Dipeptidyl peptidase-4 inhibitor-induced autoimmune diseases: Current evidence

Roy, Ayan; Sahoo, Jayaprakash; Narayanan, Niya; Merugu, Chandhana; Kamalanathan, Sadishkumar; Naik, Dukhabandhu

doi:10.4239/wjd.v12.i9.1426

Cited by 10 publications

(9 citation statements)

References 114 publications

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“…However, given the lower incidence of certain autoimmune disease, limited evidences are accessible. Case reports and retrospective studies of DPP4i utilization in T2DM patients demonstrated an association between the use of DPP4i and bullous pemphigoid, a severe autoimmune skin disease (18,(173)(174)(175)(176)(177). Importantly, DPP4iinduced bullous pemphigoid does not remit fully after withdrawal of DPP4i, suggesting that DPP4i induces and aggravate the process of bullous pemphigoid rather than a reversible side effect of DPP4i (18).…”

Section: Dpp4 In Other Autoimmune Diseasesmentioning

confidence: 99%

“…Case reports and retrospective studies of DPP4i utilization in T2DM patients demonstrated an association between the use of DPP4i and bullous pemphigoid, a severe autoimmune skin disease (18,(173)(174)(175)(176)(177). Importantly, DPP4iinduced bullous pemphigoid does not remit fully after withdrawal of DPP4i, suggesting that DPP4i induces and aggravate the process of bullous pemphigoid rather than a reversible side effect of DPP4i (18). Although the exact mechanisms underlying DPP4i-associated bullous pemphigoid is currently unclear, the breakdown of immunotolerance of BP180, the major autoantigen of bullous pemphigoid, might be a key reason.…”

Section: Dpp4 In Other Autoimmune Diseasesmentioning

confidence: 99%

“…With its involvement in immune regulation and fibrosis, DPP4 may have a pivotal implication in the development of autoimmune disease. Clinical evidence has suggested an association between the use of DPP4 enzymatic inhibitors and several autoimmune disorders, which is summarized by Zhao group and Sahoo group in 2014 and 2021 respectively (18,19). While DPP4 has been considered a moonlighting protein due to its multifunctional features in different types of cells, an updated comprehensive summary of DPP4's immunoregulatory actions including both enzymatic dependent and independent functions is needed.…”

Section: Introductionmentioning

confidence: 99%

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Emerging Role of Dipeptidyl Peptidase-4 in Autoimmune Disease

et al. 2022

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Dipeptidyl-peptidase IV (DPP4), originally identified as an aminopeptidase in 1960s, is an ubiquitously expressed protease presented as either a membrane-bound or soluble form. DPP4 cleaves dipeptide off from the N-terminal of its substrates, altering the bioactivity of its substrates. Subsequent studies reveal that DPP4 is also involved in various cellular processes by directly binding to a number of ligands, including adenosine deaminase, CD45, fibronectin, plasminogen, and caveolin-1. In recent years, many novel functions of DPP4, such as promoting fibrosis and mediating virus entry, have been discovered. Due to its implication in fibrotic response and immunoregulation, increasing studies are focusing on the potential role of DPP4 in inflammatory disorders. As a moonlighting protein, DPP4 possesses multiple functions in different types of cells, including both enzymatic and non-enzymatic functions. However, most of the review articles on the role of DPP4 in autoimmune disease were focused on the association between DPP4 enzymatic inhibitors and the risk of autoimmune disease. An updated comprehensive summary of DPP4’s immunoregulatory actions including both enzymatic dependent and independent functions is needed. In this article, we will review the recent advances of DPP4 in immune regulation and autoimmune rheumatic disease.

