Altered Immune Response in Diabetes

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1		Susmita Barman	--	1472	2023-04-13 07:07:55	\|
2	format change	Peter Tang	Meta information modification	1472	2023-04-13 07:17:02	\|

This entry is adapted from the peer-reviewed paper 10.3390/biologics3010004

Patients with diabetes often have more invasive infections, which may lead to an increase in morbidity. The human body has incredible defences against millions of bacteria, viruses, fungi, poisons, and parasites. The immune system normally protects against infections, but numerous disorders and deficiencies may impair it. Bacteria may infiltrate through open wounds and cause infections. Natural barriers, including intact skin and mucosal surfaces and the reactive oxygen species, cytokines, and chemokines within their mechanistic organization, help our defence system to fight against pathogens. Due to the immune system’s inability to combat microorganisms, infections are a significant concern for people with diabetes. Numerous research have investigated diabetes-related pathways that decrease pathogen resistance. These processes include the inhibition of cytokine production, abnormalities in phagocytosis, immune cell malfunction, and an inability to destroy microbials.

diabetes mellitus altered immune response invasive infection

1. Oxidative Stress in Diabetes

In immune-suppressed diabetic conditions, increased glucose may raise ROS (Reactive Oxygen Species) and proinflammatory cytokines, limiting macrophage activity in systemic circulation ^[1]^[2]^[3]. The recent observation documented GSH (glutathione) production and activated AGE (advanced glycation end products) and RAGE (receptor for advanced glycation end products) for the elevation of TGF-β (transforming growth factor- β) due to excess hyperglycaemia ^[4]^[5]. If NADPH (nicotinamide adenine dinucleotide phosphate) is available, the enzyme GR (glutathione reductase) may recycle GSSH (oxidized glutathione). However, in diabetic individuals, NADPH is intensively used on the polyol pathway, resulting in a drop in GSH and an increase in ROS, which may change cytokine levels ^[2]. Diabetes mellites may also impair cellular immunity and weaken natural barriers. Studies have established that insulin insufficiency and hyperglycaemia are highly responsible for this phenomenon. Peripheral neuropathy, a consequence of diabetes mellitus (DM), is related to the polyol pathway and sorbitol accumulation in the nerve tissue due to SDH (sorbitol dehydrogenase) deficiency ^[6]^[7]. Additionally, immune system abnormalities are also caused by excessive use of NADPH. The loss of NADPH results in reduced GSH, increased ROS, varying cytokine profiles, and, eventually, advances immunological impairment ^[8].

2 Cytokine Response in Diabetes

In response to a pathogen, several immune cells, including macrophages and neutrophils, produce cytokines. The pattern recognition receptors of these cells identify bacterial cell wall components and release chemicals and nucleic acids to produce cytokines. These cells release cytokines that regulate and generate granulomas to confine and kill germs ^[1]. Granulomas include macrophages, multinucleated giant cells, CD4+ and CD8+ (clusters of differentiation) T-cells, B-cells, and neutrophils ^[9]. In immunocompetent people, bacterium and granulomatous immune system cells interact and release cytokines such as TNF-α (tumour necrosis factor-alpha), IL-10 (interleukin), IL-6, IL-2, IL-12, and IFN-γ (interferon-gamma) ^[10]. These cytokines play a crucial role in innate immunity. They are involved in diabetes pathogenesis and its affected, immune-mediated infection. In a study, the peripheral blood mononuclear cells (PBMCs) and isolated monocytes of patients with Type 1 diabetes (T1D) and Type 2 diabetes (T2D) released less IL-1β than controls following lipopolysaccharides (LPS) stimulation ^[11]^[12]. Tessaro et al. found that the insulin treatment of bone-marrow-derived macrophages from diabetic mice boosted the production of TNF-α and IL-6 after LPS stimulation ^[13]. In another study, T1D monocytes from PBMCs produced less IL-1 and IL-6 than healthy donors. Interestingly, another study proved that PBMCs from non-diabetics are activated by anti-CD3 antibodies and subjected to high glucose levels, suppressing cytokines IL-2, IL-6, and IL-10 ^[14]. Furthermore, in another study, the authors observed that PBMCs taken from healthy people and stimulated with dextrose octreotide exhibited less IL-6 and IL-17A production, particularly in the CD14+ and CD16+ intermediate monocytes, suggesting multiple faulty immune responses in acute hyperglycaemia ^[15]. Compared to normal mice, obese leptin-receptor-deficient (DB/DB) mice and high-fat-diet-induced hyperglycaemic mice demonstrated decreased IL-22 levels ^[16]. Tan et al. found reduced IL-12 and IFN-γ levels in diabetic PBMC cultures after infection with Burkholderia pseudomallei when compared with healthy donors. The PBMCs of diabetics had a more significant intracellular bacterial burden than healthy controls, indicating that hyperglycaemia affects the host’s defense against infectious microorganisms. Recombinant IL-12 and IFN-γ treatment decreased the bacterial load in diabetic PBMCs, demonstrating that the low production of IL-12 and IFN-γ n diabetes inhibits the immune cells’ ability to regulate bacterial development during an infection ^[17]. Therefore, hyperglycaemia in diabetes may reduce pathogen-fighting macrophage and leukocyte function.

