Previously on Bio308

1. Previously on Bio308 Signaling cascades Large intracellular signaling proteins Types 2nd Messengers Ca++ IP3 DAG Nucleotides Similarities Advantages Coordination How does it all add up in Graves’ Disease? Causes Treatments Introduction to paper discussion:

2. What could this case suggest about the cause of Graves’ disease? Case outline: 31 year old Caucasian female Smoker (before pregnancy) Previously diagnosed with Graves’ disease 4 weeks post partum Symptoms lessened during pregnancy but now have rebounded 4 week old Caucasian male Exhibiting symptoms of Graves’ disease Return visit 5 weeks later Female smoking again (but ‘never’ around baby) Graves’ symptoms have increased Infant no longer exhibiting symptoms

3. Possible causes of Graves’ disease?: Genetic predisposition, appear to need multiple ‘hits’ hormonal role suggested Gender Environment exposure to toxins (smoking), radiation, stress “Diffusible/Destructible signal” antibodies

4. Antigen (Ag) binding domain Fig 3-21 General structure of an antibody (Ab) What are antibodies? Why make Ab? What do they do? How are antibodies made? How does the body know when to make Ab?

5. Poliovirus Adenovirus +Invasion by ‘foreign body’ Antibody production Self vs. Non-self What is foreign? +Immune response mounted How? Peptides presented to B cells, ‘Designer’ Ag binding domain created +End result B cells and plasma cells produce specific Ab T cells, macrophages attack Ab-Ag complex (attack invader) Invader forcibly removed

6. Graves’ disease patients show high titer of TSI (also called LATS) Woman and child case Sometimes just not feeling like ‘self’ Autoimmune responses Relatively common 5% exhibit chronic, debilitating symptoms Causes– not known in all cases www-immuno.path.cam.ac.uk/~immuno/part1/lec12/lec12_97.html

7. www-immuno.path.cam.ac.uk/~immuno/part1/lec12/lec12_97.html Predicted effect of TSI binding? Clinical effect of TSI binding Is activation by TSI surprising? Why do TSI get made?

8. Dennis Kunkel gram negative coccobacillus Yersinia entericolitica and Graves’ disease : ONE hypothesis REMEMBER DISEASES CAN HAVE MULTIPLECAUSATIVE FACTORS Food borne pathogen Generally porcine source Can invade body through structures in intestine Can cause dysenteric diarrhea An Invader

9. Thyroid

10. Lipoprotein epitope TSH-Receptor Ligand binding site Molecular Mimicry (Remember this is a hypothesis supported by evidence in a small % of Graves’ cases. Most people do not contract Graves’ this way.)

11. Cures for Graves’ Disease Treatments: Radioactive Iodine Drugs –regulate thyroid or alleviate symptoms Surgery All require lifetime drug therapy Graves’ disease does not appear to have one causative factor but results from a combination of genetic predispositions and environmental factors

12. Case study 1: Graves’ disease Extracellular signaling Role of biological membranes Protein structure (and its importance for protein function) Signal transduction 3-D protein structure (and its importance for binding) Signaling cascades Protein modifications and their importance for activity Antibodies –specificity, role, and the importance of binding specificity

13. Next on Bio308 Discussion of journal article: Terms and technique questions Tuesday: Thursday: The paper-- figure by figure Paper and study questions are found as links under Assignments and Quizzes on Blackboard The questions will take time to complete and the article will be ‘heavy reading’-- do not put it off.