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Innate inflammation in type 1 diabetes

  • Susanne M. Cabrera
    Affiliations
    Max McGee National Research Center for Juvenile Diabetes, Children's Research Institute of Children's Hospital of Wisconsin, Milwaukee, Wis

    Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wis
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  • Angela M. Henschel
    Affiliations
    Max McGee National Research Center for Juvenile Diabetes, Children's Research Institute of Children's Hospital of Wisconsin, Milwaukee, Wis

    Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wis
    Search for articles by this author
  • Martin J. Hessner
    Correspondence
    Reprint requests: Martin J. Hessner, Section of Endocrinology, Department of Pediatrics, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, WI 53226
    Affiliations
    Max McGee National Research Center for Juvenile Diabetes, Children's Research Institute of Children's Hospital of Wisconsin, Milwaukee, Wis

    Department of Pediatrics, Medical College of Wisconsin, Milwaukee, Wis
    Search for articles by this author
Published:April 29, 2015DOI:https://doi.org/10.1016/j.trsl.2015.04.011
      Type 1 diabetes mellitus (T1D) is an autoimmune disease often diagnosed in childhood that results in pancreatic β-cell destruction and life-long insulin dependence. T1D susceptibility involves a complex interplay between genetic and environmental factors and has historically been attributed to adaptive immunity, although there is now increasing evidence for a role of innate inflammation. Here, we review studies that define a heightened age-dependent innate inflammatory state in T1D families that is paralleled with high fidelity by the T1D-susceptible biobreeding rat. Innate inflammation may be driven by changes in interactions between the host and environment, such as through an altered microbiome, intestinal hyperpermeability, or viral exposures. Special focus is put on the temporal measurement of plasma-induced transcriptional signatures of recent-onset T1D patients and their siblings as well as in the biobreeding rat as it defines the natural history of innate inflammation. These sensitive and comprehensive analyses have also revealed that those who successfully managed T1D risk develop an age-dependent immunoregulatory state, providing a possible mechanism for the juvenile nature of T1D. Therapeutic targeting of innate inflammation has been proven effective in preventing and delaying T1D in rat models. Clinical trials of agents that suppress innate inflammation have had more modest success, but efficacy may be improved by the addition of combinatorial approaches that target other aspects of T1D pathogenesis. An understanding of innate inflammation and mechanisms by which this susceptibility is both potentiated and mitigated offers important insight into T1D progression and avenues for therapeutic intervention.

      Abbreviations:

      AAs (autoantibodies), AAT (alpha-1 antitrypsin), BB (biobreeding rat strain), BBDP (biobreeding diabetes prone), BBDR (biobreeding diabetes resistant), ELISA (enzyme-linked immunosorbent assay), GI (gastrointestinal), HLA (human leukocyte antigen), HRS (high-risk sibling (healthy, autoantibody negative, and possess DR3 and/or DR4 haplotype)), IFN-α (interferon gamma), IL-1 (interleukin 1), IL-10 (interleukin 10), IL-1RN (interleukin 1 receptor antagonist), KRV (Kilham's rat virus), LRS (low-risk sibling (healthy, autoantibody negative, lacking either DR3 or DR4 haplotype)), MHC (major histocompatibility complex), PBMC (peripheral blood mononuclear cell), Poly I:C (polyinosinic-polycytidylic acid), PRR (pattern recognition receptor), PTPN22 (protein tyrosine phosphatase nonreceptor type 22), RO T1D (recent-onset type 1 diabetes), T1D (type 1 diabetes mellitus), TGF-β (transforming growth factor β), TLR (toll-like receptor), Tregs (regulatory T lymphocytes), uHC (unrelated healthy control (no family history of type 1 diabetes))
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      References

        • Harjutsalo V.
        • Sjoberg L.
        • Tuomilehto J.
        Time trends in the incidence of type 1 diabetes in Finnish children: a cohort study.
        Lancet. 2008; 371: 1777-1782
        • Zheng S.
        • Mathews C.E.
        Metabolic abnormalities in the pathogenesis of type 1 diabetes.
        Curr Diab Rep. 2014; 14: 519
        • Pugliese A.
        The multiple origins of type 1 diabetes.
        Diabet Med. 2013; 30: 135-146
        • Dabelea D.
        The accelerating epidemic of childhood diabetes.
        Lancet. 2009; 373: 1999-2000
        • Steck A.K.
        • Rewers M.J.
        Genetics of type 1 diabetes.
        Clin Chem. 2011; 57: 176-185
        • Noble J.A.
        • Valdes A.M.
        • Varney M.D.
        • et al.
