Previously on Bio308

Types

Similarities

2nd Messengers

IP3 DAGCa++

Advantages Coordination

Nucleotides

Large intracellularsignaling proteins

Others

On to Off

BUT Internal signaling in Graves’ Patients is fine…

There goes another perfectly good hypothesis, rejected due to data.

Next on Bio 308Graves’ disease:

Comparing information from other situationsand Disease specific information to come up withhypothesis for the molecular basis of this disease

Causes

How does it all add up?

Treatments

Introduction to paper discussion:

What could this case suggest about the cause of Graves’ disease?

Return visit 5 weeks laterFemale smoking again (but ‘never’ around

baby) Graves’ symptoms have increasedInfant no longer exhibiting symptoms

Case outline: 31 year old Caucasian female

Smoker (before pregnancy)Previously diagnosed with Graves’ disease4 weeks post partum Symptoms lessened during pregnancy but

now have rebounded4 week old Caucasian male

Exhibiting symptoms of Graves’ disease

Possible causes of Graves’ disease?:

Genetic predisposition, appear to need multiple ‘hits’

Gender hormonal role suggested

Environment exposure to toxins (smoking), radiation, stress

“Diffusible/Destructible signal” antibodies

What are antibodies?

Fig 3-21

General structure of an antibody (Ab)

Antigen (Ag) binding domain

How are antibodies made?

How does the body knowwhen to make Ab?

Why make Ab? What do they do?

Antibody production

Self vs. Non-self

+Invasion by ‘foreign body’Adenovirus

Poliovirus

What is foreign?

+Immune response mountedHow?

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

Woman and child caseSometimes 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 allcases

Graves’ disease patientsshow high titer of TSI (alsocalled LATS)

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 TSIsurprising?

Why do TSI get made?

Yersinia entericolitica and Graves’ disease : ONE hypothesisREMEMBER DISEASES CAN HAVE MULTIPLECAUSATIVE FACTORS

Dennis Kunkelgram negative coccobacillus

Food borne pathogenGenerally porcine sourceCan invade body through structures in intestineCan cause dysenteric diarrhea

Thyroid

Lipoprotein epitope

TSH-ReceptorLigand binding site

Molecular Mimicry

(Remember this is a hypothesis supported byevidence in a small % of Graves’ cases. Most people do not contract Graves’ this way.)

Cures for Graves’ Disease

Treatments:

Radioactive IodineDrugs –regulate thyroid or alleviate symptoms Surgery

All require lifetime drug therapy

Graves’ disease does not appear to have one causative factorbut results from a combination of genetic predispositions andenvironmental factors

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 ofbinding specificity

Next on Bio308

Discussion of journal article:

Tuesday 9/20:

Thursday9/22 : The paper-- figure by figure

Paper and study questions are found as links under Assignments and Quizzes on BlackboardThe questions will take time to complete and thearticle will be ‘heavy reading’ do not put it off.

Terms and technique questions