Diabetes mellitus tipe 1 merupakan gangguan metabolisme glukosa yang disebabkan oleh kerusakan sel β pankreas akibat proses autoimun atau idiopatik sehingga produksi insulin berkurang atau terhenti. Kehadiran autoantibodi seperti GAD, IA2, IAA, dan ZnT8 membantu konfirmasi diagnosis diabetes mellitus tipe 1 sebagai penyakit autoimun.
2. DM tipe-1 adalah kelainan sistemik akibat terjadinya gangguan metabolisme
glukosa yang ditandai oleh hiperglikemia kronik. Keadaan ini disebabkan oleh
kerusakan sel β pankreas baik oleh proses autoimun maupun idiopatik
sehingga produksi insulin berkurang bahkan terhenti. Sekresi insulin yang
rendah mengakibatkan gangguan pada metabolisme karbohidrat, lemak, dan
protein.
Autoantibodi yang berkaitan dengan diabetes adalah glutamicacid
decarboxylase 65 autoantibodies (GAD); tyrosine phosphataselike insulinoma
antigen 2 (IA2); insulin autoantibodies (IAA); dan β-cellspecifi c zinc
transporter 8 autoantibodies (ZnT8). Ditemukannya satu atau lebih dari
autoantibodi ini membantu konfi rmasi diagnosis DM tipe-1
DEFINISI
4. Selama beberapa dekade, diabetes mellitus tipe 1 (T1DM)
diyakini sebagai penyakit autoimun yang diperantarai sel T
Hubungan antara sistem kekebalan tubuh dan T1DM pertama
kali diamati pada tahun 1973, ketika antigen HLA ditemukan
terkait dengan insulin-dependent diabe-
tes mellitus
antigen HLA menyumbang hingga 50% dari risiko genetik T1DM
(khususnya lokus HLA kelas II), yang menunjukkan bahwa
presentasi selektif peptide autoantigen spesifik terlibat dalam
patogenesis T1DM
MHC kelas I dapat berikatan dengan sel T sitotoksik, sedangkan MHC kelas II dapat berikatan dengan sel limfosit T helper. Selain itu terdapat perbedaan lainnya, yaitu molekul MHC kelas II ini banyak terdapat pada sel-sel APC seperti sel dendritik dan makrofag
Interactions between innate and adaptive immune cell types during the development of type 1 diabetes. In the pancreas, conventional dendritic cells (cDCs) initiate T1D by capturing and processing β-cell antigens released after β-cell death. This process can be a consequence of a physiological apoptosis or subsequent to viral infection. In the latter case, antiviral responses mediated by iNKT cells and plasmacytoid dendritic cells (pDCs) crossplay can efficiently inhibit viral replication, preventing tissue damage and T1D. Self-antigen-loaded cDCs migrate to the draining lymph nodes and prime β-cell antigen-specific T cells. Macrophages present in both the pancreas and the lymph nodes can promote the activation of cDCs and T cells through pro-inflammatory cytokine secretion. B cells are present in the pancreas and lymph nodes where they could present β-cell antigens to islet-specific T cells and secrete auto-antibodies. Consequent to all these events, activated macrophages, diabetogenic T cells and NK cells present in the pancreas can destroy β-cells through various effector molecules. Conversely, innate immune cells can promote several regulatory mechanisms. According to the cytokine milieu and/or the stimuli that they received (such as viral infection) DCs can expand regulatory T (Treg) cells through the production of IDO, IL-10 and TGF-β. iNKT cells can promote the recruitment and the tolerogenic functions of cDCs and pDCs. Lastly, β-cells themselves can prevent their destruction by inhibiting diabetogenic T cells via PD-L1/PD-1 pathway. The dual functions of innate immune cells can promote or inhibit the development of T1D. Abbreviations: Ag, antigen; APC, antigen presenting cell; cDC, conventional dendritic cell; ICOS, inducible T cell co-stimulator; IDO, indoleamine 2,3-dioxygenase; IFN-γ, interferon γ; IL-, interleukin-; Grz/pfr, granzyme/perforin; Mf, macrophage; NK, natural killer cell, NKT, natural killer T cell; NO, nitric oxide; pDC, plasmacytoid dendritic cell; PD-L1, programmed cell death ligand 1; Teff, effector T cell; TGF-β, tumor growth factor β; TNF-α, tumor necrosis factor α; Treg, regulatory T cell.
