Immunological Mechanisms of Diabetes Flashcards
What was our previous understanding of T2D?
what is our current understanding of T2D
type 1 was only associated with what?
it was… obesity, resistance and hyperinsulinemia caused by insulin resistance.
NOW… beta cell loss, beta cell mass decrease, insulin secretion decreased… caused by resistance and glucotoxicity causes B cell overwork and causes b cell to die.
IN THE PAST: type 1 was only thought to be Beta cell loss, but now type 2 and 1 are!
Biggest change from before and now our present thoughts of T2D?
hyperinsulinemia before
now we think secretion of insulin is decreased
T2D is considered as what disease? in what tissues?
what is it characterized by? early stage vs late stage?
most common complication? after that what happens?
Chronic inflammatory disease in both adipose tissue and the pancreas… obesity associated inflammation
hyperglycemia, insulin resistance, impairment of insulin secretion. (EARLY STAGES = HYPERINSULINEMIA (glucose isn’t going in)… LATER = DECREASED (cells say fuck it)
renal failure –> coronary artery disease (atherosclerosis) –> blindness –> stroke
lean body and normal pancreas and pancreatic cells?
where does glucose go?
what are the levels of FFA in circulation?
what is activated in adipose tissues?
liver?
glucose goes to skeletal muscle, adipose tissue, liver easily (insulin dependent organs)
low
M2 macrophages are found in adipose tissues –> pro inflammatory that make IL-1B + IL-1Ra (IL1 receptor antagonist, which inhibits IL1a and b) which form complexes that prevent IL-1 activating of other cells.
the same kind of process is happening in the liver with alternatively activated kupffer cells
what is associated with insulin resistance?
obesity is characterized by what?
INFLAMMATION
chronic activation of inflammatory pathways.
M2 macrophages are found in the normal adipose cells. what does it do?
what other cells are found?
prevent developing of inflammatory responses –> anti-inflammatory response and tissue repair.
Treg cells
Th2
Eosinophils present
when disease progresses in obesity, what happens to our macrophages?
what other cells are found here during disease progression.
M2-like macrophages become converted into M1 macrophages
Th1 cells
CTLs
Neutrophils
What increases the macrophage presence?
which ones are anti-inflammatory? which are they associated with?
Interferon-gamma
IL-10 (act on all cells). have a lot of antiinflammatory stuff
TGF-Beta
IL-10 does what?
what allows more M2s to form?
what can help convert M2 to M1?
what determines if its m1 or m2?
what is M1 doing to the adipocyte? M2?
prevents generation of M1 macrophages. it doesn’t allow cells to change to M1 (because remember m1 m2 balance is dynamic)
if we have prevailing IL-4 IL-13, it’ll lock our macrophages into M2
but if we have LPS or IFN-gamma, that same M2 can be converted.
if the signal of LPS or IFN-gamma is higher than the blocking mechanism of IL-10, you’ll have M1. depends on the signal!
M1 is making adipocytes insulin resistant (obesity)
M2 is making adipocytes insulin sensitive (lean)
what types of FFAs are found in lean patients?
T2D patients?
what’s happening to have these?
if we have a pt with m1 dominating adipocytes, what are they going to be producing?
short chain free fatty acids
medium and long chain
if you have M1s working, they’re going to form the adipocyte to be producing long and medium chains.
long/medium chain FAs
Chemokines –> recruit stuff
TnFa –> recruit more M1
What are the other pro inflammatory cytokines other than LPS and IFN-gamma
TNFa, IL-1B, IL-6, IL-12 resistin, NO
Th1 and Th2 in accordance to M1 and M2?
what does M1 and M2 produce?
M2 produce IL-10 which inhibit M1 macrophages
M1 produces IFNgamma, TNF, and IFNgamma helps make more M1
Th1 and Th2 are distinguished by what it produces. Th2 produces IL-10 including IL4, IL5, IL13 which help produce more M2.
