Immunological Mechanisms of Diabetes Flashcards
1
Q
- Early stages of T2D are characterized by _
- Later stages of T2D are characterized by _
- What are some complications that can result from elevated blood sugar levels?
A
- Hyperinsulinemia
- Insulin secretion decrease
- Renal failure, CAD, blindness, stroke
2
Q
- In healthy individuals, there is expression of _ antagonist and suppression of _
A
- IL-1
- IL-1Beta (pro-inflammatory cytokines)
3
Q
_ are the predominant macrophages active in healthy individuals (induced by IL-3 and IL-4)
What other cell types are expressed in a healthy/lean person?
They secrete what cytokines?
A
- M2 macrophages
- Treg, Th2, Eosinophils
- Secrete anti-inflammatory cytokines:
- IL-10 (which suppresses M1 activation)
- TGF-Beta
4
Q
- _ are the predominant macrophages in patients with obesity (are induced by LPS and IFNgamma and inhibited by IL-10_
- What other cell types are present in these patients?
- What cytokines do these secrete?
A
- M1 macrophages
- Th1 cells, CTLs, Neutrophils
- Secrete pro-inflammatory cytokines
- TNF
- IL-12
- IFNalpha
- IFNbeta
- IL-6
- IL-15
- IL-18
5
Q
- _ free fatty acids are more common in healthy patients
- _ free fatty acids are more common in obese patients
A
- Short chain
- Medium/Long chain
6
Q
_ inflammation in obesity can lead to insulin resistance and T2D
A
Adipose tissue
7
Q
- How does glucotoxicity, lipotoxicity, and beta cell death contribute to T2D
A
8
Q
_ is a FFA recognized by TLRs (TLR2/TLR4) and produces cytokines that are precursors for M1 macrophages and lead to increased inflammation, increased Ag presentation, and activation of CTLs that ultimately leads to destruction of Beta Pancreatic Islets
A
- Palmitic acid (long chain)
9
Q
- What are environmental factors in the development of T2D?
A
- Sedentary lifestyle
- High Fat Diet
- Pollution
- Pesticides/Herbicides
- Traffic related pollutants (Diesel, PM, NO2)
10
Q
- What is the role of microflora in the development of T2D?
- What are the two mechanisms by which this happens
A
- Increase in Firmicutes/Bacteriodetes ratio (esp decrease in bacteriodetes) aids in development of obesity
- Why is this important?
- Gut microbiota facilitate energy harvest (increase in adipocytes, FFA production, leading to insulin resistance and inflammation)
- Initiate inflammatory response
11
Q
- Fecal transplantations are potential future treatments for T2D in the fact that they induce _ producing intestinal bacteria into the recipient of the transplant
A
- Butyrate-producing bacteria
12
Q
T1D is an AID characterized by _ cell mediated destruction of beta cells in the pancreas via the production of auto-Abs
Diabetes was considered a _ condition until insulin was available for therapy
_ was the youngest nobel prize winner for his work (worked alongside Macleod)
A
- T cell
- Terminal
- Banting
13
Q
- Patients with T1D are more likely to develop _
- Most cases of T1D ate characterized by _ markers of beta cell destruction and strong _ associations
- _ cell mediated AID
A
- Ketoacidosis
- Autoantibody, HLA
- TH1
14
Q
- Insulinitis
A
- Infiltration of mononuclear and CD8+ T cells into islets of Langerhans
15
Q
- Summary of physiological contributions to T1D
A
16
Q
- Role of infections in T1D development
A
- Bacteria act as adjuvants
- Viruses:
- Enteroviruses
- Mumps
- Rubella
- Cytomegalovirus
- Retrovirus
- Viruses can act against b cells by:
- Direct cytotoxicity
- Triggering of autoimmunity by molecular mimicry
17
Q
- Tolerance to insulin may be compromised by stopping _ too soon and inducing _ too early
A
- Breast-feeding (breast milk contains a lot of insulin)
- Cows milk (much less insulin)
18
Q
- What are some other environmental factors that contribute to the development of T1D?
A
- Wheat gluten
- Gluten-sensitive enteropathy
- Lack of Vitamin D
- Psychological stress
19
Q
-
Role of Microflora in T1D:
- _ is more common in patients with T1D
-
T1D patients often present with _ of the intestinal mucosa which leads to a decrease in the _ producer genera in the gut
- Normally helps with _ synthesis and _ formation
- Lack of this in T1D patients leads to an increased _
A
- Celiac Disease
- Chronic inflammation, butyrate
- Mucin synthesis, tight junction formation
- Gut permeability
20
Q
- What are the most important genes determining T1D susceptibility?
A
- Insulin gene-Ag for autoimmune response
- Regulators of insulin gene expression in thymus (AIRE)
- HLA region (DR/DQ)-presentation of insulin Ags for CD8+ T Cells
- CTLA-4 gene-regulation of autoimmune response
21
Q
- How is central tolerance established?
