7. Immune Mechanisms of DB Flashcards
Type 1 DM can be immune mediated or idiopathic. Immune mediated type 1 DM is d/t what?
B-cell destruction.
Both will result in insulin dependence, with a loss of B-cells.
What is Type 2 DM?
Insulin resistance and relative insulin deficiency.
What is the clinical distinction for type 2 DM?
Oral hypoglycemic agents only work early in the disease process.
What are the mechanisms for T2D?
- B cells loss
- Decrease in B cell mass
- Decrease in Insulin-secretion
What are the causes of T2D?
Insulin resistance and glucotoxicity cause B-cells to overwork and failure, leading to overt and late T2D.
T2D is caused by ____________ in both the ________ and ______ that results in the development in the disease.
Chronic infllmation
Adipose tissue
& pancreas
T2D is characteristized by what 3 things?
- Hyperglycemia
- Insulin resistance
- Impairment in insulin secretion
T2D patients. have elevated blood sugar, resulting in what four things?
What contributes to the development of the disease?
- Renal failure, CAD, blindness and stroke.
- Genetic and lifestyle factors.
In patients that are normal-weight and nondiabetic, insulin secretion will result in
____ serum insulin
____ serum glucose
____ serum FFA
_____ IL-1B
_____ IL-1R ANT
Low
Low
Low
Low
HIGH
Insulin-sensitive individuals (norma), normal insulin secretion will do what:
_______ uptake of glucose from the circulation by skeletal. m and adipose tissue.
________ FFA release from adipose tissue
________ hepatic gluconeogenesis.
increase
inhibit
supress
In insulin-sensitive individuals, when insulin is secreted, how do adipose tissue macrophasges and kupffer cells react?
- Express IL-1 receptor antagonic
- Supress IL-1B
What is obesity characterized by and why is it linked to T2D?
Obesity causes chronic activation of inflammatory pathways.
Inflammation in obesity is linked to insulin resistance.
As we go from lean -> onset. of obsity ->chronic obesity, what changes?
we will start to express more immune cells in our adipose tissue;.
When we are lean, we have mostly [m2 macrophages, T-reg cells, Th2 cells and eosinophils].
- In chronic obesity, we. have mostly [m1 macrophages, Th1 cells, CTLs and neutrophils].
Obesity causes changes in adipocyte metabolism and gene expression.
Under lean-conditions (insulin-sensitive), what do adipocytes secrete?
Adipocytes will secrete
- Anti-inflammatory FFA (short-chain), IL-13 and IL-4.
- Those will then cause alternative activation of M2 MO, which secrete anti-inflammatory cytokines like IL-10, which will also inhibit M1 MO activation.
Obesity causes changes in adipocyte metabolism and gene expression.
Under obesity-conditions (insulin-resistant), what do adipocytes secrete?
Adipocytes will secrete
- Proinflammatory FFA (long and medium-chain FA)
- MCP-1 and TNF-alpha, which activate M1 MO.
M1 MO will then release pro-inflammatory mediatorys such as TNF-alpha, IL-1B, IL6, NO that act on adipocytes to cause insulin-resistance.
In T2D who are insulin-resistance, how do B-cells die?
Stressed beta cells will release insulin into bloodstream; resulting in:
- high serum insulin
- High serum glucose
- High serum FA
- High serum IL-1B
- Low serum IL-1Ra
That will result in glucotoxicity, lipotoxicity. and IL-1B toxicity -> [recruitment of MO, islet inflammation, increase antigen presentation and B-cell specific CTL licesnsing] -> B cell death.
In obsese patients, adipose tissues release __________, a _____- chain FFA. What happens next?
Palmitate, a long-chain FFA.
- B-cells in the pancreas sense palmitate via the TLR4-myD88 and recruit inflammatory monocytes to islets via chemokines.
- Monocytes–> M1 MO.
- M1 MO will -> increase inflammation, increase Ag presentation, activate cytoxic T-cells.
M2 MO and M1 are counterbalancings. M1 produces TNF and IL12, which stimulates NK cells to make INF-y.
M2 MO produces IL-10, which inhibit M1 MO.
IL-1 makes TNF and IFN-y –> + activate M1
Th2–> IL10, 4, 5 13. IL4, 13 and 10 will + M2 MO
T2D is a multifactorial disease, arising from the presence of T2D risk alleles and a disease-conducive environment. 52 common varients have been identified.
