costimulation: crucial controls of immune tolerance and function”, Immunological reviews, 229 (1). 88-100. May 2009.
In article      View Article  PubMed 
 
[2]  Chen, L. and Flies, D.B., “Molecular mechanisms of T cell co-stimulation and co-inhibition”, Nature reviews. Immunology, 13 (4).227. April 2013.
In article      View Article  PubMed 
 
[3]  Dotan, A., Muller, S., Kanduc, D., David, P., Halpert, G. and Shoenfeld, Y., “The SARS-CoV-2 as an instrumental trigger of autoimmunity”, Autoimmunity reviews, 20 (4). April 2021.
In article      View Article  PubMed 
 
[4]  Balomenos, D. and Martínez-A, C., “Cell-cycle regulation in immunity, tolerance and autoimmunity”, Immunology today, 21 (11). 551-555. 2000.
In article      View Article 
 
[5]  Poto, R., Troiani, T., Criscuolo, G., Marone, G., Ciardiello, F., Tocchetti, C.G. and Varricchi, G., “Holistic Approach to Immune Checkpoint Inhibitor-Related Adverse Events”, Frontiers in immunology, 13 March 2022.
In article      View Article  PubMed 
 
[6]  Kumar, P., Bhattacharya, P. and Prabhakar, B.S., “A comprehensive review on the role of co-signaling receptors and Treg homeostasis in autoimmunity and tumor immunity”, Journal of Autoimmunity, 95 77-99. December 2018.
In article      View Article  PubMed 
 
[7]  Kumar, P., Saini, S. and Prabhakar, B.S., “Cancer immunotherapy with check point inhibitor can cause autoimmune adverse events due to loss of Treg homeostasis”, Seminars in Cancer Biology, 64 (December 2018). 29-35. 2020.
In article      View Article  PubMed 
 
[8]  Robert, C.,”A decade of immune-checkpoint inhibitors in cancer therapy”, Nature communications, 11 (1). December 2020.
In article      View Article  PubMed 
 
[9]  Wang, D.Y., Salem, J.E., Cohen, J. V., Chandra, S., Menzer, C., Ye, F., Zhao, S., Das, S., Beckermann, K.E., Ha, L., et al.,”Fatal Toxic Effects Associated With Immune Checkpoint Inhibitors: A Systematic Review and Meta-analysis”, JAMA oncology, 4 (12). 1721-1728. December 2018.
In article      View Article  PubMed 
 
[10]  Khan, S. and Gerber, D.E., “Autoimmunity, checkpoint inhibitor therapy and immune-related adverse events: A review”, Seminars in Cancer Biology, 64 (January). 93-101. 2020.
In article      View Article  PubMed 
 
[11]  Ben Zvi, C., Ehrenfeld, M. and Shoenfeld, Y., “[IMMUNOTHERAPY WITH CHECKPOINT INHIBITORS (ICPI) AND IMMUNE RELATED ADVERSE EVENTS (IRAE’S)].”, Harefuah, 159 (7). 508-515. July 2020 Available: https://www.ncbi.nlm.nih.gov/pubmed/32720769.
In article      
 
[12]  Orlova, R., Zhukova, N., Malkova, A. and Shoenfeld, Y., “Hypothesis for the development of immune-related adverse events in immune checkpoint inhibitors therapy”, Cancer treatment and research communications, 31 January 2022.
In article      View Article  PubMed 
 
[13]  Lerner, A. and Benzvi, C.,”Checkpoint Inhibitors and Induction of Celiac Disease-like Condition”, Biomedicines, 10 (3). March 2022.
In article      View Article  PubMed 
 
[14]  Fernández-Mestre, M., Sánchez, K., Balbás, O., Gendzekhzadze, K., Ogando, V., Cabrera, M. and Layrisse, Z., “Influence of CTLA-4 gene polymorphism in autoimmune and infectious diseases”, Human immunology, 70 (7). 532-535. July 2009.
In article      View Article  PubMed 
 
[15]  Ulker, M., Yazisiz, V., Sallakci, N., Avci, A.B., Sanlioglu, S., Yegin, O. and Terzioglu, E., “CTLA-4 gene polymorphism of exon 1(+49 A/G) in Turkish systemic lupus erythematosus patients”, International journal of immunogenetics, 36 (4). 245-250. August 2009.
In article      View Article  PubMed 
 
[16]  Du, L., Yang, P., Hou, S., Zhou, H. and Kijlstra, A., “No association of CTLA-4 polymorphisms with susceptibility to Behçet disease”, British Journal of Ophthalmology, 93 (10). 1378-1381. October 2009.
In article      View Article  PubMed 
 