As previously mentioned, hyperglycaemia also changes macrophage function. A study found that chronic hyperglycaemia impaired phagocytosis by affecting the activity of complement receptors on isolated monocytes. Long-term glucose sensitivity may impair the glycolic ability and reserves of macrophages. In contrast to hyperglycaemia, insulin deficiency in T2D has not been thoroughly studied regarding the function of macrophages against infections, necessitating research in this direction. ^[18]. In an in vitro study, elevated glucose inhibited antibacterial activity and phagocytosis in mouse bone marrow macrophages ^[19]. Additionally, peritoneal macrophages from diabetic animals showed decreased phagocytosis in the same research. Many studies have documented that, in diabetic conditions, increased TNF-α expression induces a local inflammatory response through a cascade of cytokines. This increases vascular permeability, recruiting macrophages and neutrophils to the site of infection ^[20]^[21]. In another in vitro study, insulin intervention restored alveolar macrophage phagocytosis and cytokine release. This study suggests that exogenous insulin in diabetes may boost immune cell activity to fight pathogens by activating TNF-α and IL-6 ^[22]. In contrast, it is also possible that TNF- and IL-6 may cause insulin resistance. Therefore, exogenous insulin should be administered under strict control ^[23]^[24]. Furthermore, elevated plasma levels of TNF-α and IL-6 were shown to be associated with DM-induced LV dysfunction ^[25]. Liu et al. found that resident peritoneal macrophages (RPMs) from DB/DB mice had substantially lower phagocytosis and adherence ^[26].

3. Neutrophil Function and Other Immune Abnormalities in Diabetes

In addition to the generation of ROS, immunoglobulin-mediated opsonization, and phagocytosis, hyperglycaemia also impairs neutrophil degranulation and the formation of neutrophil extracellular traps (NETs). In one study, researchers found that individuals with induced hyperglycaemia who were exposed to bacterial wall components displayed lower neutrophil degranulation. ^[27]. Following previous results, Joshi et al. found that hyperglycaemia reduced neutrophil activity to create NETs, making infections more likely ^[28]. Natural killer (NK) cells regulate conditions in the innate cellular immune system, similar to other resistant components. The diabetes-related metabolic disorder affects NK cell activity, particularly the (natural killer group 2D) NKG2D/ligand axis. On the other hand, hyperglycaemia-mediated ER (endoplasmic reticulum) stress may contribute to diabetes-related NK cell dysfunction. Further research is needed to identify the dynamics of this interaction and how anti-diabetic medications affect ER stress protein expression in diabetes ^[29].

4. Immune Abnormalities in T1 Diabetes

T1D is a congenital autoimmune disorder produced by autoreactive CD4+ and CD8+ T-cells, which identify pancreatic antigens such as insulin or glutamic acid cecarboxylase (GAD) and kill insulin-producing β-cells ^[30]. How endogenous β-cell antigens become immunogenic is still open to exhaustive study. There is growing evidence that viral infection is a major environmental factor in the development and progression of T1D. Nevertheless, patients with T1D are also more susceptible to infections of the lower respiratory tract, urinary tract, and skin and mucosal membranes, as well as bacterial skin and mucous membrane infections and mycotic skin and mucous membrane infections ^[31]. Genome-wide association studies have helped achieve an understanding of genetic vulnerability. By contrast, immunological research has shown new immune-dysregulation mechanisms in the central tolerance, apoptotic pathways, or peripheral tolerance mediated by regulatory T-cells in T1D ^[32]^[33]^[34].