        HLA class I and genetic susceptibility to type 1 diabetes: results from the Type 1 Diabetes Genetics Consortium.
        Diabetes. 2010; 59: 2972-2979
        • Gough S.C.
        • Simmonds M.J.
        The HLA region and autoimmune disease: associations and mechanisms of action.
        Curr Genomics. 2007; 8: 453-465
        • Mangalam A.K.
        • Taneja V.
        • David C.S.
        HLA class II molecules influence susceptibility versus protection in inflammatory diseases by determining the cytokine profile.
        J Immunol. 2013; 190: 513-518
        • Concannon P.
        • Rich S.S.
        • Nepom G.T.
        Genetics of type 1A diabetes.
        N Engl J Med. 2009 16; 360: 1646-1654
        • Atkinson M.A.
        • Eisenbarth G.S.
        Type 1 diabetes: new perspectives on disease pathogenesis and treatment.
        Lancet. 2001; 358: 221-229
        • Eisenbarth G.S.
        Type I diabetes mellitus. A chronic autoimmune disease.
        N Engl J Med. 1986; 314: 1360-1368
        • Bingley P.J.
        Clinical applications of diabetes antibody testing.
        J Clin Endocrinol Metab. 2010; 95: 25-33
        • Ziegler A.G.
        • Rewers M.
        • Simell O.
        • et al.
        Seroconversion to multiple islet autoantibodies and risk of progression to diabetes in children.
        JAMA. 2013; 309: 2473-2479
        • Knip M.
        • Korhonen S.
        • Kulmala P.
        • et al.
        Prediction of type 1 diabetes in the general population.
        Diabetes Care. 2010; 33: 1206-1212
        • Zipris D.
        Innate immunity in type 1 diabetes.
        Diabetes Metab Res Rev. 2011; 27: 824-829
        • Todd J.A.
        Etiology of type 1 diabetes.
        Immunity. 2010; 32: 457-467
        • Wang X.
        • Jia S.
        • Geoffrey R.
        • Alemzadeh R.
        • Ghosh S.
        • Hessner M.J.
        Identification of a molecular signature in human type 1 diabetes mellitus using serum and functional genomics.
        J Immunol. 2008; 180: 1929-1937
        • Keymeulen B.
        • Vandemeulebroucke E.
        • Ziegler A.G.
        • et al.
        Insulin needs after CD3-antibody therapy in new-onset type 1 diabetes.
        N Engl J Med. 2005; 352: 2598-2608
        • Pescovitz M.D.
        • Greenbaum C.J.
        • Krause-Steinrauf H.
        • et al.
        Rituximab, B-lymphocyte depletion, and preservation of beta-cell function.
        N Engl J Med. 2009; 361: 2143-2152
        • Stiller C.R.
        • Dupre J.
        • Gent M.
        • et al.
        Effects of cyclosporine immunosuppression in insulin-dependent diabetes mellitus of recent onset.
        Science. 1984; 223: 1362-1367
        • Ablamunits V.
        • Henegariu O.
        • Hansen J.B.
        • et al.
        Synergistic reversal of type 1 diabetes in NOD mice with anti-CD3 and interleukin-1 blockade: evidence of improved immune regulation.
        Diabetes. 2012; 61: 145-154
        • Pagni P.P.
        • Bresson D.
        • Rodriguez-Calvo T.
        • et al.
        Combination therapy with an anti-IL-1beta antibody and GAD65 DNA vaccine can reverse recent-onset diabetes in the RIP-GP mouse model.
        Diabetes. 2014; 63: 2015-2025
        • Gillespie K.M.
        • Bain S.C.
        • Barnett A.H.
        • et al.
        The rising incidence of childhood type 1 diabetes and reduced contribution of high-risk HLA haplotypes.
        Lancet. 2004; 364: 1699-1700
        • Steck A.K.
        • Armstrong T.K.
        • Babu S.R.
        • Eisenbarth G.S.
        Type 1 diabetes genetics C. Stepwise or linear decrease in penetrance of type 1 diabetes with lower-risk HLA genotypes over the past 40 years.
        Diabetes. 2011; 60: 1045-1049
        • Medzhitov R.
        Recognition of microorganisms and activation of the immune response.
        Nature. 2007; 449: 819-826
        • Atkinson M.A.
        • Chervonsky A.
        Does the gut microbiota have a role in type 1 diabetes? Early evidence from humans and animal models of the disease.
        Diabetologia. 2012; 55: 2868-2877
        • Bach J.F.
        • Chatenoud L.
        The hygiene hypothesis: an explanation for the increased frequency of insulin-dependent diabetes.
