Immune Mechanisms of Diabetes Flashcards
T2D and obesity behavioral and environmental triggers
LO1
Microbiome
- delivery mode
- antibiotic usage
- diet: processed foods
Diet
- total calorie intake
- macronutrients
- micronutrients
- vitamins
- high fat diet
Energy Expenditure
- basal metabolism
- exercise
- sedentary behavior
- ambient temperature
Early life influences
- maternal disease
- placental function
- maternal nutrition
- postnatal growth
Other
- particulate matter
- NO2
- pesticide
- sleep debt
- endocrine disruptors
- chronic inflammation
T2D and obesity genetic risk factors
LO1
- ethnicity: greater risk for african american, hispanic, and native american
- Pima Native Americans: 10 fold higher prevalence than general population
- offspring with 1 T2D parent: 40% risk
- offspring with 2 T2D parents: 70% risk
- monozygotic twins: 34%
- dizygotic twins: 16%
What are the differences in LEAN adipose tissue vs OBESE adipose tissue?
LO2
LEAN: more Treg cells, Th2 cells, NK T cells, M2 macrophages, and eosinophils –> more IL-4, IL-13, IL-10, and adiponectin (all antiinflammatory)
OBESE: more Th1 cells, M1 macrophages, CD8+ T cells, B cells, dendritic cells, mast cells, and neutrophils due to increased migration from blood –> more leptin, elastase, IFN gamma, TNF alpha, IL1beta, and IL-6 (all inflammatory)
What is the effect of IL-6 in T2D?
LO3
acute inflammatory response; role in adipose inflammation and insulin resistance well documented
What is the effect of IL-6 on the pancreas?
LO3
increase GLP-1
What is the effect of IL-6 on the intestine?
LO3
increase GLP-1
What is the effect of IL-6 on adipose tissue?
LO3
increase lipolysis and AMPK
What is the effect of IL-6 on muscle?
LO3
increase GLUT4 translocation and lipolysis
What is the effect of IL-6 on the liver?
LO3
increase acute-phase response, SOCS-3, and insulin resistance
What does use of IL-6 in clinical settings increase the patient’s risk for?
LO3
risk of inflammation, cancer, and rheumatoid arthritis
What is the process for FFA induction of adipose inflammation?
LO2
- long chain FFA palmitate is a ligand for TLR4 present on adipocytes
- receptor/ligand binding leads to pro-inflammatory cytokine and chemokine production
- recruitment and differentiation of M1 macrophages
- inflammatory state leads to sustained beta cell dysfunction
What are the innate immune responses that increase in obesity?
LO3
M1 macrophages
Mast cells
What are the innate immune responses that decrease in obesity?
LO3
M2 macrophages
eosinophils
What are the adaptive immune responses that increase in obesity?
LO3
B2 cells
CD8+ T cells
INF gamma Th1 cells
What are the adaptive immune responses that decrease in obesity?
LO3
Treg
What cytokines increase in obesity?
LO3
TNF alpha
IFN gamma
IgG2c antibodies
Th1 response
What cytokines decrease in obesity?
LO3
IL-4
IL-10
IL-13
Th2 response
What are histological changes in T2D?
LO3
islet hyalinization: central hyaline deposits replace dead beta cells in late stages
Describe T1D
LO4
- true autoimmunity
- T cell mediated –> Type IV hypersensitivity
- T cell mediated destruction of of beta cells resulting in insulin deficiency
- autoantibody production used as markers of beta-cell destruction
- strong HLA associations
- prone to ketoacidosis
- insulitis: lymphocytic infiltrate within islets
What is insulitis?
LO4
lymphocytic infiltrate within islets
What are complications of T1D?
LO4
- kidney failure
- cardiovascular disease
- diabetic retinopathy
- foot ulcers
Describe the mechanism of T1D
LO4
- genetic predisposition and environmental factors lead to autoantigen formation on insulin-producing beta cells and circulate in the blood stream and lymphatics.
- Processing and presentation of autoantigen by antigen presenting cells.