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Section: Dpp4 In Other Autoimmune Diseasesmentioning

confidence: 99%

Section: Dpp4 In Other Autoimmune Diseasesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Emerging Role of Dipeptidyl Peptidase-4 in Autoimmune Disease

et al. 2022

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“…This hypothesis could be supported by the previous observation that all severe combined immunodeficiency patients and immunodeficient mice have reduced levels of sDPP4 [ 13 ]. Furthermore, additional evidence on the effect of low DPP4 levels on an overall reduced immune effector response is supported by the multiple DPP4 inhibitors approved for therapeutic use in different autoimmune diseases [ 36 ]. DPP4 inhibitors are used to treat autoimmune related diabetes mellitus in children and adults as well as autoimmune encephalomyelitis [ 37 – 39 ].…”

Section: Discussionmentioning

confidence: 99%

Low levels of soluble DPP4 among Saudis may have constituted a risk factor for MERS endemicity

et al. 2022

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Most of the cases of Middle East respiratory syndrome coronavirus (MERS-CoV) were reported in Saudi Arabia. Dipeptidyl peptidase-4 (DPP4) was identified as the receptor for the virus. The level of soluble DPP4 (sDPP4) was found to be reduced in MERS-CoV infected patients while high levels of sDPP4 were suggested to be protective against MERS-CoV in animal models. We investigated whether the Saudi population has lower levels of sDPP4 which makes them more susceptible to MERS-CoV infection and, therefore, could explain the larger number of cases from the country. Blood samples were collected from 219 Saudi blood donors and 200 blood donors from other ethnic groups. The plasma level of sDPP4 was measured by ELISA and the following SNPs in the DPP4 gene; rs35128070, rs1861978, rs79700168, and rs17574, were genotyped by TaqMan SNP genotyping assay. The average level of plasma sDDP4 was significantly lower in Saudis than other Arabs and non-Arabs (P value 0.0003 and 0.012, respectively). The genotypes AG of rs35128070 and GT of rs1861978 were significantly associated with lower sDPP4 among Saudis (P value 0.002 for each). While both genotypes AA and AG of rs79700168 and rs17574 were associated with significantly lower average sDPP4 level in Saudis compared to other ethnic groups (P value 0.031 and 0.032, and 0.027 and 0.014, respectively). Herein, we report that the Saudi population has lower levels of plasma sDPP4 than other ethnic groups, which is associated with genetic variants in the DPP4 gene. This may have contributed to increase the susceptibility of the Saudi population to MERS-CoV infection and could be a factor in the long-lasting persistence of the virus in the country.

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“…Recently, several studies have evaluated the association of different DPP-4i with overall autoimmune diseases directly, although age as an important determining factor of autoimmunity is associated with DPP-4i use ( 10 – 14 ). In our case, he was treated with DPP-4i for T2DM until the onset of DPP-4i-related BP.…”

Section: Discussionmentioning

confidence: 99%

Case Report: Appearance of Various Disease-Specific Antibodies After the Onset of Dipeptidyl Peptidase-4 Inhibitor-Associated Bullous Pemphigoid

et al. 2022

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Bullous pemphigoid (BP) is a rare autoimmune blistering disease, and the prevalence of type 2 diabetes mellitus (T2DM) is relatively high in subjects with BP. It is known that dipeptidyl peptidase-4 inhibitor (DPP-4i), one kind of antidiabetic drugs, can cause BP, although precise mechanism of DPP-4i-related BP remains unclear. In this report, we showed a case with appearance of various disease-specific antibodies after the onset of DPP-4i-related BP. Furthermore, various disease-specific antibodies became positive and showed high titers two years after the onset of DPP-4i-related BP and discontinuation of DPP-4i. These data showed that it is possible for immune tolerance to be broken after the onset of DPP-4i-related BP, and it may be important to check autoimmune antibodies in DPP-4i-related BP subjects even when BP symptoms are improved.

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Dipeptidyl peptidase-4 inhibitor-induced autoimmune diseases: Current evidence

Cited by 10 publications

References 114 publications

Emerging Role of Dipeptidyl Peptidase-4 in Autoimmune Disease

Emerging Role of Dipeptidyl Peptidase-4 in Autoimmune Disease

Low levels of soluble DPP4 among Saudis may have constituted a risk factor for MERS endemicity

Case Report: Appearance of Various Disease-Specific Antibodies After the Onset of Dipeptidyl Peptidase-4 Inhibitor-Associated Bullous Pemphigoid

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