        Cold Spring Harb Perspect Med. 2012; 2: a007799
        • Abela A.G.
        • Fava S.
        Association of incidence of type 1 diabetes with mortality from infectious disease and with antibiotic susceptibility at a country level.
        Acta Diabetol. 2013; 50: 859-865
        • von Herrath M.G.
        • Fujinami R.S.
        • Whitton J.L.
        Microorganisms and autoimmunity: making the barren field fertile?.
        Nat Rev Microbiol. 2003; 1: 151-157
        • Vaarala O.
        • Atkinson M.A.
        • Neu J.
        The “perfect storm” for type 1 diabetes: the complex interplay between intestinal microbiota, gut permeability, and mucosal immunity.
        Diabetes. 2008; 57: 2555-2562
        • Bosi E.
        • Molteni L.
        • Radaelli M.G.
        • et al.
        Increased intestinal permeability precedes clinical onset of type 1 diabetes.
        Diabetologia. 2006; 49: 2824-2827
        • Carratu R.
        • Secondulfo M.
        • de Magistris L.
        • et al.
        Altered intestinal permeability to mannitol in diabetes mellitus type I.
        J Pediatr Gastroenterol Nutr. 1999; 28: 264-269
        • Kuitunen M.
        • Saukkonen T.
        • Ilonen J.
        • Akerblom H.K.
        • Savilahti E.
        Intestinal permeability to mannitol and lactulose in children with type 1 diabetes with the HLA-DQB1*02 allele.
        Autoimmunity. 2002; 35: 365-368
        • Sapone A.
        • de Magistris L.
        • Pietzak M.
        • et al.
        Zonulin upregulation is associated with increased gut permeability in subjects with type 1 diabetes and their relatives.
        Diabetes. 2006; 55: 1443-1449
        • Secondulfo M.
        • Iafusco D.
        • Carratu R.
        • et al.
        Ultrastructural mucosal alterations and increased intestinal permeability in non-celiac, type I diabetic patients.
        Dig Liver Dis. 2004; 36: 35-45
        • Kostic A.D.
        • Gevers D.
        • Siljander H.
        • et al.
        The dynamics of the human infant gut microbiome in development and in progression toward type 1 diabetes.
        Cell Host Microbe. 2015; 17: 260-273
        • Mordes J.P.
        • Serreze D.V.
        • Greiner D.L.
        • Rossini A.A.
        Animal models of autoimmune diabetes.
        LIppincott, Williams, and Wilkins, Philadelphia2004
        • Jacob H.J.
        • Pettersson A.
        • Wilson D.
        • Mao Y.
        • Lernmark A.
        • Lander E.S.
        Genetic dissection of autoimmune type I diabetes in the BB rat.
        Nat Genet. 1992; 2: 56-60
        • MacMurray A.J.
        • Moralejo D.H.
        • Kwitek A.E.
        • et al.
        Lymphopenia in the BB rat model of type 1 diabetes is due to a mutation in a novel immune-associated nucleotide (Ian)-related gene.
        Genome Res. 2002; 12: 1029-1039
        • Daheron L.
        • Zenz T.
        • Siracusa L.D.
        • Brenner C.
        • Calabretta B.
        Molecular cloning of Ian4: a BCR/ABL-induced gene that encodes an outer membrane mitochondrial protein with GTP-binding activity.
        Nucleic Acids Res. 2001; 29: 1308-1316
        • Pandarpurkar M.
        • Wilson-Fritch L.
        • Corvera S.
        • et al.
        Ian4 is required for mitochondrial integrity and T cell survival.
        Proc Natl Acad Sci U S A. 2003; 100: 10382-10387
        • Schulteis R.D.
        • Chu H.
        • Dai X.
        • et al.
        Impaired survival of peripheral T cells, disrupted NK/NKT cell development, and liver failure in mice lacking Gimap5.
        Blood. 2008; 112: 4905-4914
        • Lundsgaard D.
        • Holm T.L.
        • Hornum L.
        • Markholst H.
        In vivo control of diabetogenic T-cells by regulatory CD4+CD25+ T-cells expressing Foxp3.
        Diabetes. 2005; 54: 1040-1047
        • Poussier P.
        • Ning T.
        • Murphy T.
        • Dabrowski D.
        • Ramanathan S.
        Impaired post-thymic development of regulatory CD4+25+ T cells contributes to diabetes pathogenesis in BB rats.
        J Immunol. 2005; 174: 4081-4089
        • Tirabassi R.S.
        • Guberski D.L.
        • Blankenhorn E.P.
        • et al.