[17]  Gouda, N.S., Fawzy, M.S. and Toraih, E.A., “Impact of cytotoxic T-lymphocyte-associated protein 4 codon 17 variant and expression on vitiligo risk”, Journal of clinical laboratory analysis, 35 (6). June 2021.
In article      View Article  PubMed 
 
[18]  Abida, O., Bahloul, E., Ben Jmaa, M., Sellami, K., Zouidi, F., Fakhfakh, R., Mahfoudh, N., Turki, H. and Masmoudi, H., “Chromosome 2q33genetic polymorphisms in Tunisian endemic pemphigus foliaceus”, Molecular genetics & genomic medicine, 8 (11). November 2020.
In article      View Article  PubMed 
 
[19]  Xu, W., Ren, M., Ghosh, S., Qian, K., Luo, Z., Zhang, A., Zhang, C. and Cui, J., “Defects of CTLA-4 Are Associated with Regulatory T Cells in Myasthenia Gravis Implicated by Intravenous Immunoglobulin Therapy”, Mediators of inflammation, 2020.
In article      View Article  PubMed 
 
[20]  Khalid Kheiralla, K.E.,”CTLA-4 (+49A/G) Polymorphism in Type 1 Diabetes Children of Sudanese Population”, Global medical genetics, 8 (1). 011-018. March 2021.
In article      View Article  PubMed 
 
[21]  Borysewicz-Sańczyk, H., Sawicka, B., Wawrusiewicz-Kurylonek, N., Głowińska-Olszewska, B., Kadłubiska, A., Gościk, J., Szadkowska, A., Łosiewicz, A., Młynarski, W., Kretowski, A., et al., “Genetic Association Study of IL2RA, IFIH1, and CTLA-4 Polymorphisms With Autoimmune Thyroid Diseases and Type 1 Diabetes”, Frontiers in pediatrics, 8 August 2020.
In article      View Article  PubMed 
 
[22]  Du, P., Ma, X. and Wang, C., “Associations of CTLA4 Gene Polymorphisms with Graves’ Ophthalmopathy: A Meta-Analysis”, International journal of genomics, 2014.
In article      View Article  PubMed 
 
[23]  Louthrenoo, W., Kasitanon, N., Wongthanee, A., Kuwata, S. and Takeuchi, F., “CTLA-4 polymorphisms in Thai patients with rheumatoid arthritis, systemic lupus erythematosus, and systemic sclerosis”, International journal of rheumatic diseases, 24 (11). 1378-1385. November 20219.
In article      View Article  PubMed 
 
[24]  Agarwal, K., Czaja, A.J., Jones, D.E.J. and Donaldson, P.T., “Cytotoxic T lymphocyte antigen-4 (CTLA-4) gene polymorphisms and susceptibility to type 1 autoimmune hepatitis”, Hepatology (Baltimore, Md.), 31 (1). 49-53. 2000.
In article      View Article  PubMed 
 
[25]  Favorova, O.O., Favorov, A. V., Boiko, A.N., Andreewski, T. V., Sudomoina, M.A., Alekseenkov, A.D., Kulakova, O.G., Gusev, E.I., Parmigiani, G. and Ochs, M.F., “Three allele combinations associated with multiple sclerosis”, BMC medical genetics, 7 July 2006.
In article      View Article  PubMed 
 
[26]  Yu, L., Shao, M., Zhou, T., Xie, H., Wang, F., Kong, J., Xu, S., Shuai, Z. and Pan, F., “Association of CTLA-4 (+49 A/G) polymorphism with susceptibility to autoimmune diseases: A meta-analysis with trial sequential analysis”, International immunopharmacology, 96 July 2021.
In article      View Article  PubMed 
 
[27]  Eskandari-Nasab, E., Tahmasebi, A. and Hashemi, M., “Meta-analysis: the relationship between CTLA-4 +49 A/G polymorphism and primary biliary cirrhosis and type I autoimmune hepatitis”, Immunological investigations, 44 (4). 331-348. May 2015.
In article      View Article  PubMed 
 
[28]  Ismail, N.A., Toraih, E.A., Ameen, H.M., Gomaa, A.H.A. and Marie, R.E.S.M., “Association of Rs231775 Genetic Variant of Cytotoxic T-lymphocyte Associated Protein 4 with Alopecia Areata Disease in Males: A Case-Control Study”, Immunological investigations, 50 (8). 977-986. 2021.
In article      View Article  PubMed 
 