A
- Negative selection when doiuble positive CD4+/CD8+ T cell binds self peptides presented in thymus within Class I and Class II MHC with a high enough affinity to receive an apoptotic signal
22
Q
- Genetic mechanisms (allelic variation, alternative splicing, epigenetic regulation) of gene expression can lead to suboptimal expression of _ cell auto-Ags and lead to imperfect tolerance
- Can lead to mismatched expression patterns in _ and _
- _ cells are involved in negative selection of self-reactive T cells (these cells also transcribe an important protein _, that acts as a transcription factor)
A
- Islet cell auto-Ags
- Pancreas-Thymus
- Thymic epithelial cells
- AIRE
23
Q
_ is a protein transcribed by T epithelial cells and is important in negative selection of self reactive T cells
If not present, can lead to autoimmunity
A
- AIRE
24
Q
Role of AIRE in development of T1D:
Transcriptional expression of _ is controlled by AIRE
Malfunctioning of AIRE results in _ in the thymus
This causes a failure in deletion of _ and breaking of central tolerance
A
- Insulin
- Lower levels of Insulin mRNA
- Insulin reactive T cells
25
* ***Insulin Gene (IDDM2) and the development of T1D***
* ***Mapped to a region contraining the _ in _ region of insulin gene***
* ***\_ polymorphism is categorized into three classes (I,II,III)***
* ***\_ alleles are . associated with lower insulin mRNA synthesis***
* ***Leads to low Ag (insulin) synthesis***
* ***Low Ag presentation in the thymus*********
* ***Failure to delete self-reactive T cells***
* ***Break of central tolderane***
* VNTR, promoter
* VNTR
* **Class I**
26
* ***Role of HLA in T1D:***
* ***HLA \_/\_ and \_/\_ are high risk alleles***
* ***Which alleles are most common?***
* ***Which alleles are most common in children***
* ***These HLA Class II molecules lack _ of beta chain***
* ***HLA Class II haplotypes like \_/\_ confer dominant protection***
* DQ2/DQ8 and DR3/DR4
* DQ2/DQ8 ( I went 2 DQ and 8 a blizzard)
* DR3/DR4 (children like going to the DR at ages 3/4)
* Asp57
* DR2/DR6
27
* _ is a susceptability locus to be associated with T1D
* It encodes a glycoprotein that is an **inhibitory CD28 homologue and binds _ protein**
* **May counter regulate the CD28 dependent TCR activation of T Cells**
* **Function is _ and activation of apoptosis**
* **Decreased expression may contribute to T1D**
* CTLA4
* B7
* suppression of T cell activation
28
***Immunopathogenesis of T1D***
* Beta cell death occurs
* DCs present in islets and take up released Beta Cell Ag
* Release of proinflammatory cytokines (Type 1 IFNs) can activate DCs and promote antigen presentation to T cells
* T cells (pancreas specific) activated
* T cells move to pancreas where they proliferate and accumulate to result in pancreatic inflammation
* APCs present Ag to Class II MHC molecules and secrete IL-12
* IFN gamma further stimulated by activation of CD4 cells
* Th2 is inhibited and enhancement of IL-1beta, TNF-alpha and free radical production by macrophages occurs
29
* _ is more prevalent in children with T1D than non-diabetic children
* Both occur d/t failure of regulatory mechanisms controlled by \_
* Susceptibility to T1D is enhanced if _ fail to prevent activation/expression of _ T cells
* _ from individuals with T1D are less able to control proliferation and cytokine production by _ T Cells
* Asthma
* Tregs
* Tregs, autoreactive T cells
* Tregs, effector T cells
30
* MOA of Tregs:
* Suppress _ cell activation and inhibit proliferation and differentiation of _ cells
* Produce _ cytokines (IL-10 and TGF-Beta)
* _ ability of APCs to stimuate T Cells
* Consume _ (deprives other T cells of this growth factor, leading to reduced proliferation and differentiation of T cells dependent on this cytokine)
* B cell, NK cells
* Immunosuppressive cytokines (IL-10, TGF-Beta)
* Decrease ability of APCs to stimulate T cells
* Consume IL-2
31
* Role of microflora in T1D
* Change the bacterioidetes/firmicutes ration
* Modifies balance of Treg (Th1 and Th17) in GALT
* Defect in FoxP3 and Tregs
32
* ***AutoAbs in T1D:***
* ***\_ are present with increased frequency among those diagnosed with T1D***
* ***\_ compared to metabolic changes associated with T1D and can be used to predict disease and confirm diagnosis***
* ***What are the identified AutoAbs?***
* ***What is the pathogenic role of auto-Abs in T1D?***
* ICA (Islet Cell Autoantibodies)
* Appear early
* **Identified auto-Abs:**
* **GAD65 (Glutamic acid decarboxylase)**
* **IA-2, tyrosine phosphatase (Insulinoma Antigen 2)**
* **IAA (Insulin Autoantibodies)**
* **May affect time course of T1D development**
33
* Pathogenic Role of Auto-Abs
34
* Diagnostic role of Auto-Abs