        Infection with viruses from several families triggers autoimmune diabetes in LEW*1WR1 rats: prevention of diabetes by maternal immunization.
        Diabetes. 2010; 59: 110-118
        • Mordes J.P.
        • Bortell R.
        • Doukas J.
        • et al.
        The BB/Wor rat and the balance hypothesis of autoimmunity.
        Diabetes Metab Rev. 1996; 12: 103-109
        • Zipris D.
        • Hillebrands J.L.
        • Welsh R.M.
        • et al.
        Infections that induce autoimmune diabetes in BBDR rats modulate CD4+CD25+ T cell populations.
        J Immunol. 2003; 170: 3592-3602
        • Chen Y.G.
        • Mordes J.P.
        • Blankenhorn E.P.
        • et al.
        Temporal induction of immunoregulatory processes coincides with age-dependent resistance to viral-induced type 1 diabetes.
        Genes Immun. 2013; 14: 387-400
        • Ellerman K.E.
        • Richards C.A.
        • Guberski D.L.
        • Shek W.R.
        • Like A.A.
        Kilham rat triggers T-cell-dependent autoimmune diabetes in multiple strains of rat.
        Diabetes. 1996; 45: 557-562
        • Mordes J.P.
        • Bortell R.
        • Blankenhorn E.P.
        • Rossini A.A.
        • Greiner D.L.
        Rat models of type 1 diabetes: genetics, environment, and autoimmunity.
        ILAR J. 2004; 45: 278-291
        • Guberski D.L.
        • Thomas V.A.
        • Shek W.R.
        • et al.
        Induction of type I diabetes by Kilham's rat virus in diabetes-resistant BB/Wor rats.
        Science. 1991; 254: 1010-1013
        • Blankenhorn E.P.
        • Cort L.
        • Greiner D.L.
        • Guberski D.L.
        • Mordes J.P.
        Virus-induced autoimmune diabetes in the LEW.1WR1 rat requires Iddm14 and a genetic locus proximal to the major histocompatibility complex.
        Diabetes. 2009; 58: 2930-2938
        • Kahn H.S.
        • Lawrence J.M.
        • Morgan T.M.
        • et al.
        Association of type 1 diabetes with month of birth among US youth: the SEARCH for Diabetes in Youth Study.
        Diabetes Care. 2009; 32: 2010-2015
        • Moltchanova E.V.
        • Schreier N.
        • Lammi N.
        • Karvonen M.
        Seasonal variation of diagnosis of Type 1 diabetes mellitus in children worldwide.
        Diabet Med. 2009; 26: 673-678
        • Andreoletti L.
        • Hober D.
        • Hober-Vandenberghe C.
        • et al.
        Detection of coxsackie B virus RNA sequences in whole blood samples from adult patients at the onset of type I diabetes mellitus.
        J Med Virol. 1997; 52: 121-127
        • Craig M.E.
        • Howard N.J.
        • Silink M.
        • Rawlinson W.D.
        Reduced frequency of HLA DRB1*03-DQB1*02 in children with type 1 diabetes associated with enterovirus RNA.
        J Infect Dis. 2003; 187: 1562-1570
        • Helfand R.F.
        • Gary Jr., H.E.
        • Freeman C.Y.
        • Anderson L.J.
        • Pallansch M.A.
        Serologic evidence of an association between enteroviruses and the onset of type 1 diabetes mellitus. Pittsburgh Diabetes Research Group.
        J Infect Dis. 1995; 172: 1206-1211
        • Lonnrot M.
        • Korpela K.
        • Knip M.
        • et al.
        Enterovirus infection as a risk factor for beta-cell autoimmunity in a prospectively observed birth cohort: the Finnish Diabetes Prediction and Prevention Study.
        Diabetes. 2000; 49: 1314-1318
        • Nairn C.
        • Galbraith D.N.
        • Taylor K.W.
        • Clements G.B.
        Enterovirus variants in the serum of children at the onset of type 1 diabetes mellitus.
        Diabet Med. 1999; 16: 509-513
        • Richardson S.J.
        • Willcox A.
        • Bone A.J.
        • Foulis A.K.
        • Morgan N.G.
        The prevalence of enteroviral capsid protein VP1 immunostaining in pancreatic islets in human type 1 diabetes.
        Diabetologia. 2009; 52: 1143-1151
        • Sarmiento L.
        • Cabrera-Rode E.
        • Lekuleni L.
        • et al.
        Occurrence of enterovirus RNA in serum of children with newly diagnosed type 1 diabetes and islet cell autoantibody-positive subjects in a population with a low incidence of type 1 diabetes.
        Autoimmunity. 2007; 40: 540-545
        • Yeung W.C.