- Activation of Th1 lymphocytes –> IFN gamma and IL-2
- IFN gamma –> activation of macrophages with release of IL-1 and TNF alpha
- IL-2 –> activation of autoantigen specific T cytotoxic CD8 cells
- Activation of Th2 lymphocytes –> IL-4 –> activation of B lymphocytes to produce islet autoantibodies and antiGAD65 antibodies
- all lead to destruction of beta cells with decreased insulin secretion
Genetics of T1D: familial clustering and concordance
LO5
- mother: 2-3% lifetime risk
- father: 5-6% lifetime risk
- both: 30% lifetime risk
- sibling: 6% lifetime risk
- general public: 0.4% risk
- monozygotic twins: 30-50%
- dizygotic twins: 10%
patients and relatives at increased risk for other autoimmune diseases
What are genes associated with T1D?
LO5
HLA alleles DQ2/DQ8 and DR3/DR4
INS-insulin gene
AIRE
CTLA-4
What are the high risk HLA alles for T1D?
-chromosome
LO5c
- chromosome 6
- DQ2/DQ8 and DR3/DR4
- DQ2/DQ8 halotypes DR3DQ2 and DR4DQ8 found in >90%
- heterogenous genotypes DR3/DR4 are most common in children diagnosed prior to age 5
- HLA class II lacking Asp57 of beta chain are common amongst T1D
What halotype confers protection against T1D?
LO5c
HLA Class II halotype DR2/DQ6
Role of AIRE mutation in T1D
LO5e
- AIRE expression and presentation of insulin in thymus to developing T cells is critical to protecting against development of T1D
- AIRE is necessary to express self antigen (for insulin) in the thymus, where self proteins would not normally be expressed
Insulin gene’s role in T1D
LO5d
chromosome 11 IDDM2
- VNTR in promotor region
- relative increase in risk 2 fold with two class I alleles –> lower insulin mRNA synthesis
- reduction in tolerance to insulin and precursors due to low presentation
CTLA-4 gene role in T1D
LO5f
- chromosome 2 IDDM12
- defect in CTLA-4 expression on Tregs and activated T cells decreases ability to down regulate immune response and maintain tolerance
What are perinatal and intrauterine environmental risk factors for T1D?
LO5
- decreased by transplacental transmission of antibodies
- increased by cesarean deliveries
- increased by higher birthweight
- interplay between maternal age and birth order
What are postnatal environmental risk factors for T1D?
LO5
- decreased by breastfeeding
- increased by cow milk exposure
- decreased by vitamin D intake
- decreased by childhood infections
- increased by obesity
- viral infections
- other dietary factors
What is the difference between breast milk and cow’s milk?
LO5b
breast milk contains more insulin –> exposure so that the body does not destroy insulin
What is the relationship between breast feeding and T1D?
LO5b
inverse correlation between decreased breast-feeding and increased T1D
What are dietary risk factors for T1D?
LO5a
- gluten is a potent diabetogen –> T1D risk increased in CD patients
- vitamin D deficiency –> increased risk of T1D if living with little sunlight
How do viruses increase the risk of T1D?
- mechanisms
- viruses
LO5
- direct cytotoxicity
- molecular mimicry –> cells that destroy infection also destroy beta cells
- mumps
- rubela
- cytomegalovirus
- enteroviruses
- retroviruses
What chemicals cause direct destruction of beta cells?
LO5
- N-nitroso compounds
- Alloxan
- compounds in smoked meat/foods
What compounds from streptomyces are cytotoxic to beta cells?
LO5
- streptozocin
- bafilomycin A1
What is the processing, presentation, and activation process for T1D?
LO6b
- DC present antibodies of damaged beta cell to Th1 and CD8+ T cells
- CD8+ cells go to pancreas and destroy beta cells by perforin and granzymes to induce apoptosis (main mechanism)
- through cross presentation Th1 cells interact with B cells to produce autoantibodies
What are the roles of autoantibodies in T1D?
LO6a
Islet Cell Antigens (ICAs):
glutamic acid decarboxylase GAD65
insulinoma antigen-2 IA-2
insulin auto-antibodies IAA
presence confirms diagnosis of T1D
(presence of 2 or more is highly predictive of future T1D - 5 year risk)
DO NOT INFLUENCE PATHOGENESIS
What is the common pathway for asthma and T1D?
LO7
Tregs
How does T1D influence Tregs?
LO7
leads to change in Treg population/effector function, can become unstable and lose Foxp3 expression –> Tregs now express IFN gamma and IL-17
What would CTLA-4 do in treatment of T1D?
LO7
bind to IL-2 to inhibit inflammation