What is insulin release going to be in an obese patient in the beginning of T2D? how about when diagnosed?
what about serum glucose?
FFA?
IL-1B?
Il-1Ra?
hyper secreted.. this is because it’s starting to freak out that there’s too much glucose in the cell (resistance)
when it is diagnosed you have high serum insulin still present… it hasn’t left because consumption of it has been reduced
you have high serum glucose
high serum FFA because adipocytes are rupturing
high serum IL-1B
low IL-1Ra
What is released in obese adipose tissue? how is it released?
what is it recognized as?
what recognizes it mostly?
cells are ruptured through islet inflammation, and palmitic acid is released (long-chain saturated FFA).. this could be considered as a DAMP!!
they’re recognized by TLR4 (mostly) and TLR2
How does TLR4 recognize palmitic acid?
what happens after it recognizes it?
it recognizes Lipid part of lipid polysaccharide, recognizes palmitic acid.
it changes transcriptional activation to release inflammatory monocytes (precursor for M1)
M1 regulates the influx of immune cells and islet inflammation.
what happens if you have a parent with T2D.. what’s your chance?
what about both parents?
If you have a child and you have type 2 diabetes.. 40% chance.
if both parents have type 2.. their chance is 70%
for T2D
if only genetic.. what do you expect in monozygotic twins?
dizygotic
if it was totally genetic, it should be 100%… but only 34% among monozygotic twins. this means that there is the other 66% is a risk factor from environmental factors
dropping as well.. 16%
Pima indians and T2D?
10x higher prevalence of T2D than the general US population?
what are the behavioral factors of T2D?
what about pollution?
traffic?
sedentary lifestyles and high-fat diets.
chronic exposure to pesticides, herbicides, which disturb glucose metabolism.
chronic exposure to TRAFFIC-related pollutants is associated.. usually diesel particles (Particulate matter (PM) and NO2)
what are the behavioral factors of T2D?
what about pollution?
traffic?
sedentary lifestyles and high-fat diets.
chronic exposure to pesticides, herbicides, which disturb glucose metabolism.
chronic exposure to TRAFFIC-related pollutants is associated.. usually diesel particles (Particulate matter (PM) and NO2)
How is microflora associated with T2D?
what’s the ratio to know? what does it mean?
what about energy harvest?
weight gain associated with increase in Firmicutes/Bacteriodetes ratio.
(so lowering of bacteriodetes essentially)
gut microbiota might facilitate energy harvest (some people are better at burning fuel)
also it’s said it can initiate an inflammatory process.
butyrate-producing intestinal bacteria and T2B?
how do we know it’s part of it?
critical for our body and they’re reduced in type 2 diabetes.
doing a fecal transplant you could see insulin levels drop! It’s still unstable but it’s a big area of research
Type 1 diabetes characterized as?
what does it result in?
what are they prone to? UNIQUE TO T1D
immune mediated destruction of pancreatic B cells resulting in insulin deficiency
ketoacidosis
in most cases, what are found in T1D patients? be specific
how are most characterized? (2 things)
T cell mediated autoimmune disorder
autoantibody markers of B-cell destruction and strong HLA ASSOCIATIONS!!
with the onset of T1D… what infiltrates the islets of langerhans? (2)
what is this infiltrate called?
mononuclear cells and CD8 T cells
“Insulitis”
what are the concordance rate for T1D in monozygotic twins?
every year incidence goes up how much?
not 100%.. 30-50%, suggesting additional non genetic influences.
3%… so something is changing in the environment.
What are the strongest factors that are prenatal triggers for T1D?
postnatal?
what other things promote progression
maternal enteroviral infection, older maternal age
enteroviral infection, infant weight gain
overweight or increased height velocity, puberty, insulin resistance, psychological stress
what’s super important for early introduction into the diet?
maternal Vitamin D intake reduces the rate of type 1 diabetes!! so breastfeeding.
if we have infections that are not viral but bacterial.. does it have an affect no T1D?
they could act as adjuvants for immune response to food Ags.