The lifetime risk for developing T2D if one parent has T2D is ____, and _____ when both parents have T2D.
40%
70%
What is the concordance rate of T2D in MZ twins and DZ twins?
MZ- 34%
DZ- 16%
________ have a 10 fold higher prevalence of T2D than general U.S population.
PIMA INDIANS
Twin studies show an important role in environmental and behavorial factors in developing T2D. Senendary life-styles and high fat diets can also cause it.
What is an environmental risk-factor?
Pollution; trafffic pollution. and pesticides, herbicides.
What is the role of microflora in T2D?
Weight gain–> increase intestinal microbiota (firmicutes/ bacteroidetes ratio) -> inflammation and insulin resistance.
There is a ______ relationship between intestinal microbiota and metabolic health.
recipricol.
What can be a Tx for insulin resistance and type 2 DM?
Faecal transplation (butyrate producing bacteria)
What is T1D?
Chronic autoimmune disease where by T-cells destroy pancreatic B-cell, causing insulin deficiency.
Insulin is one of the key target Ags recognized by auto-reactive T-cells, which destroy our B-cells. In 1965, pancreatic islet. inflammation was a hallmark of recent onset T1D. This was then followed by what?
Auto-antibodies, which became the first biomarker of T1D, which target insulin.
In the 1980s, it was established that T1D is d/t what?
Autoreactive T-lymphocytes and auto-antibodies that target insulin.
DB was considered a terminal condition before insulin was available for therapy.
In Jan 11, 1922, a 14yo boy became the 1st recipient of insulin.
Patients with T1D are prone to ________ and most cases are characterized by _____________ markers of what?
Patients with T1D are prone to ketoacidosis and most cases are characterized by auto-ab markers that. cause B-cell destruction and strong HLA associations.
At the time clinical sx of T1D show, _____ of the B-cells are destroyed.
Onset of T1D is associated with __________ infiltrating of the islets of langerhans.
60-80%.
Mononuclear cells and CD8+ Tcells (insulitis)
Physiological contributions to T1D fall in what three cateogies?
1. Bone marrow and thymus
2. Immune system
3. B-cells of the pancrease
What environmental factors contribute to T1D?
These factors and what, contribute to T1D?
- 1. Diet
- 2. Virus
- 3. Toxins and stress.
These factors, in combination with genes, can cause a decrease in islet mass and increase in MHC 1 -> Increase in Th1/Th2 cells -> B cell death -> type 1 DN.
Concordance rate of T1D in MZ twins is what? What does this suggest?
What supports this?
30-50% , this suggests there genes are not the only important cause.
- Incidence is increasing by 3% per year, thus, we cant soelely blame genes.
- Epidemiological and animal studies show a indirect link to environment
- 350 fold variation in the incidence of T1D in different countries around da world
What are prenatal triggers to T1D?
1. Maternal enteroviral infection******
2. Older maternal age.
What are postnatal triggers to T1D?
1. Enteroviral infections ***
- Infant weight gain
- Serious life events
What are promoters of progression to T1D?
- 1. Overweight or increased height velocity
- 2. Puberty
- 3. Insulin resistance
- 4. Psychological stress
What are the protective factors for T1D?
- Higher omega 3 FA
- Introduction of solid foods while breastfeeding and after 4 months.
What viruses are implicated in T1D?
- Enteroviruses
- Mumps
- Rubella
Viruses attack B-cells through what mechanisms?
1. Direct cytotoxicity
2. Trigger autoimmunity by molecular mimicry
Breast-feeding vs. Cow milk in T1D.
- Breastfeeding will decrease risk for Type 1 DB because it contains a high amount of insulin.
- Cow milk contains much less, so early exposure can lead to T1D because they will make auto-ab.
- It is good to introduce cow milk and cereal SLOWLY.
are the breastfeeding and cow milk studies consistent?
there is some inconsistency d/t
- differences in composition of milk
- genetic variation in cow proteins
- differences in milk-sensitive db prone patients.
What are other environmental factors for T1D?
- Wheat gluten. Risk of T1D is higher in pts that have gluten-sensitive enteropathy.
- Decreased Vit. D.
- Psychological stress.
Many T1D patients have celiac disease (CD).
What is the role of microflora in T1D patients?
