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Home , Autoimmune disease, Type 1 diabetes

14th EFLM Continuous Postgraduate Course in Clinical Chemistry and Laboratory Medicine

Diabetes as autoimmune - manifested T1D is based traditionally on Diabetes type I mellitus typical clinical symptoms: , in- creased thirst, , weakness, hunger, re- current and in severe insulinopenia the Evgenija Homsak patient are prone to diabetic . Impor-

Department for Laboratory Diagnostics, University Clinical tant diagnostic parameters are also for T1D char- Centre Maribor, Maribor, Slovenia acteristic HLA gene and especially different auto- against of β cells, which could Corresponding author: evgenija .homsak@ukc-mb .si be present several years before clinical manifesta- tion of disease .

Introduction mellitus (T1D), also known as insu- Pathogenesis lin - dependent diabetes mellitus, is a chronic im- T1D is an autoimmune disorder against the β cells mune mediated disease that is characterized by of the , that remain only 10-20% selective loss of producing β cells of the functioning at the time of diagnosis . For T1D is pancreatic islets in genetically susceptible sub- characteristic subclinical prodrome of variable du- jects . The majority (95%) of cases are attributable ration, as the pathogenetic process begins years to an autoimmune-mediated destruction of β cells before the clinical onset, when the tolerance to (type 1a) while a small minority (5%) of cases re- self-autoantigens is lost (5) . The whole process and sults from an idiopathic destruction or failure of β factors that contribute to and influence the de- cells (type 1b) (1) . T1D is observed in approximate- struction of the β cells is still not known . Still limit- ly 5-10% of diabetes mellitus patient . It may be ed current knowledge of pathogenesis of T1D as present at any age and with equal affection of is based on several impor- both sexes . It appears most typically in early life tant known facts, which have been gained with a peak around the puberty, but one-fourth of through several studies, mostly using animal mod- cases are diagnosed in adults . T1D remains the els and confirmed by human clinical trials . This most common form of diabetes in childhood, ac- process occurs in genetically susceptible subjects, counting for approximately two-thirds of new di- is probably triggered by one or more environmen- agnoses of diabetes in patients ≤19 years of age in tal agents, and usually progresses over many the United States, despite the increasing rate of months or years during which the subject is . The incidence of T1D varies 50- asymptomatic and euglycemic . Important genetic 100 fold around the world, with the highest rates predisposition in the presence of not yet defined in northern Europe, with 57 4. cases/100 0. 00 per triggers and modulators from the environment year in and with relatively low incidence of could influence on modulation of 0 6. /100 0. 00 in China (2) . The incidence of child- to lose the tolerance to auto-antigens and results hood T1D is rising rapidly in all population, espe- with several autoimmune reactions, local inflam- cially in the age under 5 years, that suggests a mation (), specific (LyT) and strong environmental contribution . Lately, (LyB) responses, production, and cell through several studies, there are strong efforts to destructions . The proposed mechanism of autoim- understand and explain pathogenesis and find mune process start with presenta- the new therapeutic options of the disease ac- tion of self antigens on presenting cells cording to potential auto-antigens (insulin) and (dendritic, LyB, ), that after releasing different environmental factors, as an important (IL)-12 activate LyT (CD4 T) that produce key in the development of T1D . But the role of spe- important key INF-γ . They inhibit Th2 cy- cific factors such as viruses or ingested food (milk) tokine production, enhance production of toxic remains controversial (3,4) . Diagnosis of clinical cytokine (IL-β, TNF-α) and free radical by mac-