[29]  Zhang, M., Ni, J., Xu, W.D., Wen, P.F., Qiu, L.J., Wang, X.S., Pan, H.F. and Ye, D.Q., “Association of CTLA-4 variants with susceptibility to inflammatory bowel disease: a meta-analysis”, Human immunology, 75 (3). 227-233. March 2014.
In article      View Article  PubMed 
 
[30]  Pastuszak-Lewandoska, D., Sewerynek, E., Domańska, D., Gładyś, A., Skrzypczak, R. and Brzeziańska, E., “CTLA-4 gene polymorphisms and their influence on predisposition to autoimmune thyroid diseases (Graves’ disease and Hashimoto’s thyroiditis)”, Archives of medical science: AMS, 8 (3). 415-421. June 2012.
In article      View Article  PubMed 
 
[31]  Carr, E.J., Niederer, H.A., Williams, J., Harper, L., Watts, R.A., Lyons, P.A. and Smith, K.G.C., “Confirmation of the genetic association of CTLA4 and PTPN22 with ANCA-associated vasculitis”, BMC Medical Genetics, 10 December 2009.
In article      View Article  PubMed 
 
[32]  Holopainen, P., Arvas, M., Sistonen, P., Mustalahti, K., Collin, P., Mäki, M. and Partanen, J., “CD28/CTLA4 gene region on chromosome 2q33 confers genetic susceptibility to celiac disease. A linkage and family-based association study”, Tissue antigens, 53 (5). 470-475. 1999.
In article      View Article  PubMed 
 
[33]  Naluai, Å.T., Nilsson, S., Samuelsson, L., Gudjónsdóttir, A.H., Ascher, H., Ek, J., Hallberg, B., Kristiansson, B., Martinsson, T., Nerman, O., et al., “The CTLA4/CD28 gene region on chromosome 2q33 confers susceptibility to celiac disease in a way possibly distinct from that of type 1 diabetes and other chronic inflammatory disorders”, Tissue antigens, 56 (4). 350-355. 2000.
In article      View Article  PubMed 
 
[34]  Popat, S., Hearle, N., Hogberg, L., Braegger, C.P., O’Donoghue, D., Falth-Magnusson, K., Holmes, G.K.T., Howdle, P.D., Jenkins, H., Johnston, S., et al., “Variation in the CTLA4/CD28 gene region confers an increased risk of coeliac disease”, Annals of human genetics, 66 (Pt 2). 125-137. March 2002.
In article      View Article  PubMed 
 
[35]  Song, G.G., Kim, J.H., Kim, Y.H. and Lee, Y.H., “Association between CTLA-4 polymorphisms and susceptibility to Celiac disease: a meta-analysis”, Human immunology, 74 (9).1214-1218. September 2013.
In article      View Article  PubMed 
 
[36]  Pesce, G., Auricchio, R., Bagnasco, M. and Saverino, D., “Oversecretion of soluble CTLA-4 in various autoimmune diseases overlapping celiac disease”, Genetic testing and molecular biomarkers, 18 (1). 8-11. January 2014.
In article      View Article  PubMed 
 
[37]  King, A.L., Moodie, S.J., Fraser, J.S., Curtis, D., Reid, E., Dearlove, A.M., Ellis, H.J. and Ciclitira, P.J., “CTLA-4/CD28 gene region is associated with genetic susceptibility to coeliac disease in UK families”, Journal of medical genetics, 39 (1). 51-54. 2002.
In article      View Article  PubMed 
 
[38]  van Belzen, M.J., Mulder, C.J.J., Zhernakova, A., Pearson, P.L., Houwen, R.H.J. and Wijmenga, C., “CTLA4 +49 A/G and CT60 polymorphisms in Dutch coeliac disease patients”, European journal of human genetics: EJHG, 12 (9). 782-785. September 2004.
In article      View Article  PubMed 
 
[39]  Hunt, K.A., McGovern, D.P.B., Kumar, P.J., Ghosh, S., Travis, S.P.L., Walters, J.R.F., Jewell, D.P., Playford, R.J. and van Heel, D.A.,”A common CTLA4 haplotype associated with coeliac disease”, European journal of human genetics: EJHG, 13 (4). 440-444. April 2005.
In article      View Article  PubMed 
 
[40]  Brophy, K., Ryan, A.W., Thornton, J.M., Abuzakouk, M., Fitzgerald, A.P., McLoughlin, R.M., O’Morain, C., Kennedy, N.P., Stevens, F.M., Feighery, C., et al., “Haplotypes in the CTLA4 region are associated with coeliac disease in the Irish population”, Genes and immunity, 7 (1). 19-26. January 2006.
In article      View Article  PubMed 
 