Thus far, several lines of evidence imply that diabetes-related comorbidities significantly contribute to immune disorders. Many studies explored diabetic immune responsive function to explain that the putative vulnerability to infections and hyperglycaemia was shown to decrease the immune response system against antimicrobial activity in various trials. However, most immune response studies on diabetes-related infections show persistent immunological impairment. The above discussion makes understanding the issue challenging and explains the significant findings of different epidemiological studies. Therefore, diabetes is a complicated disease with several metabolic problems, making it challenging to trace the increased infection susceptibility through a single pathway or cell type. Additionally, multiple dysregulated physiological reactions affect organ failure and the 10% mortality rate. Furthermore, many diabetic survivors eventually die from recurring, nosocomial, and secondary infections, despite having a history of recovery. Recent studies demonstrate that even after clinical “recovery” from a deadly invasive infection, innate and adaptive immune responses remain altered, causing chronic inflammation, immunological suppression, and bacterial persistence. Moreover, diabetes lowers immune cell function directly; thus, diabetic patients demonstrated a decreased bactericidal clearance, increased infectious comorbidities, and an increased mortality. Since diabetes-associated immune abnormalities increase mortality, immunological modulatory medication may enhance patient outcomes. Over the next two decades, diabetic infectious mortality is expected to climb significantly higher due to the increasing older and obese populations, worldwide adoption of a Western diet and lifestyle, and multidrug-resistant bacterial development and persistence. Understanding the underlying mechanism of diabetes-induced immune cell abnormalities that remain after an infection attack helps to identify possible targeted treatment strategies to boost innate and adaptive immune function, minimize infectious complications, and improve diabetic survival from fatal invasive infectious diseases.