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rophage, and activate cytotoxic CD8T cells that af- ulation is important for predicting disease, accura- fects the β cells . Important connection between cy of diagnosis, prognosis and treatment . LyT and LyB causes activation of LyB for produc- LyT and LyB involvement: and in- tion of auto-antibodies . Auto-antibodies, several volvement of LyT is further supported with the , cytotoxic CD8T cells with releasing per- presence of specific LyT infiltrates within inflamed forine, granzymes or by Fas-mediated islets of of patient with T1D, according to affect and progressively destroy the β cells . Addi- Imagawa and co-workers, who found close corre- tionally local production attracts auto- lation between serological and histological mark- reactive lymphocytes that potentiate the destruc- ers and histological evidence of cellular autoim- tive autoimmune process . (4,5,6) In pathogenesis munity (10) . Insulitis as autoimmune inflammation of T1D we could find some similarities with other could be present years before is autoimmune , like celiac disease; the com- evident . Ly B cells also serve as antigen presenting mon genetic susceptibility, unknown hypothetical cells and as producing cells (6) . trigger from environment, infection, driving auto- Both Ly as important actors of disease could be antigen, autoantibodies and outcome (1/5 of with target of the future therapeutic options . HLA conferred susceptibility progresses to clinical disease) . Autoantibodies: There are five disease related autoantibodies: islet cell antibodies (ICA), insulin Genetics: Disease susceptibility is highly associat- autoantibodies (IAA) with epitope on B-chain of ed with the inheritance or presence of certain hu- insulin molecule, autoantibodies against 65-kDa man leukocyte antigen (HLA), which is characteris- isoform of glutamic acid decarboxilase (GAD65), tic for autoimmune diseases . HLA molecules are tyrosine related IA-2 molecule or in- responsible for presentation of (also au- sulinoma associate antigen-2 antibodies (IA-2) and to-antigens) to Ly T cells and are involved in thym- zinc transporter protein (ZnT8) . Presence of auto- ic selection of new generated T cell repertoire antibodies are evident years before clinical onset (central tolerance), to avoid potential autoimmune and are mostly the first sign of autoimmune pro- clones that could be released into the periphery . cess, that will or not progress to T1D . Several stud- Therefore, a defect within the or presence ies confirm their important role in prediction of of specific HLA molecules allows autoimmune T the disease development and appearance accord- cells to escape central tolerance . HLA genes on ing to the detection of different specific autoanti- short arm of chromosome 6p21 3. with alleles DR3 bodies (4,5,11) . Mrena and co-workers in the Finn- and DR4 as well as the associated alleles DQ2 and ish DIPP study observed that presence of positivity DQ8, that are expressed either as DR3DQ2 or for only a single autoantibody specificity for sev- DR4DQ8, are present in more than 90% of individ- uals with T1D (7) . Remain 10% of T1D might have eral years represents in most cases harmless non- influence of 20 non-HLA genes . Among them are progresive β cell autoimmunity, whereas the pres- important polymorphisms on insulin locus on ence of two or more autoantibodies reflects a pro- chromosome 11p5,5 (PTPN22 and INS VNTR) that gressive process (10) . But their direct pathogenetic contributes approximately 10% to the familial ag- role is controversial, since transfer of autoantibod- gregation of disease (8) . As with HLA, peripheral T ies, using serum of diabetic humans, alone did not cell repertoires may be significantly influenced by reconstitute disease and that pro- polymorphisms in the insulin gene affecting thy- vides little therapeutic benefit (6,12) . mocyte selection . Recent studies identifies auto- Environment factors as a triggers and drivers immune disease associated polymorphisms of T of disease: There is still unexplained cause of ini- cell regulatory gene CTLA-4 (chromosome 2q22), tiation of the autoimmune process and why the that reduce the efficiency of regulatory function of auto-antigens become auto-antigenic . The factors LyT4CD4 cells (9) . Understanding the genetics of that control progression from insulitis (inflamma- T1D as well the determination of susceptible pop- tion of the β cells) to diabetes remain largely un-