[41]  King, A.L., Moodie, S.J., Fraser, J.S., Curtis, D., Reid, E., Dearlove, A.M. and Ciclitira, P.J., “Coeliac disease: investigation of proposed causal variants in the CTLA4 gene region”, European journal of immunogenetics: official journal of the British Society for Histocompatibility and Immunogenetics, 30 (6). 427-432. December 2003.
In article      View Article  PubMed 
 
[42]  Simone, R., Brizzolara, R., Chiappori, A., Milintenda-Floriani, F., Natale, C., Greco, L., Schiavo, M., Bagnasco, M., Pesce, G. and Saverino, D.,”A functional soluble form of CTLA-4 is present in the serum of celiac patients and correlates with mucosal injury”, International immunology, 21 (9). 1037-1045. 2009.
In article      View Article  PubMed 
 
[43]  Alfadhli, S., “Overexpression and secretion of the soluble CTLA-4 splice variant in various autoimmune diseases and in cases with overlapping autoimmunity”, Genetic testing and molecular biomarkers, 17 (4). 336-341. April 2013.
In article      View Article  PubMed 
 
[44]  Saverino, D., Simone, R., Bagnasco, M. and Pesce, G., “The soluble CTLA-4 receptor and its role in autoimmune diseases: An update”, Autoimmunity Highlights, 1 (2). 73-81. November 2010.
In article      View Article  PubMed 
 
[45]  Schneider, H. and Rudd, C.E., “Diverse mechanisms regulate the surface expression of immunotherapeutic target ctla-4”, Frontiers in immunology, 5 (DEC). 2014.
In article      View Article 
 
[46]  Falade, A.S., Reynolds, K.L., Zubiri, L., Deshpande, V., Fintelmann, F.J., Dougan, M. and Mooradian, M.J., “Case Report: Fulminant Celiac Disease With Combination Immune Checkpoint Therapy”, Frontiers in immunology, 13 April 2022.
In article      View Article  PubMed 
 
[47]  Watari, K., Konnai, S., Maekawa, N., Okagawa, T., Suzuki, Y., Murata, S. and Ohashi, K., “Immune inhibitory function of bovine CTLA-4 and the effects of its blockade in IFN-γ production”, BMC veterinary research, 15 (1). October 2019.
In article      View Article  PubMed 
 
[48]  Leblanc, J., Hoibian, S., Boucraut, A., Ratone, J.P., Stoffaes, L., Dano, D., Louvel-Perrot, D., Chanez, B., Chretien, A.S., Madroszyk, A., et al., “Celiac Disease After Administration of Immune Checkpoint Inhibitors: A Case Report”, Frontiers in immunology, 12 December 2021.
In article      View Article  PubMed 
 
[49]  Badran, Y.R., Shih, A., Leet, D., Mooradian, M.J., Coromilas, A., Chen, J., Kem, M., Zheng, H., Borowsky, J., Misdraji, J., et al., “Immune checkpoint inhibitor-associated celiac disease”, Journal for immunotherapy of cancer, 8 (1). June 2020.
In article      View Article  PubMed 
 
[50]  Liu, X., Shi, Y., Zhang, D., Zhou, Q., Liu, J., Chen, M., Xu, Y., Zhao, J., Zhong, W. and Wang, M., “Risk factors for immune-related adverse events: what have we learned and what lies ahead?”, Biomarker research, 9 (1). December 2021.
In article      View Article  PubMed 
 
[51]  De Moel, E.C., Rozeman, E.A., Kapiteijn, E.H., Verdegaal, E.M.E., Grummels, A., Bakker, J.A., Huizinga, T.W.J., Haanen, J.B., Toes, R.E.M. and Van Der Woude, D., “Autoantibody Development under Treatment with Immune-Checkpoint Inhibitors”, Cancer immunology research, 7 (1). 6-11. January 2019.
In article      View Article  PubMed 
 
[52]  Kristiansen, O.P., Larsen, Z.M. and Pociot, F., “CTLA-4 in autoimmune diseases--a general susceptibility gene to autoimmunity?”, Genes and immunity, 1 (3). 170-184. 2000.
In article      View Article  PubMed 
 
[53]  Tison, A., Quéré, G., Misery, L., Funck-Brentano, E., Danlos, F.X., Routier, E., Robert, C., Loriot, Y., Lambotte, O., Bonniaud, B., et al., “Safety and Efficacy of Immune Checkpoint Inhibitors in Patients With Cancer and Preexisting Autoimmune Disease: A Nationwide, Multicenter Cohort Study”, Arthritis & rheumatology (Hoboken, N.J.), 71 (12). 2100-2111. December 2019.
In article      View Article  PubMed 
 
