Immunological Mechanisms of Diabetes Flashcards
What causes T2D in general?
chronic inflammation in both adipose tissue and pancreas both genetic and lifestyle factors contribute to it
associated with obesity
In a normal person, what immunological things does insulin do?
promotes release of IL1Ra (anti-inflammatory)
inhibits IL-1beta (inflammatory)
How does obesity contribute to T2DM?
characterized by chronic activation of inflammatory pathways –> inflammation causally linked to insulin resistance
What inflammatory mediators are present in chronic obesity?
M1 macrophages
Th1 cells
CTLs
Neutrophils
What immune mediators that are anti-inflammatory are predominant in lean people?
M2 macrophages
Treg cells
Th2 cells
eosinophils
What Free fatty acids predominate in T2D pts?
Normal, lean ppl?
long and medium-chain FAs = bad
short-chain FAs = good
How are M1 macrophages activated in T2D ppl?
LPS IFN-gamma –> M1 –> TNFalpha, IL-1beta, IL-6, resistin, NO, etc –> insulin resistant
How are M2 macrophages acitvated and what do they do to lean ppl?
IL-4, IL-3 –> M2 –> IL-10 –> promotes insulin sensitivity via short chain FFAs, IL-13 and IL-4
What type of fat is bad in obese people and what does it do?
visceral fat
induces inflammatory cascades –> leukocyte-endothelial interaction –> coupled angiogenesis and adipogenesis and adipocyte dell death
What is MCP-1?
factor that helps recruit and activate macrophages
seen in obesity
What things contribute to beta cell death in T2D?
high serum IL-1beta
low serum IL-1Ra
glucotoxicity
lipotoxicity
What is the significance of palmitic acid?
long-chain FFA released by obese adipose tissue –> TLR4/MyD88 –> chemokines –> m1 macrophages recruited and inflammation ensues –> beta cell dysfunction
What are the genetics of T2D?
multifactorial disease related to 52 common risk variants
40% of dev if 1 parent has T2D
70% of developing if 2 parents have it
How is pollution related to T2D?
chronic exposure to organic land pollutants –> disturbs glucose metabolism and induces insulin resistance
chronic exposure to traffic-related pollutants (particulate matter and NO2) –> assoc w/ higher rates of T2D
What is the link btw gut microflora and insulin resistance?
increase in the firmicutes/bacteroidetes ratio linked to insulin resistance
recent studies w/ fecal transplants show butryate-producing intestial bacteria protect against T2D
What is the immune cause of T1D?
autoauntibodies that attack beta islet cells
cytotoxic T cells also attack insulin
Type IV hypersensitivity
When was insulin first used to treat a Type 1 diabetic?
Jan 11, 1922
nobel prize to Frederick Grant Banting and John James Richard Macleod
What is insulitis?
infiltration of islets by mononuclear cells and CD8 T cells
What are some phys contributions from the bone marrow and thymus toward T1D?
defective thymic selection
potential for self-Ags presented in incorrect register of MHC binding
Aire and VNTR expression in thymus
defects in lymphocyte precursors
genetic susceptibility
What are some phys contributions of beta cells toward T1D? (7)
expression of class 1 MHC
production of cytokines and chemokines
free-radical sensitivity
ptential to present high quantities of self-Ag via MHC II
susceptibility to viral tropism and inability to resolve inflammation
limited replication potential
rate of immune destruction influenced by metabolic activity
What is the concordance rate for T1D in monozygotic twins?
30-50% = suggests non-genetic influences
What are some key environmental factors being studied in T1D?
incidence is increasing abt 3% each year
evidence linking the environment ant T1D in himans is indirect
350 fold variation in indicence of T1D in different countries
What are the most significant pre and post-natal triggers for T1D?
pre: maternal enteroviral infection, older maternal age
post: enteroviral infection, infant weight gain, serious life events
What are the main promoters of progression of T1D?
overweight or increased height velocity
puberty
insulin resistance
psychological stress
What are the main pre and post-natal protective factors against T1D?
high vitamin D intake in pregnancy
breastfeeding until 4 mos
higher omega-3 fatty acids
*no known factors slowing progression
What is the role of infections in T1D development?
bacteria may act as adjuvants for the immune response
virues have been implicated in T1D –> may act against beta cells thru cytotoxicity or triggering autoimmunity via molecular mimicry
What are the viruses linked to T1D?
enteroviruses
mumps
rubella
cytomegalovirus
retroviruses
What is the link btw milk and T1D?
early exposure to cow milk in life may contribute to T1D
cow’s milk has less insulin –> immune tolerance to insulin might get compromised
*inconsistency in results
How is gluten linked to T1D?
risk of T1D is higher in pt’s w/ gluten-sensitive enteropathy
high prevalence of celiac disease in diabetics
butyrate-producing microflora scarce in T1D pts
What genes determine T1D susceptibility?
