Levings Application 3 Flashcards
insulin function (3)
- 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
where is insulin produced and by what cell (2)
- produced in pancreatic islets
- produced by beta cells in islets
what does the pancreatic islet of a T1D look like (2)
- all beta cells in the islet are destroyed
- insulin must be obtained exogenously as a result
autoimmunity in T1D
- CD8+ T cells specific for islet proteins destroy beta cells
stages of T1D: pre-T1D (3)
- genetic risk
- immune activation: beta cells are attacked
- immune response: development of single autoantibody
stages of T1D (4)
- stage 1: normal glucose tolerance (more than 2 autoantibodies)
- stage 2: abnormal glucose tolerance
- state 3: clinical diagnosis
- stage 4
autoantibodies
- antibodies that target self-tissue
T1D autoantibodies and lifetime risk
- increased number if islet autoantibodies is correlated with increased lifetime risk of T1D
T1D pathogenesis (4)
- 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
how does immunity to islets go wrong: rare
- single coding mutation in gene essential for central or peripheral tolerance
example of rare purely genetic cause of T1D (2)
- IPEX syndrome
- classic triad of dermatitis, T1D, and enteropathy
how does immunity in islets go wrong: more common
- intersection of genetic susceptibility and an environmental trigger
immunity in islets go wrong: genetic susceptibility
- small changes in expression/function of 1+ genes which affect overall function of T cell tolerance
immunity in islets go wrong: environmental triggers (3)
- prenatal triggers
- postnatal triggers
- promoters of progression
immunity in islets go wrong: environmental triggers examples (2)
- viral trigger (molecular mimicry)
- microbiome trigger
environmental triggers: viral trigger (2)
- viral peptide mimics self peptide
- APC presents both self and non-self peptide simultaneously
environmental triggers: gut microbiota (2)
- 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
proposed mechanism of action of anti-CD3
- alter APC-T cell by partial depleting autoreactive T cells and inducing FOXP3+ Treg cells t0 activate and inhibit autoreactive T cells
CD3
- protein complex and T cell co-receptor that is involved in activating both the cytotoxic T cell and T helper cells
anti-CD3 antibody
- modifies CD8+ lymphocytes to take on T cell unresponsive phenotype
problems with anti-CD3 antibody (3)
- flu-like symptoms
- cross-linking to TCR/CD3 complex, which released cytokines
- development of anti-mouse antibodies, causing rapid clearance and reduced efficacy
development of anti-mouse antibodies: solution
- humanizing antibodies
OKT3
- oligomeric and specific chain of CD3 complex
teplizumab (3)
- 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
T cell exhaustion
- persistent antigen following antigen with inhibitory receptor:inhibitory receptor ligand bindings
teplizumab effects
- decreases lymphocyte count and increases % of exhausted CD8+ T cells
making Tregs from conventional T cells
- gene editing must be done to force FOXP3 expression
