Cellular immunological changes in patients with LADA are a mixture of those seen in patients with type 1 and type 2 diabetes

Singh, K. N.; Martinell, Mats; Luo, Zhengkang; Espes, Daniel; Stålhammar, Jan; Sandler, Stellan; Carlsson, Per‐Ola

doi:10.1111/cei.13289

Cited by 27 publications

(45 citation statements)

References 59 publications

(87 reference statements)

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“…We speculate that NK cells might possess a protective property, which would explain why that the NK cell number was decreased in response of the increased IFN‐γ + cells among NK cells. In accordance with this result, we have previously found that the proportion of CD56 high NK cells, which are considered to be IFN‐γ‐producing cells, are increased in LADA patients compared to healthy controls and T2D patients, but similar to T1D patients …”

Section: Discussionsupporting

confidence: 82%

“…Neutrophils were reported to be decreased in the peripheral blood of T1D patients, indicating that they might migrate to local organs . Nevertheless, we did not find any alteration of CD15 low neutrophils in the peripheral blood of T1D patients compare to healthy controls . In the present study, we found a decreased proportion of neutrophils in PDLNs of MLDSTZ mice.…”

Section: Discussioncontrasting

confidence: 72%

“…16 Nevertheless, we did not find any alteration of CD15 low neutrophils in the peripheral blood of T1D patients compare to healthy controls. 29,45 In the present study, we found a decreased proportion of neutrophils in PDLNs of MLDSTZ mice. On the other hand, the response of B-1a lymphocytes were apparently later when compared to NOD mice since MLDSTZ mice were hyperglycemic and showed a moderate degree of insulitis on day 10.…”

Section: Discussionsupporting

confidence: 65%

“…In accordance with this result, we have previously found that the proportion of CD56 high NK cells, which are considered to be IFN-γ-producing cells, 61 are increased in LADA patients compared to healthy controls and T2D patients, but similar to T1D patients. 29 In this study, we have investigated the kinetics of innate and adaptive immune cells response during the early development of T1D in mouse model. We found that the proportions of DCs, pDCs, and B cells are increased at an early stage of T1D development in MLDSTZ-treated mice and that further mediates activation of other immune cells such as B1-a lymphocytes, Th1, and Tc cells, which might then migrate from secondary lymphoid organs to the pancreatic islets and contribute to insulin-producing β-cell damage (Figure 7).…”

Section: Discussionmentioning

confidence: 99%

“…28 In addition, we have reported a higher of proportion of NK cells in latent autoimmune diabetes mellitus in the adult (LADA) patients compare to healthy controls and T2D patients, but similar to T1D patients, suggesting a role of NK cells in T1D. 29 However, the kinetic response of NK cells has not been studied in animal models of T1D.…”

Section: Introductionmentioning

confidence: 98%

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Kinetics of immune cell responses in the multiple low‐dose streptozotocin mouse model of type 1 diabetes

et al. 2019

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In type 1 diabetes (T1D), the insulin‐producing β cells are destructed by immune mechanisms. It has been hypothesized that the very first immune response in T1D onset comes from innate immune cells, which further activates the adaptive immune cells to attack the islets. Despite intensive research on characterization of islet‐infiltrating immune cells, the kinetics of different immune cells in multiple low‐dose streptozotocin (MLDSTZ)‐induced T1D mouse model is still much unclear. Therefore, we investigated the proportions of innate immune cells such as neutrophils, dendritic cells (DCs), plasmacytoid dendritic cells (pDCs), macrophages, natural killer (NK) cells, and adaptive immune cells (T and B lymphocytes) in thymi, pancreatic‐draining lymph nodes, and spleens of MLDSTZ mice on days 3, 7, 10, and 21 after the first injection of STZ by flow cytometry. The proportions of DCs and B cells were increased from day 3, while the proportions of B‐1a lymphocytes and interferon‐γ+ cells among NK cells were increased, but NK cells were decreased on day 10 in MLDSTZ‐treated mice, illustrating that the initial immune response is induced by DCs and B cells. Later, the proportions of T helper 1 and cytotoxic T cells were increased from day 7, suggesting that the innate immune cells precede adaptive immune cell response in MLDSTZ mice. Altogether, our data demonstrate a possible sequence of events regarding the involvement of DCs, pDCs, NK cells, B‐1a lymphocytes, B, and T cells at the early stage of T1D development.