multifactorial autoimmune disease
T1D pts and their relatives are at increased risk for other autoimmune diseases
may be no specific diabetes gene, but only wrong combos of normal polymorphisms
What are the most significant genes associated with T1D?
insulin gene = Ag for autoimmune response
AIRE = regulator of insulin gene expression in the thymus
HLA region = presentation of insulin Ags for CD8 t cells
CTLA-4 gene = regulation of autoimmune response
How is central tolerance established?
when double positive CD4/CD8 T cell binds self peptides presented by thymic epithelial cells –> apoptosis signal
What is AIRE?
autoimmune regulator transcription factor
controls thymic expression and presentation of self-molecules (insulin) to do central tolerance
malfunctioning –> lower levels of insulin mRNA in thymus
bad tolerization to islet cell molecules–> autoreactive T cells
How is the insulin gene (IDDM2) related to T1D?
variable number of tandem repeats in promoter region = class I, II, and III polymorphisms
class I = lowest number of repeats –> assoc w/ lower insulin mRNA synthesis –> low Ag presentation in thymus –> failure of deleting self-reactive CD8 T cells
What are the high risk HLA alleles for T1D?
DQ2/DQ8 and DR3/DR4 = high risk
DQ2/DQ8 in 90% of ppl with T1D
DR3/DR4 = most common in kids diagnosed before age 5 (50%)
What are the HLA class II negative and protective factors to know?
HLA class II molecules that lack Asp57 of beta chain often found in T1D individuals
DR2/DQ6 = dominant protection
What is the link btw CTLA-4 and T1D?
CTLA4 = susceptibility locus assoc w/ T1D
encodes glycoprotein that is an inhibitory CD28 homologue and binds B7 protein
may counter-regulate CD28-dependent TCR activation of T cells –> activates apoptosis of self-reactive ones
What does CTLA4 do on Teff or Treg cells?
binds to B7 or APCs or removes them –> reduced B7 costimulation –> inhibition of T cell activation
*this is good if self-reactive
How does beta cell death occur?
DCs are always present in islets and can take up beta cell Ag –> proinflammatory cytokines my activate this self presentation to T cells
can be due to viral infection or stress
T cells then are activated in LNs that drain pancreas –> proliferate to cause organ-spec inflammation
How do T helper cells contribute to T1D?
Th17 and Th1 –> proinflammatory cytokines
What type of local APCs are important in T1D pathogenesis?
local APCs that can present self Ag on class II MHc
secrete IL-12
How is IFN-gamma important in t1D?
released by Self-reactive CD4 T cells
inhibits Th2 cytokine production (IL-4, IL-5, IL-10)
enhances IL-1beta and TNF-alpha and free radical production
What is interesting about T1D and asthma?
T1D = Th1 dominant disease
Asthma = Th2 dominant
you would think you would have one or the other, but high prevalence of asthma in T1 diabetics
bc failure of FOXP3 tregs to work
How do Tregs stop autoimmunity?
suppress APCs directly through cell-cell interactions
release IL-10 and TGF-beta
might act directly on Teffs
consume IL-2 –> deprives other T cells of it
How might gut bacteria be linked to autoimmunity?
diet, infections, antibiotics –> might alter bacteriodetes/firmicutes ration –> modifies balance of Treg: Th1/th17 ratio
What is the controversy of the role of Auto-Abs?
might just affect the time course of development
plasmapheresis doesn’t help
if you transfer blood serum from T1D animal to an unaffected animal –> no result in t1d
but if you transplant T cells from T1D animal –> induces T1D in another
What is the diagnostic value of autoantibodies in T1D pts?
one Ab = 5-10% 5 year risk
2 Abs = 40% 5 year risk
3 Abs = 60% 5 year risk
What is CD25?
IL-2 receptor
Where does central B cell tolerance occur?
in the bone marrow
can do receptor editing, apoptosis, or anergy
What is the regulatory receptor on B cells?
Fc receptor that recognizes IgG or IgM
How does obesity affect glucose uptake?
makes it much less efficient
not using muscles is a major component
How does obesity itself initiate inflammation?
adipocytes become engorged with lipids –> pinch off the blood supply –> can cause small areas of necrosis –> inflammation
What does TNF do?
increases vascular permeability
associated w/ M1 macrophages
How is IL-6 related to T2D?
initiates inflammatory response
role in T2D and insulin resistance is well documented
get inflammation/CRP in liver
stimulates GLP-1 and lipolysis
Where does palmitate bind?
TLR4 on adipocytes
(TLR4 present on macrophages and adipocytes)
What cytokines do Th2, Tregs, and M2 macrophages promote and are seen in lean people?
IL-4
IL-10
IL-13
What type of hypersensitivity is T1D?
type IV
T-cell mediated
If both parents have t1D, what is a child’s risk of getting it?
30%
What are autoantibodies in T1D to?
islet cell antigens (ICAs):
GAD65
IA-2
IAA (insulin autoantibodies)
What cytokine is associated w/ activation of auto-Ag specific CD8 T cells?
IL-2
