Levings Application 3

Question 1

insulin function (3)

Answer 1

• stimulates glucose uptake from blood into tissue
• stimulates glycogen formation in the liver
• released from pancreas when blood sugar is high to lower the blood sugar

Question 2

where is insulin produced and by what cell (2)

Answer 2

• produced in pancreatic islets
• produced by beta cells in islets

Question 3

what does the pancreatic islet of a T1D look like (2)

Answer 3

• all beta cells in the islet are destroyed
• insulin must be obtained exogenously as a result

Question 4

autoimmunity in T1D

Answer 4

• CD8+ T cells specific for islet proteins destroy beta cells

Question 5

stages of T1D: pre-T1D (3)

Answer 5

• genetic risk
• immune activation: beta cells are attacked
• immune response: development of single autoantibody

Question 6

stages of T1D (4)

Answer 6

• stage 1: normal glucose tolerance (more than 2 autoantibodies)
• stage 2: abnormal glucose tolerance
• state 3: clinical diagnosis
• stage 4

Question 7

autoantibodies

Answer 7

• antibodies that target self-tissue

Question 8

T1D autoantibodies and lifetime risk

Answer 8

• increased number if islet autoantibodies is correlated with increased lifetime risk of T1D

Question 9

T1D pathogenesis (4)

Answer 9

• APC activates autoreactive CD4+ T cell
• CD4+ T cell and cytotoxic T lymphocyte go to capillary
• B cell activation by CD4+ T cell and creation of autoantibodies for islet Ab
• pancreatic beta cell destruction

Question 10

how does immunity to islets go wrong: rare

Answer 10

• single coding mutation in gene essential for central or peripheral tolerance

Question 11

example of rare purely genetic cause of T1D (2)

Answer 11

• IPEX syndrome
• classic triad of dermatitis, T1D, and enteropathy

Question 12

how does immunity in islets go wrong: more common

Answer 12

• intersection of genetic susceptibility and an environmental trigger

Question 13

immunity in islets go wrong: genetic susceptibility

Answer 13

• small changes in expression/function of 1+ genes which affect overall function of T cell tolerance

Question 14

immunity in islets go wrong: environmental triggers (3)

Answer 14

• prenatal triggers
• postnatal triggers
• promoters of progression

Question 15

immunity in islets go wrong: environmental triggers examples (2)

Answer 15

• viral trigger (molecular mimicry)
• microbiome trigger

Question 16

environmental triggers: viral trigger (2)

Answer 16

• viral peptide mimics self peptide
• APC presents both self and non-self peptide simultaneously

Question 17

environmental triggers: gut microbiota (2)

Answer 17

• intestinal permeability increase or gut microbiota diversity decrease
• lead to molecular mimicry, inflammation, Treg imbalance, and activate T cells that lead to beta cell destruction

Question 18

proposed mechanism of action of anti-CD3

Answer 18

• alter APC-T cell by partial depleting autoreactive T cells and inducing FOXP3+ Treg cells t0 activate and inhibit autoreactive T cells

Question 19

CD3

Answer 19

• protein complex and T cell co-receptor that is involved in activating both the cytotoxic T cell and T helper cells

Question 20

anti-CD3 antibody

Answer 20

• modifies CD8+ lymphocytes to take on T cell unresponsive phenotype

Question 21

problems with anti-CD3 antibody (3)

Answer 21

• flu-like symptoms
• cross-linking to TCR/CD3 complex, which released cytokines
• development of anti-mouse antibodies, causing rapid clearance and reduced efficacy

Question 22

development of anti-mouse antibodies: solution

Answer 22

• humanizing antibodies

Question 23

OKT3

Answer 23

• oligomeric and specific chain of CD3 complex

Question 24

teplizumab (3)

Answer 24

• humanized IgG1 antibody
• developed by grafting complementarity determining region of OKT3 into a human IgG1 backbone
• two point mutations in Fc portion decrease binding to FcR

Question 25

T cell exhaustion

Answer 25

• persistent antigen following antigen with inhibitory receptor:inhibitory receptor ligand bindings

Question 26

teplizumab effects

Answer 26

• decreases lymphocyte count and increases % of exhausted CD8+ T cells

Question 27

making Tregs from conventional T cells

Answer 27

• gene editing must be done to force FOXP3 expression