[54]  Vanderlugt, C.L. and Miller, S.D., “Epitope spreading in immune-mediated diseases: implications for immunotherapy”, Nature reviews. Immunology, 2 (2). 85-95. 2002.
In article      View Article  PubMed 
 
[55]  Kwek, S.S., Dao, V., Roy, R., Hou, Y., Alajajian, D., Simko, J.P., Small, E.J. and Fong, L., “Diversity of antigen-specific responses induced in vivo with CTLA-4 blockade in prostate cancer patients”, Journal of immunology (Baltimore, Md. 1950), 189 (7). 3759-3766. October 2012.
In article      View Article  PubMed 
 
[56]  Vojdani, A., Lerner, A. and Vojdani, E., “Cross-Reactivity and Sequence Homology between Al-Pha-Synuclein and Food Products: A Step Further for Parkinson’s Disease Synucleinopathy”, Cells, 10 (5).1111. May 2021.
In article      View Article  PubMed 
 
[57]  Vojdani, A., Monro, J., Lanzisera, F. and Sadeghi, H., “Serological cross-reactivity between viruses and their contribution to autoimmunity”, Autoimmunity reviews, 20 (7). July 2021.
In article      View Article  PubMed 
 
[58]  Lerner, A. and Benzvi, C., “Let Food Be Thy Medicine’: Gluten and Potential Role in Neurodegeneration”, Cells, 10 (4). 2021.
In article      View Article  PubMed 
 
[59]  Lerner, A., Aminov, R. and Matthias, T., “Transglutaminases in Dysbiosis As Potential Environmental Drivers of Autoimmunity”, Frontiers in microbiology, 8 (JAN). January 2017.
In article      View Article 
 
[60]  Bascuñán, K.A., Araya, M., Roncoroni, L., Doneda, L. and Elli, L., “Dietary Gluten as a Conditioning Factor of the Gut Microbiota in Celiac Disease”, Advances in nutrition (Bethesda, Md.), 11 (1). 160-174. January 2020.
In article      View Article  PubMed 
 
[61]  VIVARELLI, S., FALZONE, L., LEONARDI, G.C., SALMERI, M. and LIBRA, M., “Novel insights on gut microbiota manipulation and immune checkpoint inhibition in cancer (Review)”, International journal of oncology, 59 (3). September 2021.
In article      View Article  PubMed 
 
[62]  Zhang, M.L. and Deshpande, V., “Histopathology of Gastrointestinal Immune-related Adverse Events: A Practical Review for the Practicing Pathologist”, The American journal of surgical pathology, 46 (1). E15-E26. January 2022.
In article      View Article  PubMed 
 
[63]  Zhang, M.L., Neyaz, A., Patil, D., Chen, J., Dougan, M. and Deshpande, V., “Immune-related adverse events in the gastrointestinal tract: diagnostic utility of upper gastrointestinal biopsies”, Histopathology, 76 (2). 233-243. January 2020.
In article      View Article  PubMed 
 
[64]  Mendo, R., Figueiredo, P. and Mascarenhas, L., “Checkpoint Inhibitor-Induced Gastroduodenitis: An Unusual Manifestation”, GE Portuguese journal of gastroenterology, 28 (2). 150-152. February 2021.
In article      View Article  PubMed 
 
[65]  Gadhok, R., Paulon, E., Tai, C., Olushola, T., Barragry, J., Rahman, F., Di Caro, S. and Mehta, S., “Gastrointestinal consequences of cancer treatment: evaluation of 10 years’ experience at a tertiary UK centre”, Frontline gastroenterology, 12 (6). 2020.
In article      View Article  PubMed 
 
[66]  Chatzileontiadou, D.S.M., Sloane, H., Nguyen, A.T., Gras, S. and Grant, E.J., “The Many Faces of CD4 + T Cells: Immunological and Structural Characteristics”, International journal of molecular sciences, 22 (1).1-27. January 2020.
In article      View Article  PubMed 
 
[67]  Cook, L., Munier, C.M.L., Seddiki, N., van Bockel, D., Ontiveros, N., Hardy, M.Y., Gillies, J.K., Levings, M.K., Reid, H.H., Petersen, J., et al., “Circulating gluten-specific FOXP3 + CD39 + regulatory T cells have impaired suppressive function in patients with celiac disease”, The Journal of allergy and clinical immunology, 140 (6). 1592-1603. e8. December 2017.
In article      View Article  PubMed 
 
[68]  Valk, E., Rudd, C.E. and Schneider, H., “CTLA-4 trafficking and surface expression”, Trends in immunology, 29 (6). 272-279. June 2008.
In article      View Article  PubMed