1. Previously on Bio308 Types Similarities 2 nd Messengers IP 3 DAG Ca ++ AdvantagesCoordination Nucleotides Large intracellular signaling proteins Causes How does it all add up in Graves’ Disease? Treatments Introduction to paper discussion:

2. What could this case suggest about the cause of Graves’ disease? Return visit 5 weeks later Female smoking again (but ‘never’ around baby) Graves’ symptoms have increased Infant no longer exhibiting symptoms 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

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

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

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

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

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

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

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 Signal transduction Signaling cascades Protein structure (and its importance for protein function) 3-D protein structure (and its importance for binding) Protein modifications and their importance for activity Antibodies –specificity, role, and the importance of binding specificity

13. Next on Bio308 Discussion of journal article: 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. Terms and technique questions