What viruses have been implicated in T1D?
Enteroviruses Mumps Rubella cytomegalovirus retroviruses
how do viruses act against B cells
viruses have direct cytotoxicity against B cells.. they go into the B cell and replicate and destroy B cells
but they also trigger autoimmunity by molecular mimicry!! –> structure of the viruses slightly remind the host of itself but it attacks and then it attacks itself because the host gets confused
Breast feeding vs T1D correlation?
inverse correlation between a decrease in breast feeding and an increase in T1D risk.
biggest difference in different types of milk (cow and human)
human milk has significant levels of insulin, cows don’t.
so the presence of mother breastfeed helps maintain a tolerance of insulin. so if you introduce cow milk early it might compromise it.
gluten and T1D?
other environmental factors for T1D??
T1D is higher in patients with gluten sensitive enteropathy.
Vitamin D! *north-south gradient of T1D incidence in Europe (higher incidence in Scandinavia, lower in Greece)
psychological stress.
what’s the role of microflora in T1D (celiac)?
what genera are T1D people lacking in their microflora?
what do these genera do normally?
celiac disease is connected… T1D patients often present with chronic inflammation of the intestinal mucosa even in the absence of CD.
BUTYRATE PRODUCER are scarcely represented in T1D patients!
butyrate dependent species increase mucin synthesis and tight junction assembly… hence why T1D patients could be responsible for increased gut permeability.
risk of developing T1D before age 20 with a parent with T1D?
6%
T1D patients with their relatives are more likely for what?
more autoimmune diseases
What genes are the most susceptible and what do they do?
Insulin gene –> ag for immune response
Regulators of insulin gene expression –> expression in the thymus
HLA (HLA-DR and -DQ) regions –> presentation of insulin Ags for CD8 T cells
CTLA-4 - regulation of autoimmune response
how does negative tolerance work?
side note, MHC class 1 leads to what type of T cell?
class 2?
epithelial cells in the thymus when we have the thymocytes developing and becoming Cd4 or CD8 they’re at one time double positive
these epithelial cells, if there’s a strong reaction of class 1 or class 2, it’ll be immediately sent for apoptosis since it can’t recognize it too much
if it’s a class 2.. CD4, it’ll be that from now on.
if its a class 1… it’ll become a CD8
imperfect tolerance?
if we have suboptimal presentation of those antigens of islet cells.. it can be imperfect tolerance..
some antigens aren’t properly tested and slip through the cracks.
FOR T1D, what happens for the expression of insulin that leads to abnormal expression?
could have weird alternative splicing leading to mismatched expression patterns in pancreas and thymus
AIRE?
what happens if it malfunctions?
what does this have to do with insulin?
super important for induction of central tolerance against insulin.. helps negatively select stuff only in thymocytes.
if this malfunctions –> you have low levels of insulin mRNA.. since AIRE is responsible for transcription of expression of insulin.
so synthesis of antigen is low–> presenting to class 1 and 2 is less, so it allows the cells to skip negative selection.
this breaks central tolerance!
IDDM2?
where is it located?
what are the categories?
What happens if you have a type 1 problem in the gene? what does this result in?
insulin gene.
it’s in the promoter region of the insulin gene containing VNTR (variable number of tandem repeat)
it’s categorized by class I , II (intermediate), III (low)
susceptible class 1 alleles of the insulin are associated with LOWER insulin mRNA synthesis –> Log Ag (insulin) synthesis –> low Ag presentation in the thymus –> failure of deleting self reactive CD8 cells!
So tolerance is broken easier! can’t delete self-reactive CD8 T cells
what’s the role of HLA in T1D
what are the high risk alleles?
which one is associated with children?
HLA remember encodes for MHC class 1 or 2, so if we have a problem with this, it won’t see the antigen (insulin) in the system
DQ2/DQ8 and DR3/DR4 are high risk
90% of individuals with T1D have the DQ2/DQ8
DR3/DR4 are common in kids with T1D less than 5yo
HLA class 2 molecules that lack what and in what chain are found in people with T1D?