        • Rawlinson W.D.
        • Craig M.E.
        Enterovirus infection and type 1 diabetes mellitus: systematic review and meta-analysis of observational molecular studies.
        BMJ. 2011; 342: d35
        • Laitinen O.H.
        • Honkanen H.
        • Pakkanen O.
        • et al.
        Coxsackievirus B1 is associated with induction of beta-cell autoimmunity that portends type 1 diabetes.
        Diabetes. 2014; 63: 446-455
        • Richardson S.J.
        • Leete P.
        • Bone A.J.
        • Foulis A.K.
        • Morgan N.G.
        Expression of the enteroviral capsid protein VP1 in the islet cells of patients with type 1 diabetes is associated with induction of protein kinase R and downregulation of Mcl-1.
        Diabetologia. 2013; 56: 185-193
        • Barrett J.C.
        • Clayton D.G.
        • Concannon P.
        • et al.
        Genome-wide association study and meta-analysis find that over 40 loci affect risk of type 1 diabetes.
        Nat Genet. 2009; 41: 703-707
        • Virgin H.W.
        • Todd J.A.
        Metagenomics and personalized medicine.
        Cell. 2011; 147: 44-56
        • Ferreira R.C.
        • Guo H.
        • Coulson R.M.
        • et al.
        A type I interferon transcriptional signature precedes autoimmunity in children genetically at risk for type 1 diabetes.
        Diabetes. 2014; 63: 2538-2550
        • Kallionpaa H.
        • Elo L.L.
        • Laajala E.
        • et al.
        Innate immune activity is detected prior to seroconversion in children with HLA-conferred type 1 diabetes susceptibility.
        Diabetes. 2014; 63: 2402-2414
        • Jia S.
        • Kaldunski M.
        • Jailwala P.
        • et al.
        Use of transcriptional signatures induced in lymphoid and myeloid cell lines as an inflammatory biomarker in type 1 diabetes.
        Physiol Genomics. 2011; 43: 697-709
        • Kaldunski M.
        • Jia S.
        • Geoffrey R.
        • et al.
        Identification of a serum-induced transcriptional signature associated with type 1 diabetes in the BioBreeding rat.
        Diabetes. 2010; 59: 2375-2385
        • Levy H.
        • Wang X.
        • Kaldunski M.
        • et al.
        Transcriptional signatures as a disease-specific and predictive inflammatory biomarker for type 1 diabetes.
        Genes Immun. 2012; 13: 593-604
        • Bieg S.
        • Simonson W.
        • Ellefsen K.
        • Lernmark A.
        Rel B is an early marker of autoimmune islet inflammation in the biobreeding (BB) rat.
        Pancreas. 2000; 20: 47-54
        • Hessner M.J.
        • Wang X.
        • Meyer L.
        • et al.
        Involvement of eotaxin, eosinophils, and pancreatic predisposition in development of type 1 diabetes mellitus in the BioBreeding rat.
        J Immunol. 2004; 173: 6993-7002
        • Geoffrey R.
        • Jia S.
        • Kwitek A.E.
        • et al.
        Evidence of a functional role for mast cells in the development of type 1 diabetes mellitus in the BioBreeding rat.
        J Immunol. 2006; 177: 7275-7286
        • Sarmiento J.
        • Wallis R.H.
        • Ning T.
        • et al.
        A functional polymorphism of PTPN22 is associated with type 1 diabetes in the BioBreeding rat.
        J Immunol. 2015; 194: 615-629
        • Valladares R.
        • Sankar D.
        • Li N.
        • et al.
        Lactobacillus johnsonii N6.2 mitigates the development of type 1 diabetes in BB-DP rats.
        PLoS One. 2010; 5: e10507
        • Hara N.
        • Alkanani A.K.
        • Ir D.
        • et al.
        Prevention of virus-induced type 1 diabetes with antibiotic therapy.
        J Immunol. 2012; 189: 3805-3814
        • Allantaz F.
        • Chaussabel D.
        • Stichweh D.
        • et al.
        Blood leukocyte microarrays to diagnose systemic onset juvenile idiopathic arthritis and follow the response to IL-1 blockade.
        J Exp Med. 2007; 204: 2131-2144
        • Khaenam P.
        • Rinchai D.
        • Altman M.C.
        • et al.
        A transcriptomic reporter assay employing neutrophils to measure immunogenic activity of septic patients' plasma.
        J Transl Med. 2014; 12: 65
        • Zhang Q.
        • Fillmore T.L.
        • Schepmoes A.A.
        • et al.
        Serum proteomics reveals systemic dysregulation of innate immunity in type 1 diabetes.