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Section: Discussionsupporting

confidence: 82%

Section: Discussioncontrasting

confidence: 72%

Section: Discussionsupporting

confidence: 65%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

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Kinetics of immune cell responses in the multiple low‐dose streptozotocin mouse model of type 1 diabetes

et al. 2019

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Increased spontaneous CCL2 (MCP‐1) and CCL5 (RANTES) secretion in vitro in LADA compared to type 1 diabetes and type 2 diabetes: Action LADA 14

Ooms

Strom

Straßburger

et al. 2021

Diabetes Metabolism Res

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Aims: Immune-mediated type 1 diabetes (T1D) in adulthood and latent autoimmune diabetes in adults (LADA) share similar pathological mechanisms but differ clinically in disease progression. The aim of this study was to acquire insights into spontaneous and stimulated chemokine secretion of immune cells in different diabetes types. Materials and Methods:We investigated in vitro spontaneous, mitogen (PI) and antigen (HSP60, p277, pGAD, pIA2) stimulated chemokine secretion of leucocytes from patients with T1D (n = 32), LADA (n = 22), type 2 diabetes (T2D; n = 49), and glucose-tolerant individuals (n = 13). Chemokine concentration in supernatants was measured for CCL2 (MCP-1), CXCL10 (IP10) and CCL5 (RANTES) using a multiplex bead array assay.Results: Spontaneous secretion of CCL2 and CCL5 were higher in LADA compared to T1D and T2D (all p < 0.05) while CXCL10 was similar in the groups. Mitogenstimulated secretion of CCL2 in LADA was lower compared to T1D and T2D (all p < 0.05) while CXCL10 and CCL5 were similar in all groups. Upon stimulation with pIA2 the secretion of CCL2 in LADA was lower compared to T2D (p < 0.05). Spontaneous CXCL10 secretion in LADA was positively associated with body mass index (r 2 = 0.35; p = 0.0035) and C-peptide (r 2 = 0.30; p = 0.009). Conclusions: Chemokine secretion is altered between different diabetes types.Increased spontaneous secretion of CCL2 and CCL5 and decreased secretion of CCL2, upon stimulation with PI and pIA2, in LADA compared to T1D and T2D could reflect altered immune responsiveness in LADA patients in association with their slower clinical progression compared to insulin dependence. K E Y W O R D SCCL2, CCL5, CXCL10, latent autoimmune diabetes in adults, type 1 diabetes, type 2 diabetes A complete list of the members of the Action LADA Group can be found in the Appendix.This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

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Innate immunity in latent autoimmune diabetes in adults

Hao

Pearson

Wong

et al. 2021

Diabetes Metabolism Res

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Latent autoimmune diabetes in adults (LADA) is an autoimmune disease that shares some genetic, immunological and clinical features with both type 1 diabetes and type 2 diabetes. Immune cells including CD4 + T cells, CD8 + T cells, B cells, macrophages and dendritic cells (DCs) have been detected in the pancreas of patients with LADA and a rat model of LADA. Therefore, similar to type 1 diabetes, the pathogenesis of LADA may be caused by interactions between islet β-cells and innate and adaptive immune cells. However, the role of the immunity in the initiation and progression of LADA remains largely unknown. In this review, we have summarized the potential roles of innate immunity and immune-modulators in LADA development. Furthermore, we have examined the evidence and discussed potential innate immunological reasons for the slower development of LADA compared with type 1 diabetes. More in-depth mechanistic studies are needed to fully elucidate the roles of innate immune-associated genes, molecules and cells in their contributions to LADA pathogenesis. Undertaking these studies will greatly enhance the development of new strategies and optimization of current strategies for the diagnosis and treatment of the disease. K E Y W O R D Sautoimmune, diabetes mellitus, innate immune cells, innate immunity, latent autoimmune diabetes in adults | INTRODUCTIONLatent autoimmune diabetes in adults (LADA), also known as type 1.5 diabetes or slow-onset diabetes in adults, is an autoimmune disease that shares some genetic, immunological and clinical features with both type 1 diabetes and type 2 diabetes. [1][2][3][4][5] The disease was first described in 1983 6 and was defined as LADA in 1993. 7 Although LADA accounts for approximately 1.5%-14.2% of the type 2 diabetes population, 8-14 no unified criteria or management guidelines have existed for LADA. Recently, a panel of international experts defined a strategy for LADA management, which will be greatly helpful to the diagnosis and treatment of the disease in clinical practice. 15 GADA level is considered as the most valuable discriminatory parameter to predict the development of β-cell function in LADA. 16 Compared with low level of glutamic acid decarboxylase antibody (GADA), high level of GADA in LADA is associated with faster insulin progression, indicating that the presence of high level of GADA was a significant predictor of insulin requirement in LADA. 17 Our group also found that patients with high level of GADA showed a worse baseline and accelerated decline of β-cell function, 18 while the metabolic phenotypes and β-cell function in LADA patients with a low level of GADA were similar to that in type 2 diabetes patients. 19 It was reported that the presence of N-terminally truncated GAD65 autoantibody in individuals with adult-onset diabetes is associated with the clinical

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Cellular immunological changes in patients with LADA are a mixture of those seen in patients with type 1 and type 2 diabetes

Cited by 27 publications

References 59 publications

Kinetics of immune cell responses in the multiple low‐dose streptozotocin mouse model of type 1 diabetes

Kinetics of immune cell responses in the multiple low‐dose streptozotocin mouse model of type 1 diabetes

Increased spontaneous CCL2 (MCP‐1) and CCL5 (RANTES) secretion in vitro in LADA compared to type 1 diabetes and type 2 diabetes: Action LADA 14

Innate immunity in latent autoimmune diabetes in adults

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