HLA class II that lack Asp57 of the beta chain often found in people with T1D
CTLA-4 gene (IDDM12)? what does it stand for?
What does it do?
what could contribute to T1D
Cytotoxic T Lymphocyte Activation 4
CTLA4 normally down regulates immune responses and is seen in regulatory T cells. it functions to suppress T cell activation and activation of its apoptosis.
CTLA-4 (if affected in T1D people) may counter-regulate CD28 dependent TCR activation of T cells.. so no more negative selection
low amounts could effect it too.
What is central tolerance again?
negative selection –> process of eliminating developing B or T lymphocytes that are reactive to self. tolerance ensures the immune system doesn’t attack itself
CTLA4 when it’s not there?
if CTLA4 is not expressed very high in the body but particularly on Treg, you wouldn’t be able to turn off other cells.
T cell is activated when it shouldn’t be.
What is the whole process of T1D from the start of Beta cell death
Beta cell death in the islets –> DCs pick up released Beta cell antigen (Insulin) –> pro inflammatory cytokines (type 1 interferons) as a result to infection or stress activate DCs and promote presentation –> T cells activated in lymph nodes that drain to pancreas –> T cells traffic to pancreas where they proliferate and accumulate resulting in organ specific inflammation
What do the APCs do when they have the Ags?
what happens once it makes this?
once you have pro inflammatory stuff, what’s going to finalize the destruction?
activate Ag-specific CD4 cells to further make IFN-gamma
IFN-gamma inhibits TH2 cytokine production (IL-4, IL-5, IL-10) and enhance IL-1B, TNF-a, and free radical production by macrophages which are toxic to islet beta cells.
this brings cytotoxic macrophages and CD8 lymphocytes –> destroy beta cells through FasL, granzyme, and Perforin
Asthma is usually what kind of response?
TH2 type of response
why are diabetic kids more likely to have asthma?
Treg cells
Treg cells fail to prevent activation/expansion of auto-reactive T cells… they can’t control the proliferation of and cytokine production by effector Teffs compared to those without diabetes
What do Treg cells do?
suppress APCs directly through cell-cell interaction or indirectly through cytokines IL4, IL-10, TGFB
preventing the development of autoimmune responses
they might also act on Teffs.
what is the mechanism of action of Tregs? (3)
(CD4+/CD25+)
produce IL-10 and TGF-B (for immunosuppressive nature)
reduced ability of APCs to stimulate T cells
Consumption of IL-2
Role of Tregs in microflora of T1D? (2 things that affect them)
factors of changing bacteriodetes/firmicutes ratio modifies the balance of Treg/Th1+Th17 in the GALT.
also there was a defect recently found in FoxP3 (which makes Treg cells) in the small intestine of T1D patients
what are the Islet Cell autoantibodies common in T1D?
why do we care?
why are they controversial?
what happens if your pt comes to clinic and you look for these?
GAD65
IA2
IAA
they’re present in increased frequency, helping confirm diagnosis of T1D
they may affect the time course of T1D: the more you have the higher chance you have.
if you have 1 you have less chance of getting it over time in a follow up then if you have 2 or 3.
HIGHLY predictive.
T1D, what’s the most likely hypersensitivity reaction going to be?
Type 4
What is the function of the AIRE protein?
activate the expression of tissue-specific proteins in the thymus
Educational immune tolerance to self-antigens is induced primarily in the thymus where tissue-restricted antigens (TRAs) are presented to T lymphocytes by cells of the thymic stroma – a process known as central tolerance. The expression of these TRAs is controlled in part by a transcription factor encoded by the autoimmune regulatory (AIRE) gene.
what do Cytotoxic T lymphocytes recognize?
MHC Class 1 and B7
In addition to compromising β cell function and survival, cytokines and chemokines may recruit which of the following immune cells?
Macrophages