        J Exp Med. 2013; 210: 191-203
        • Aly T.A.
        • Ide A.
        • Humphrey K.
        • et al.
        Genetic prediction of autoimmunity: initial oligogenic prediction of anti-islet autoimmunity amongst DR3/DR4-DQ8 relatives of patients with type 1A diabetes.
        J Autoimmun. 2005; 25: 40-45
        • Chen Y.G.
        • Cabrera S.M.
        • Jia S.
        • et al.
        Molecular signatures differentiate immune states in type 1 diabetic families.
        Diabetes. 2014; 63: 3960-3973
        • Miyara M.
        • Yoshioka Y.
        • Kitoh A.
        • et al.
        Functional delineation and differentiation dynamics of human CD4+ T cells expressing the FoxP3 transcription factor.
        Immunity. 2009; 30: 899-911
        • Mandrup-Poulsen T.
        • Bendtzen K.
        • Nerup J.
        • Dinarello C.A.
        • Svenson M.
        • Nielsen J.H.
        Affinity-purified human interleukin I is cytotoxic to isolated islets of Langerhans.
        Diabetologia. 1986; 29: 63-67
        • Sandler S.
        • Andersson A.
        • Hellerstrom C.
        Inhibitory effects of interleukin 1 on insulin secretion, insulin biosynthesis, and oxidative metabolism of isolated rat pancreatic islets.
        Endocrinology. 1987; 121: 1424-1431
        • Spinas G.A.
        • Hansen B.S.
        • Linde S.
        • et al.
        Interleukin 1 dose-dependently affects the biosynthesis of (pro)insulin in isolated rat islets of Langerhans.
        Diabetologia. 1987; 30: 474-480
        • Maedler K.
        • Sergeev P.
        • Ris F.
        • et al.
        Glucose-induced beta cell production of IL-1beta contributes to glucotoxicity in human pancreatic islets.
        J Clin Invest. 2002; 110: 851-860
        • Yamada K.
        • Takane-Gyotoku N.
        • Yuan X.
        • Ichikawa F.
        • Inada C.
        • Nonaka K.
        Mouse islet cell lysis mediated by interleukin-1-induced Fas.
        Diabetologia. 1996; 39: 1306-1312
        • Dayer-Metroz M.D.
        • Wollheim C.B.
        • Seckinger P.
        • Dayer J.M.
        A natural interleukin 1 (IL-1) inhibitor counteracts the inhibitory effect of IL-1 on insulin production in cultured rat pancreatic islets.
        J Autoimmun. 1989; 2: 163-171
        • Zumsteg U.
        • Reimers J.I.
        • Pociot F.
        • et al.
        Differential interleukin-1 receptor antagonism on pancreatic beta and alpha cells. Studies in rodent and human islets and in normal rats.
        Diabetologia. 1993; 36: 759-766
        • Dinarello C.A.
        • Simon A.
        • van der Meer J.W.
        Treating inflammation by blocking interleukin-1 in a broad spectrum of diseases.
        Nat Rev Drug Discov. 2012; 11: 633-652
        • Dogan Y.
        • Akarsu S.
        • Ustundag B.
        • Yilmaz E.
        • Gurgoze M.K.
        Serum IL-1beta, IL-2, and IL-6 in insulin-dependent diabetic children.
        Mediators Inflamm. 2006; 2006: 59206
        • Hussain M.J.
        • Maher J.
        • Warnock T.
        • Vats A.
        • Peakman M.
        • Vergani D.
        Cytokine overproduction in healthy first degree relatives of patients with IDDM.
        Diabetologia. 1998; 41: 343-349
        • Bradshaw E.M.
        • Raddassi K.
        • Elyaman W.
        • et al.
        Monocytes from patients with type 1 diabetes spontaneously secrete proinflammatory cytokines inducing Th17 cells.
        J Immunol. 2009; 183: 4432-4439
        • Kaizer E.C.
        • Glaser C.L.
        • Chaussabel D.
        • Banchereau J.
        • Pascual V.
        • White P.C.
        Gene expression in peripheral blood mononuclear cells from children with diabetes.
        J Clin Endocrinol Metab. 2007; 92: 3705-3711
        • Meyers A.J.
        • Shah R.R.
        • Gottlieb P.A.
        • Zipris D.
        Altered Toll-like receptor signaling pathways in human type 1 diabetes.
        J Mol Med. 2010; 88: 1221-1231
        • Padmos R.C.
        • Schloot N.C.
        • Beyan H.
        • et al.
        Distinct monocyte gene-expression profiles in autoimmune diabetes.