T1D patients often present with chronic inflammation of the intestinal mucosa, even in the absence of CD. Often seen in the mucosa is a absence of butyrate-producer genera (role: increase mucin and tight junctions)
- also have deficiency of mucin-degrading genera -> increases gut permeability.
There is familial clustering of T1D.
The risk of developing T1D before 20 yo is ____ % in the sibling of an affected patient and ___% in the general population
6%
0.4%
What is the concordance in in MZ and DZ twins T1D?
MZ: 30-50%
DZ: 10%
What genes determine T1D susceptility?
There is NO specific DB gene, but a wrong combination of normal polymorphisms.
T1D is a _________ autoimmune disease; thus, patients have _________ risk for other diseases (________ and _________).
T1D is a MULTIFACTORIAL autoimmune disease; thus, patients have increased risk for othre diseases (thyroid autoimmunity and Addisons disease).
About ___ genes are associated with susceptibility to T1D.
What are the 4 most significant?
18.
- Insulin gene on chromosome 11- Ag for autoimmune response
- Regulators of insulin gene expression in the thymus (AIRE)
- HLA-DR3/DR4 and HLA-DQ2/DQ8 genes on chromosome 6, which present insulin antigens to CD8+ cells
- CTLA-4 gene on chromosome 2, which is involved in regulation of an autoimmune response.
thymic expression and presentation of self-molecules isdone so by thymic epithelial cells that are involved in the negative selection of self-reactive T-cell. They are controlled by
AIRE (autoimmune regulator transcrption factor)
How is central tolerance established?
Negative selection (apoptosis of self-reactive cells) occurs when
double positive CD4/CD8+ T cells bind self- peptides in the thymus within Class I and Class II MHC with high enough enough affinity to cause apoptosis.
AIRE protein does what?
AIRE controls auto-antigen expression in the thymus.
AIRE expression and presentation of insulin in thymus is important to protecting against the development of T1D.
Transcriptional expression of insulin in the thymus is controlled by _____.
Malfunctioning of this causes what?
AIRE.
Malfunctioning of AIRE causes lower levels of insulin mRNA in the thymus. Absence of insulin -> failure of deleting insulin-reactive T cells -> breaks Central tolerance.
The insulin gene on chromosome 11 is mapped to a region that contains ____________ in what region of the gene?
a variable number of tandem repeats in the promoter region of the gene.
The insulin gene on chromosome 11 is mapped to a region that contains variable number of tandem repeats in the promotor region of the gene. The VNTR can have what three polymorphisms?
Which is ass. with T1 DB.
Class 1
Class 2
Class 3.
The class 1 VNTR makes patients susceptible to type 1 diabetes by decreasing insulin mRNA synthesis -> low insulin presentation in the thymus -> failure to delete self-reactive CD8 T-cells -> breaks central tolerance.
HLA alleles DQ_/DQ_ and DR_/DR_ are high-risk alleles.
HLA class __ molecules that lack ______ of the ____ chain are found in ppl with T1D.
HLA alleles DQ2/DQ8 and DR3/DR4 are high-risk alleles.
HLA class II molecules that lack Asp57 of the beta chain are found in ppl with T1D.
What types confer dominant protection?
DR2/DR6
What is CTLA4?
CTLA4 gene on chromosome 2 is assx with T1D. Fx of it is to suppress T-cell activation and cause apoptosis of it.
CTLA4 encodes a glycoprotein that is an inhibitor CD28 homologue and binds B7.
CTLA can inhibit T cell activation in two ways:
1. Bind and deliver inhibitory signals, inhibiting T-cell activation (cell-intrinsic CTLA-4 function.
2.
Blocks and removes B7 cells on APC, making it unavailable to co-stimulation to CD28, and blocks T-cell activation (cell-extensic CTLA-4 fx)
B7 has higher affinity for CTLA4 or CD28?
CTLA-4
In T1D, B-cells of the pancreas can die due to physiology or as a result of infection.
DC’s are always present in the islet and can do what?
1. B cell with infection of bad B cell
2. Release of pro-inflammatory cytokines (IFN-y).
What happens next?
- DCs are activated and present the B cells ANT to T cells.
- CD4 (Th1 cells) are activated in the LN that drain the panceras.
- Once activated, they go to the pancreas, proliferate and cause inflammation
What. does the activated CD4 cell then do?
- Activated CD4+ T cell can then do two things: Actcated Treg cells or Teffector cells.