Timelines for type 1 diabetes.A: model for linear beta-cell mass decay, as originally proposed by Eisenbarth (124). In the contextof genetic predisposition, an environmental trigger induces islet autoimmunity and beta-cell death leading to a sequence of prediabetic stagesand eventually clinical onset.B: it is widely acknowledged that the time window between initiation of autoimmunity and clinical onset is highlyvariable. Chatenoud and Bluestone (89) proposed some scenarios leading to the observed variability. Versatile interaction between geneticfactors and environmental challenges such as viral infections likely contribute to the fluctuations in beta-cell mass before onset.C: we haveintroduced the concept of T1D as a relapsing-remitting disease, dependent on cyclical disruption and restoration of the balance betweeneffector and Tregs and potentially counteracted by beta-cell proliferation (462). This model also provides a mechanistic rationale for itsvariable course.D: the fertile field hypothesis postulates the existence of a time window following viral infection during which at-riskindividuals may develop autoimmunity (463). Infection with a certain virus would temporarily create a fertile field. Whereas initial exposureto virus (e.g., via APC presentation; purple cells) will generate a normal antiviral response (green T cells), subsequent generation ofautoreactive cells (red T cells) may occur via cross-reactivity with viral antigens (molecular mimicry) or direct recognition of autoantigens(bystander activation). Bystander activation is thought to be mediated by APC that process and present self-antigens, with the potential toraise autoreactive T cells only in the presence of viral “danger” signals.
how T1D might arise. This figure represents the beta-cell mass or function (represented by the orange line) as well as the differentimmunological phases (columns with alphabetized tabs on top) that occur in the relevant anatomical sites (rows with numerical tabs on the right).Specific events will be referred to via alphanumerical coordinates in the following explanation. Once the orange line of beta-cell function falls intothe red zone, the individual is clinically diagnosed with type 1 diabetes. A complicated series of events precedes this and remains largely unnoticed.Initially, an unfortunate concurrence of genetic susceptibility (a1) and an environmental trigger (a2) sets an individual up for developing diabetesby causing two events. In the pancreas, beta-cells upregulate interferon (IFN)-(b3) and subsequently MHC class I (c3). This exposes the beta-cellsto attack by autoreactive CD8 T cells with specificity for antigens in the pancreas (c3). Consequently, the released beta-cell antigens are picked upby resident antigen-presenting cells (APC) (c3) and transferred to the pancreas-draining lymph node (LN) (c2). Meanwhile in the periphery (c1), theenvironmental trigger has caused a metabolomic switch creating a proinflammatory environment that favors effector T-cell responses over Tregfunction. Beta-cell antigens presented in this proinflammatory context and with CD4 help (c2) initiate conversion of B cells into plasma cells (d2)and the appearance of insulin autoantibodies (seroconversion) (d1). Also, autoreactive CD8 T cells are stimulated to proliferate (d2) and migrateinto the pancreas (d3). The stress induced by this second wave of beta-cell killing (d3), which involves perforin, IFN-, and tumor necrosis factor(TNF)-, causes some beta-cells to halt insulin production (pseudoatrophy). The killing also causes the release of new beta-cell antigens that arepicked up by APCs, including migrated B cells (d3), and get shuttled to the pancreatic LN (d3-d2). This engages new specificities of CD4 and CD8T cells (e2) and B cells (e1) in a process called epitope spreading. A subsequent wave of beta-cell killing is therefore more severe and usually resultsin severe depletion of beta-cell function and mass (e3). Surprisingly, the autoimmune inflammation can also stimulate some beta-cell proliferation(f3), so that the beta-cell mass temporarily resurrects. Also, Tregs can sometimes overpower and dampen the effector response (f3). The fluctuationbetween destructive autoreactive responses and the alleviation by immune regulation and beta-cell proliferation possibly creates a nonstoprelapse-remitting profile of beta-cell mass (orange line). Eventually, the autoreactive response wins though, and T1D is diagnosed when only 10 –30%of functional beta-cells remain. The remission after clinically diagnosed diabetes is termed the honeymoon phase (f3), a temporary state of relativeself-sufficient insulin production.
T cell progenitors are made in the bone marrow from hematopoietic stem cells. They migrate to the thymus where central tolerance mechanisms educate them to
self and non-self (negative selection). Regulatory T cells (Tregs) and pathogenic autoreactive T cells may each recognize self antigens but at differing affinities,
which could explain their opposing actions. T cells that survive thymic selection then circulate in the blood and lymph nodes, waiting to encounter their cor-
responding peptide-HLA complex. In T1D, these T cells are specific for b cell proteins such as insulin. If these islet-specific T cells come into contact with their
corresponding epitope displayed by the HLA of an APC, they will become activated in the lymph node, migrate to the islets, and begin the process of b cell
destruction. Tregs represent the suppressive cell primarily responsible for peripheral tolerance and attempt to prevent this process. If the body is unable to curb
this autoimmune attack on the b cells, then insulin deficiency, hyperglycemia, and T1D result. The majority of this process takes place locally in the lymph nodes
and pancreas and has limited the ability for biomarkers in the peripheral blood to accurately reflect disease activity in patients.