        Diabetes. 2008; 57: 2768-2773
        • Kayserova J.
        • Vcelakova J.
        • Stechova K.
        • et al.
        Decreased dendritic cell numbers but increased TLR9-mediated interferon-alpha production in first degree relatives of type 1 diabetes patients.
        Clin Immunol. 2014; 153: 49-55
        • Petrich de Marquesini L.G.
        • Fu J.
        • Connor K.J.
        • et al.
        IFN-gamma and IL-10 islet-antigen-specific T cell responses in autoantibody-negative first-degree relatives of patients with type 1 diabetes.
        Diabetologia. 2010; 53: 1451-1460
        • Cordain L.
        • Eaton S.B.
        • Sebastian A.
        • et al.
        Origins and evolution of the Western diet: health implications for the 21st century.
        Am J Clin Nutr. 2005; 81: 341-354
        • de Souza R.J.
        • Swain J.F.
        • Appel L.J.
        • Sacks F.M.
        Alternatives for macronutrient intake and chronic disease: a comparison of the OmniHeart diets with popular diets and with dietary recommendations.
        Am J Clin Nutr. 2008; 88: 1-11
        • Cani P.D.
        • Bibiloni R.
        • Knauf C.
        • et al.
        Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice.
        Diabetes. 2008; 57: 1470-1481
        • Hildebrandt M.A.
        • Hoffmann C.
        • Sherrill-Mix S.A.
        • et al.
        High-fat diet determines the composition of the murine gut microbiome independently of obesity.
        Gastroenterology. 2009; 137 (1716–24.e1–2)
        • Turnbaugh P.J.
        • Backhed F.
        • Fulton L.
        • Gordon J.I.
        Diet-induced obesity is linked to marked but reversible alterations in the mouse distal gut microbiome.
        Cell Host Microbe. 2008; 3: 213-223
        • Turnbaugh P.J.
        • Ridaura V.K.
        • Faith J.J.
        • Rey F.E.
        • Knight R.
        • Gordon J.I.
        The effect of diet on the human gut microbiome: a metagenomic analysis in humanized gnotobiotic mice.
        Sci Transl Med. 2009; 1: 6ra14
        • Walter J.
        • Ley R.
        The human gut microbiome: ecology and recent evolutionary changes.
        Annu Rev Microbiol. 2011; 65: 411-429
        • Neu J.
        • Reverte C.M.
        • Mackey A.D.
        • et al.
        Changes in intestinal morphology and permeability in the biobreeding rat before the onset of type 1 diabetes.
        J Pediatr Gastroenterol Nutr. 2005; 40: 589-595
        • Patrick C.
        • Wang G.S.
        • Lefebvre D.E.
        • et al.
        Promotion of autoimmune diabetes by cereal diet in the presence or absence of microbes associated with gut immune activation, regulatory imbalance, and altered cathelicidin antimicrobial Peptide.
        Diabetes. 2013; 62: 2036-2047
        • Visser J.T.
        • Bos N.A.
        • Harthoorn L.F.
        • et al.
        Potential mechanisms explaining why hydrolyzed casein-based diets outclass single amino acid-based diets in the prevention of autoimmune diabetes in diabetes-prone BB rats.
        Diabetes Metab Res Rev. 2012; 28: 505-513
        • Visser J.T.
        • Lammers K.
        • Hoogendijk A.
        • et al.
        Restoration of impaired intestinal barrier function by the hydrolysed casein diet contributes to the prevention of type 1 diabetes in the diabetes-prone BioBreeding rat.
        Diabetologia. 2010; 53: 2621-2628
        • Watts T.
        • Berti I.
        • Sapone A.
        • et al.
        Role of the intestinal tight junction modulator zonulin in the pathogenesis of type I diabetes in BB diabetic-prone rats.
        Proc Natl Acad Sci U S A. 2005; 102: 2916-2921
        • Chen Z.
        • Barbi J.
        • Bu S.
        • et al.
        The ubiquitin ligase Stub1 negatively modulates regulatory T cell suppressive activity by promoting degradation of the transcription factor Foxp3.
        Immunity. 2013; 39: 272-285
        • van Loosdregt J.
        • Fleskens V.
        • Fu J.
        • et al.
        Stabilization of the transcription factor Foxp3 by the deubiquitinase USP7 increases Treg-cell-suppressive capacity.
        Immunity. 2013; 39: 259-271
        • Theoharides T.C.
        • Wang L.
        • Pang X.
        • et al.
        Cloning and cellular localization of the rat mast cell 78-kDa protein phosphorylated in response to the mast cell “stabilizer” cromolyn.