- Normally: CD4+ T cell will release IL10, TGF-B and IL2 to activate the CD4+, CD25+ and FoxP3 Treg cell, which will release IL10 and inhibit CD4+ effector cells. It will also consume IL2 and TNF alpha to reduce infection and inflammation.
- In Pts with Type1 DB: CD4+ will release IL12, +CD4+ effector cells
- Teff -> makes Th2 cells (which makes antiinflammtory cytokines) and Th17, Th1 (makes pro-inflammatory cytokines).
- I_FN-y_ inhibits Th2 cytokine production (IL4, 5 and 10)
- Proinflammatory cytokines can then do two things:
- A. +CD8 and and cytoxic macorphages -> release IL1-B, TNF-alpha and free radicals and kill B cells via FasL granzyme perforin
- B. Directly kill B-cells
Counter regulatory role for Th1 and Th2 subsets would suggest that T1D would not occur in patients with astha. However, kids with T1D are more prone to have asthma.
Why?
Foxp3+ Tregs fail to prevent making auto-reactive T-cell, creating T-effector cells.
What do T-reg cells do?
Treg act in tissues and draining LN.
- They are activated by a APC that presents a auto-antigen. They supress APC directly by cell to cell interaction or indirectly by cytokines.
- They also act directly on Teffs.
T-reg cells can suppress immune responses, B-cell activation and diferentiation of NK cells.
How do T-regs supress?
- Make IL-10 and TGF-B (make immunosupressive agents)
- bind CTLA-4 to B7 on APC, preventing APCs to activate T cells
- Consume IL2 and and TNF alpha deprive other T-cells of this growth factor, reducing proliferation and differentiation.
Describe the microflora in T1D patients
- Altered hange the [bacteroidetes/firmicutes ratio] –> alter balance of Treg/Th1 and Th17 in GALT.
- T1D pts also have a defect in Foxp3 T-reg cells.
More firmicutes (SFB, Lactobacillis bifudus) TH17, TH1 cells -> inflammation -> autoimmunity.
Also defect in FOXP3
PPl just recently diagnosed with T1D will see an increase in ___________.
This change appears in advance and can be used to PREDICT the dz. If they are present, it CONFIRMS the dz.
Islet cell autoantibodies (ICA)
What kind of ICAs do we have?
- GAD65 (glutamic acid decarboxylase)
- IA-2 (insulinoma antigen-2), tyrosine phosphotases
- IAA (insulin autoantibodies)
Is there a pathogenic contribution of ICAs to DIA?
Questionable.
- cannot be transferred using serum
- plasmapheris is littler therapeutic help in pts with T1D
- T1D reported in a male with X-linked agammaglobinemia
What is the pathogenic role of auto-abs in T1D?
Auto-ab may affect the time course of T1D development
The presence of ___ autoantibidies is highly predictive of future T1Dwith a 5 year risk of more than 40%
The presence of ___ autoantibidies is highly predictive of future T1Dwith a 5 year risk of more than 60%
2
3
HLA typing + autoantibody screning is useful for what?
predicint disease in general populations.
____ have been the focus of most strategies of immunotherapy. for T1D
T cells
Define obesity as a key factor in adipose tissue inflammation.
When adipose tissue cells get larger, they can cut off blood supply leading to some necrosis.
This necrosis leads to a pro-inflammatory region that summons TNF-α, IL-1β and IL-6.
. Describe and compare immune mechanisms of type 1 diabetes (T1D) and T2D.
Type I diabetes is an autoimmune attack on β-cells leading to insulin deficiency.
Type II diabetes is insulin resistance and chronic inflammation.
AIRE is responsible for
displaying insulin and other B cell epitopes to T cells to ensure that they are not reactive to it. Defective AIRE can lead to auto reactive T cells.
Define T1D as an autoimmune disease:
a. Role of autoantibodies in T1D
Autoantibodies attack beta cells, specifically glutamic acid decarboxylase (GAD65), insulinoma antigen-2 (IA-2), and insulin auto-antibodies (IAA).
b. Role of cell-mediated immune responses (CD4+ Th1 cells and CD8+ T cells)
- CD8+ T cells utilize perforin and granzymes to trigger cell death in cells presenting type I diabetes related autoantigens.
- CD4+ Th1 cells interact with B cells to activate them and cause autoantibody production.