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known . Understanding this may provide new op- Thus, genetic markers for T1D are present from portunities for preventing disease among popula- birth, immune markers are detectable after the tion with high risk for developing T1D or halt pro- onset of the autoimmune process, and metabolic gression of the β cells lost . markers can be detected with sensitive tests once There are recently several approaches for pre- enough β cell damage has occurred, but before venting studies that might contribute to knowl- the onset of symptomatic hyperglycemia . This edge of disease process . The lack of complete long latent period is a reflection of the large num- concordance among monozygotic twins (only 20- ber of functioning β cells that must be lost before 40%) indicates that both genetic and environ- hyperglycemia occurs . mental factors contribute to the pathogenesis of T1D . There are several environmental candidates that might trigger and modulate this autoim- New therapeutic options mune process: early introduction of milk food The complete puzzle of pathogenetic process of (bovine insulin, milk casein), entero-viruses (rubel- T1D, with known all (f)actors, will give us the op- la, coxsackie), infection, . But unfortu- portunity for new therapeutic options . Recent nately resent studies gave us controversial results studies are concern on immune therapy at three and have not been able yet to confirm their une- different stages . Primary prevention is treatment quivocal role . And there are also several autoanti- of individuals at increased genetic risk, without gens as trigger candidates: insulin, GAD65, which known presence of autoantibodies . There were could represent the potential future therapeutic and still are several ongoing studies that try to find target . (4,5,6) out probable environment factors (nonautoanti- gens) and autoantigens as well, that could as ther- apeutic agent reduce T1D incidence in genetically Diagnosis predisposed infants (hydrolyzed casein milk for- The presence of autoantibodies confirms the T1D . mula, Vitamin D, insulin) . Secondary prevention is But they are also capable to identify insulin-requir- targeted at individuals with persistent islet au- ing older patients who are initially diagnosed with toantibodies . Ongoing trials involve non-autoanti- type 2 diabetes . They typically have GAD65 or IA- gen and autoantigen specific therapies (Bacillus 2 . These adult patients have a form of latent auto- Calmette-Guerin vaccine, anti-CD3 monoclonal immune diabetes in adult (LADA) or slow progres- antibodies, oral and nasal insulin, recombinant sive insulin dependent diabetes mellitus (SPIDDM) GAD65) . Trial interventions at onset of T1D also in- (6) . They can have pronounced hyperglycemia and cluded non- and autoantigen approaches (proin- after therapy with oral hypoglycemic agents for suline ) . According to current results, pri- several months or years, they may become insulin mary prevention studies are the major goal in the dependent . future as would aim to induce immunological tol- Diagnosis of T1D is still based on typical clinical erance to islet autoantigens . Unfortunately com- symptoms, as the consequences of the end stage pleted secondary prevention and intervention tri- of progressed disease . Determination and moni- als show little promise of achieving the preserva- toring of levels by measuring concentra- tion of β cell function . (5) tion of glucose, glycosylated haemoglobin There are, as already used and as a future direction (HbA1c), , according to ADA and WHO for managing the onset T1D disease, new ap- criteria, is important . But promising screening proaches of different alternative source of islet marker for general population would be genetics cells: as pancreas transplant, islet cell transplant, and autoantibodies that could define the risk pop- xenogenic islet cells (humanized pig islet cells), ex- ulation for possible preventing treatment in the pansion and trans-differentiation of pancreatic future . duct cells, fetal pancreatic stem cells and β cell

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precursors, embryonic stem cells, and engineering diagnosed . Both populations need reasonable other cells to produce insulin (duodenal K cells, treatment and possible prevention steps as well to hepatocytes, pituitary cells have been successfully prevent the disease progress to the end stage . Im- transfected) . (6) portance of understanding the complete patho- genic process of T1D is very important not only for diagnoses approaches, but also for prediction and probable prevention of disease in genetic suscepti- Conclusion ble or general population . According to these Diagnosis of T1D is no longer the matter of only knowledge there would be the possibility for crea- young population, despite the incidence in early tion and developing the new therapeutic approach- childhood rising in world population . The recogni- es that will help manage the disease on several tion of LADA type is becoming important also for points of its development, especially to prevent islet the adult patients, who have been previously not autoimmunity or halt progressive β cell destruction .

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