        J Pharmacol Exp Ther. 2000; 294: 810-821
        • Malfait A.M.
        • Malik A.S.
        • Marinova-Mutafchieva L.
        • Butler D.M.
        • Maini R.N.
        • Feldmann M.
        The beta2-adrenergic agonist salbutamol is a potent suppressor of established collagen-induced arthritis: mechanisms of action.
        J Immunol. 1999; 162: 6278-6283
        • Nishii M.
        • Inomata T.
        • Niwano H.
        • et al.
        Beta2-Adrenergic agonists suppress rat autoimmune myocarditis: potential role of beta2-adrenergic stimulants as new therapeutic agents for myocarditis.
        Circulation. 2006; 114: 936-944
        • Kopp E.
        • Ghosh S.
        Inhibition of NF-kappa B by sodium salicylate and aspirin.
        Science. 1994; 265: 956-959
        • Yang C.
        • Jurczyk A.
        • Diiorio P.
        • et al.
        Salicylate prevents virus-induced type 1 diabetes in the BBDR rat.
        PLoS One. 2013; 8: e78050
        • Hara N.
        • Alkanani A.K.
        • Dinarello C.A.
        • Zipris D.
        Histone deacetylase inhibitor suppresses virus-induced proinflammatory responses and type 1 diabetes.
        J Mol Med (Berl). 2014; 92: 93-102
        • Hara N.
        • Alkanani A.K.
        • Dinarello C.A.
        • Zipris D.
        Modulation of virus-induced innate immunity and type 1 diabetes by IL-1 blockade.
        Innate Immun. 2013; 20: 574-584
        • Mastrandrea L.
        • Yu J.
        • Behrens T.
        • et al.
        Etanercept treatment in children with new-onset type 1 diabetes pilot randomized, placebo-controlled, double-blind study.
        Diabetes Care. 2009; 32: 1244-1249
        • Gottlieb P.A.
        • Alkanani A.K.
        • Michels A.W.
        • et al.
        alpha1-Antitrypsin therapy downregulates toll-like receptor-induced IL-1beta 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
        • Wang Y.
        • Xiao Y.
        • Zhong L.
        • et al.
        Increased neutrophil elastase and proteinase 3 and augmented NETosis are closely associated with beta-cell autoimmunity in patients with type 1 diabetes.
        Diabetes. 2014; 63: 4239-4248
        • Janciauskiene S.
        • Larsson S.
        • Larsson P.
        • Virtala R.
        • Jansson L.
        • Stevens T.
        Inhibition of lipopolysaccharide-mediated human monocyte activation, in vitro, by alpha1-antitrypsin.
        Biochem Biophys Res Commun. 2004; 321: 592-600
        • Pott G.B.
        • Chan E.D.
        • Dinarello C.A.
        • Shapiro L.
        Alpha-1-antitrypsin is an endogenous inhibitor of proinflammatory cytokine production in whole blood.
        J Leukoc Biol. 2009; 85: 886-895
        • Badenhoop K.
        • Kahles H.
        • Penna-Martinez M.
        Vitamin D, immune tolerance, and prevention of type 1 diabetes.
        Curr Diab Rep. 2012; 12: 635-642
        • Ferreira G.B.
        • Gysemans C.A.
        • Demengeot J.
        • et al.
        1,25-Dihydroxyvitamin D3 promotes tolerogenic dendritic cells with functional migratory properties in NOD mice.
        J Immunol. 2014; 192: 4210-4220
        • Ataie-Jafari A.
        • Loke S.C.
        • Rahmat A.B.
        • et al.
        A randomized placebo-controlled trial of alphacalcidol on the preservation of beta cell function in children with recent onset type 1 diabetes.
        Clin Nutr. 2013; 32: 911-917
        • Gabbay M.A.
        • Sato M.N.
        • Finazzo C.
        • Duarte A.J.
        • Dib S.A.
        Effect of cholecalciferol as adjunctive therapy with insulin on protective immunologic profile and decline of residual beta-cell function in new-onset type 1 diabetes mellitus.
        Arch Pediatr Adolesc Med. 2012; 166: 601-607
        • Moran A.
        • Bundy B.
        • Becker D.J.
        • et al.
        Interleukin-1 antagonism in type 1 diabetes of recent onset: two multicentre, randomised, double-blind, placebo-controlled trials.
        Lancet. 2013; 381: 1905-1915
      1. Hessner MJ, editor. Serum signature analysis of participants of the Anti-Interleukin-1 in Diabetes Action (AIDA) Trial. Abstracts of American Diabetes Association's 73th annual meeting; 2013; Chicago, IL.