References

Meylan, E.; Tschopp, J.; Karin, M. Intracellular Pattern Recognition Receptors in the Host Response. Nature 2006, 442, 39–44.
Barman, S.; Srinivasan, K. Attenuation of Oxidative Stress and Cardioprotective Effects of Zinc Supplementation in Experimental Diabetic Rats. Br. J. Nutr. 2017, 117, 335–350.
Pradeep, S.R.; Srinivasan, K. Amelioration of Oxidative Stress by Dietary Fenugreek (Trigonella foenum-graecum L.) Seeds Is Potentiated by Onion (Allium cepa L.) in Streptozotocin-Induced Diabetic Rats. Appl. Physiol. Nutr. Metab. 2017, 42, 816–828.
Barman, S.; Srinivasan, K. Zinc Supplementation Ameliorates Diabetic Cataract Through Modulation of Crystallin Proteins and Polyol Pathway in Experimental Rats. Biol. Trace Elem Res. 2019, 187, 212–223.
Pradeep, S.R.; Srinivasan, K. Ameliorative Influence of Dietary Fenugreek (Trigonella foenum-graecum) Seeds and Onion (Allium cepa) on Eye Lens Abnormalities via Modulation of Crystallin Proteins and Polyol Pathway in Experimental Diabetes. Curr. Eye Res. 2018, 43, 1108–1118.
Chung, S.S.M.; Ho, E.C.M.; Lam, K.S.L.; Chung, S.K. Contribution of Polyol Pathway to Diabetes-Induced Oxidative Stress. JASN 2003, 14, S233–S236.
Barman, S.; Srinivasan, K. Diabetes and Zinc Dyshomeostasis: Can Zinc Supplementation Mitigate Diabetic Complications? Crit. Rev. Food Sci. Nutr. 2022, 62, 1046–1061.
Urner, S.; Ho, F.; Jha, J.C.; Ziegler, D.; Jandeleit-Dahm, K. NADPH Oxidase Inhibition: Preclinical and Clinical Studies in Diabetic Complications. Antioxid. Redox Signal. 2020, 33, 415–434.
Wangoo, A.; Johnson, L.; Gough, J.; Ackbar, R.; Inglut, S.; Hicks, D.; Spencer, Y.; Hewinson, G.; Vordermeier, M. Advanced Granulomatous Lesions in Mycobacterium Bovis-Infected Cattle Are Associated with Increased Expression of Type I Procollagen, Γδ (WC1+) T Cells and CD 68+ Cells. J. Comp. Pathol. 2005, 133, 223–234.
Giacomini, E.; Iona, E.; Ferroni, L.; Miettinen, M.; Fattorini, L.; Orefici, G.; Julkunen, I.; Coccia, E.M. Infection of Human Macrophages and Dendritic Cells with Mycobacterium Tuberculosis Induces a Differential Cytokine Gene Expression That Modulates T Cell Response1. J. Immunol. 2001, 166, 7033–7041.
Gottlieb, P.A.; Alkanani, A.K.; Michels, A.W.; Lewis, E.C.; Shapiro, L.; Dinarello, C.A.; Zipris, D. A1-Antitrypsin Therapy Downregulates Toll-Like Receptor-Induced IL-1β Responses in Monocytes and Myeloid Dendritic Cells and May Improve Islet Function in Recently Diagnosed Patients with Type 1 Diabetes. J. Clin. Endocrinol. Metab. 2014, 99, E1418–E1426.
Lachmandas, E.; Thiem, K.; van den Heuvel, C.; Hijmans, A.; de Galan, B.E.; Tack, C.J.; Netea, M.G.; van Crevel, R.; van Diepen, J.A. Patients with Type 1 Diabetes Mellitus Have Impaired IL-1β Production in Response to Mycobacterium Tuberculosis. Eur. J. Clin. Microbiol. Infect. Dis. 2018, 37, 371–380.
Tessaro, F.H.G.; Ayala, T.S.; Nolasco, E.L.; Bella, L.M.; Martins, J.O. Insulin Influences LPS-Induced TNF-α and IL-6 Release Through Distinct Pathways in Mouse Macrophages from Different Compartments. Cell. Physiol. Biochem. 2017, 42, 2093–2104.
Reinhold, D.; Ansorge, S. Elevated Glucose Levels Stimulate Transforming Growth Factor-Β1 (TGF-Β1), Suppress Interleukin IL-2, IL-6 and IL-10 Production and DNA Synthesis in Peripheral Blood Mononuclear Cells. Horm. Metab. Res. 1996, 28, 267–270.
Spindler, M.P.; Ho, A.M.; Tridgell, D.; McCulloch-Olson, M.; Gersuk, V.; Ni, C.; Greenbaum, C.; Sanda, S. Acute Hyperglycemia Impairs IL-6 Expression in Humans. Immun. Inflamm. Dis. 2016, 4, 91–97.
Yang, L.; Zhang, Y.; Wang, L.; Fan, F.; Zhu, L.; Li, Z.; Ruan, X.; Huang, H.; Wang, Z.; Huang, Z.; et al. Amelioration of High Fat Diet Induced Liver Lipogenesis and Hepatic Steatosis by Interleukin-22. J. Hepatol. 2010, 53, 339–347.
Tan, K.S.; Lee, K.O.; Low, K.C.; Gamage, A.M.; Liu, Y.; Tan, G.-Y.G.; Koh, H.Q.V.; Alonso, S.; Gan, Y.-H. Glutathione Deficiency in Type 2 Diabetes Impairs Cytokine Responses and Control of Intracellular Bacteria. J. Clin. Investig. 2012, 122, 2289–2300.
Restrepo, B.I.; Twahirwa, M.; Rahbar, M.H.; Schlesinger, L.S. Phagocytosis via Complement or Fc-Gamma Receptors Is Compromised in Monocytes from Type 2 Diabetes Patients with Chronic Hyperglycemia. PLoS ONE 2014, 9, e92977.
