LOGO Type 1 Diabetes- - IDDM Insulin Dependent Diabetes Mellitus TEAM - 窦甍 李德全 李帅 刘惠君 刘晓云 罗黎希

What is IDDM ◇ Factors Inducing IDDM ◇ Immune Mechanism Manifestations & Complications Therapy  IDDM  Insulin  Dependent  Diabetes  Mellitus Contents Type 1 diabetes(T1D), also named IDDM, is one of the most common autoimmune disease, affecting almost 20 million people worldwide.

What is IDDM FactorsSelf Ag changesImmune Response DiseaseBreaking Type 1 Diabetes Or IDDM. NOD Children & Adolescent Insulin-dependent Heredity Virus Infection Environmental Factors Recognition of specific self islet βantigens Effects of immune cells & molecules Breaking of Immune tolerance Autoimmune disease

Factors Inducing IDDM HLA-DQ β57 Asp Neutral AA HLA-DQ α52 Arg Coxsackie B virus Rubella virus Mumps virus Cytomegalovirus Epstein-Barr virus Etc. Chemicals Medicament HeredityVirusEnvironment

Virus Infection Changes of self-Ag into non-self-Ag Changes of host cell immune system function Cross reaction Host cells become target cells Initiate immune response Ab Cytokines Immune tolerance Th1/Th2 Virus & host cell have common Ag

HLA expression β cell Class Ⅰ MHC molecule High expression of Class Ⅰ MHC molecules Abnormal expression of Class Ⅱ MHC molecules Virus infection Environmental influence

Mechanism of IDDM ◇ CD4+ T cells CD8 + T cell Humoral immunity Autoimmune response β cell apoptosis and death

CD4+ T cell response  MHC Ⅱ abnormal expression Host cell turns into APC MHC Ⅱ + Self-Ag Activate CD4+ T cell Apoptosis Fas-FasL pathway Cytokine secretion Th1 IFN-γ TNF-α Macrophage IL-1β TNF-α Th1/Th2 unbalance Th0 Th1

CD4+ T cell related response  Th0 cells mainly differentiate into Th1 cells, causing Th1/Th2 unbalance.  Th1 cells produce IFN-γ& TNF-α, inducing expression of Fas protein on islet βcell, and FasL expression on CTL or macrophage(IL-1β, NO, RNIs).  IFN–γ can activate NK cell,which then hurt the target cells (β cell) with specific Ag.  IL-2 IL-12  Th2 antagonizes Th1 effects.  IL-4 and IL-10 can strongly inhabit Th-1 to produce IFN-γ, which can decrease the level of isletitis and improve β cells to produce insulin, to decrease the morbidity of IDDM

CD8+ T cell response IFN-γ TNF-α - Direct hurt of βcell Perforin - Osmotic lysis Fas-FasL pathway - Apoptosis Granzymes - Apoptosis

  O2O2 NO Co-stimu- latory signals APC Tc Perforin Th 1 IFN  MØ IL-1β TNF  Islet Pancreatic lymph node Th 1 T- and B-cell clonal ex- pansion APC Granzyme Fas FasL RNIs Apoptosis Fas FasL

Humoral Immunity  Insulin – Insulin Ab (IA)  Insulin receptor – Anti-insulin receptor Ab  Islet cell surface Ag (ICA)- Islet cell surface Ab  Glutamate decarboxylase (GAD) – Anti-glutamic acid decarboxylase Ab (GADA)

Relationship CD4+ T cell response CD8+ T cell response Humoral immunity

Further destroy β cells destruction - HSP GM ICA Residual cellsCell lysis More non-self-Ag - More HLA expression of residual β cells More T cells response - More destruction of β cells

Manifestation T1D A B D C Polyuria Polydipsia Polyphagia Ketonuria Glycouria Children Adolescent NOD Emaciation Fatigue Malaise

Complications Acute Complications Acute infection Coma Hypoglycemia Ketoacidosis Non-ketotic hyperosmolar syndrome Lactic acidosis

Complications Chronic Complications Skin infection Alzheimer’s disease Mucosa infection Large blood vessels problem Heart disease (Myocardial infarction) Stroke Small blood vessel problem Diabetic retinopathy (Blindness) Diabetic nephropathy (Albuminuria Kidney Failure ) Diabetic neuropathy Numbness Foot infection

Therapy Subcutaneous injection (Lifetime) Intravenous injection (Emergency) Gene vector Insulin-like substance Transgenic mice model stem cell Islet β cell transplantation Islet-Kidney united transplantation Gene therapyIslet transplantationInsulin therapy

LOGO Dec. 7 th, 2007

Regeneration of β cells