Pavlou, S.; Lindsay, J.; Ingram, R.; Xu, H.; Chen, M. Sustained High Glucose Exposure Sensitizes Macrophage Responses to Cytokine Stimuli but Reduces Their Phagocytic Activity. BMC Immunol. 2018, 19, 24.
Pamir, N.; McMillen, T.S.; Kaiyala, K.J.; Schwartz, M.W.; LeBoeuf, R.C. Receptors for Tumor Necrosis Factor-α Play a Protective Role against Obesity and Alter Adipose Tissue Macrophage Status. Endocrinology 2009, 150, 4124–4134.
Barman, S.; Pradeep, S.R.; Srinivasan, K. Zinc Supplementation Alleviates the Progression of Diabetic Nephropathy by Inhibiting the Overexpression of Oxidative-Stress-Mediated Molecular Markers in Streptozotocin-Induced Experimental Rats. J. Nutr. Biochem. 2018, 54, 113–129.
Ferracini, M.; Martins, J.O.; Campos, M.R.M.; Anger, D.B.C.; Jancar, S. Impaired Phagocytosis by Alveolar Macrophages from Diabetic Rats Is Related to the Deficient Coupling of LTs to the FcγR Signaling Cascade. Mol. Immunol. 2010, 47, 1974–1980.
Lehrke, M.; Broedl, U.C.; Biller-Friedmann, I.M.; Vogeser, M.; Henschel, V.; Nassau, K.; Göke, B.; Kilger, E.; Parhofer, K.G. Serum Concentrations of Cortisol, Interleukin 6, Leptin and Adiponectin Predict Stress Induced Insulin Resistance in Acute Inflammatory Reactions. Crit. Care 2008, 12, R157.
Antoniades, C.; Tousoulis, D.; Marinou, K.; Papageorgiou, N.; Bosinakou, E.; Tsioufis, C.; Stefanadi, E.; Latsios, G.; Tentolouris, C.; Siasos, G.; et al. Effects of Insulin Dependence on Inflammatory Process, Thrombotic Mechanisms and Endothelial Function, in Patients with Type 2 Diabetes Mellitus and Coronary Atherosclerosis. Clin. Cardiol. 2007, 30, 295–300.
Dinh, W.; Füth, R.; Nickl, W.; Krahn, T.; Ellinghaus, P.; Scheffold, T.; Bansemir, L.; Bufe, A.; Barroso, M.C.; Lankisch, M. Elevated Plasma Levels of TNF-Alpha and Interleukin-6 in Patients with Diastolic Dysfunction and Glucose Metabolism Disorders. Cardiovasc Diabetol 2009, 8, 58.
Liu, H.-F.; Zhang, H.-J.; Hu, Q.-X.; Liu, X.-Y.; Wang, Z.-Q.; Fan, J.-Y.; Zhan, M.; Chen, F.-L. Altered Polarization, Morphology, and Impaired Innate Immunity Germane to Resident Peritoneal Macrophages in Mice with Long-Term Type 2 Diabetes. BioMed Res. Int. 2012, 2012, e867023.
Stegenga, M.E.; van der Crabben, S.N.; Blümer, R.M.E.; Levi, M.; Meijers, J.C.M.; Serlie, M.J.; Tanck, M.W.T.; Sauerwein, H.P.; van der Poll, T. Hyperglycemia Enhances Coagulation and Reduces Neutrophil Degranulation, Whereas Hyperinsulinemia Inhibits Fibrinolysis during Human Endotoxemia. Blood 2008, 112, 82–89.
Joshi, M.B.; Lad, A.; Bharath Prasad, A.S.; Balakrishnan, A.; Ramachandra, L.; Satyamoorthy, K. High Glucose Modulates IL-6 Mediated Immune Homeostasis through Impeding Neutrophil Extracellular Trap Formation. FEBS Lett. 2013, 587, 2241–2246.
Berrou, J.; Fougeray, S.; Venot, M.; Chardiny, V.; Gautier, J.-F.; Dulphy, N.; Toubert, A.; Peraldi, M.-N. Natural Killer Cell Function, an Important Target for Infection and Tumor Protection, Is Impaired in Type 2 Diabetes. PLoS ONE 2013, 8, e62418.
Kukreja, A.; Maclaren*, N.K. Current Cases in Which Epitope Mimicry Is Considered as a Component Cause of Autoimmune Disease: Immune-Mediated (Type 1) Diabetes. CMLS Cell. Mol. Life Sci. 2000, 57, 534–541.
van der Werf, N.; Kroese, F.G.M.; Rozing, J.; Hillebrands, J.-L. Viral Infections as Potential Triggers of Type 1 Diabetes. Diabetes/Metab. Res. Rev. 2007, 23, 169–183.
Battaglia, M.; Stabilini, A.; Migliavacca, B.; Horejs-Hoeck, J.; Kaupper, T.; Roncarolo, M.-G. Rapamycin Promotes Expansion of Functional CD4+CD25+FOXP3+ Regulatory T Cells of Both Healthy Subjects and Type 1 Diabetic Patients1. J. Immunol. 2006, 177, 8338–8347.
Grazia Roncarolo, M.; Gregori, S.; Battaglia, M.; Bacchetta, R.; Fleischhauer, K.; Levings, M.K. Interleukin-10-Secreting Type 1 Regulatory T Cells in Rodents and Humans. Immunol. Rev. 2006, 212, 28–50.
Marek-Trzonkowska, N.; Myśliwec, M.; Siebert, J.; Trzonkowski, P. Clinical Application of Regulatory T Cells in Type 1 Diabetes. Pediatr. Diabetes 2013, 14, 322–332.

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Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :

Anjum Khanam

Gavirangappa Hithamani

Jayapala Naveen

Seetur R. Pradeep

Susmita Barman

Krishnapura Srinivasan

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Update Date: 13 Apr 2023

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