LC 1 - Abs and inflammation in CNS/PNS

Question 1

paraneoplastic neurological symptoms

Answer 1

• Cancers that lead to autoimmune related degeneration of the nervous system
  o Often teratoma –> stem-cell cancers that express various antigens so large potential for off-site autoimmunity –> onconeuronal Abs
• Thymoma –> thymus fails to do negative selection of T-cells  autoimmunity

Question 2

AcHR-MG - symptoms

Answer 2

• The spectrum of symptoms ranges from a purely ocular form to severe weakness of the limb, bulbar and respiratory muscles. The age of onset is variable from childhood to late adulthood with disease peaks in younger adult women and older men
  o Weakness is variable from day-to-day
• The most common presenting symptoms are ocular bulbar muscle weakness, with double vision and ptosis.
• Most patients will develop diplopia and/or ptosis some time during the course of their disease.
• In addition, up to 80% of patients with ocular onset will go on to develop generalized symptoms, usually within two years of disease onset
• Generalised symptoms include muscle weakness improved by rest and worsened by exertion and muscle fatigue  might lead to respiratory crisis (ventilation prevents death)

Question 3

AcHR-Mg - patho mechs

Answer 3

• Nicotinic AChR is a heteropentamer consisting of two α-subunits and 4 others which are organized around a central pore  creating the transmembrane protein responsible for transducing neuronal signals into muscle contractions
• Antibodies against the AChR are found in approximately 80% of MG patients. At least half of the AChR autoantibodies are directed at the AChR α-subunits (main immunogenic region)
• AChR antibodies are predominantly of the IgG1 and IgG3 subclasses
• Both able to bind to C1q  classical complement pathway
• Activate immune cells  antibody-dependant cellular cytotoxicity (ADCC)
• Binding (very rare slow channel effect – pore stays open leading to activation),
• Blocking (curare-like blocking and Ach competing), or modulating its activity.
• Antigenic modulation
• The predominant mechanism is the binding of the antibody and activation of the classical complement cascade (C1q,4,2,3,5,6,7,8,9) leading to the formation of the membrane attack complex (MAC), which causes damage of the postsynaptic membrane and destruction of synaptic folds which contain AChRs and associated proteins
  o Depolarization
  o Calcium influx
  o Cytoplasm efflux

Question 4

MG treatment

Answer 4

o Plasma exchange
o IVIg

• Medium term
  o Don’t know what to do at this timepoint
  o Thymectomy (don’t know why exactly – unless ectopic thymic nodules/thymoma)
• Long term
  o Immunosuppression
   Cyclosporine A
   Azathioprine
   MMF
   Rituximab
• Experimental
  o Proteasome inhibitors (B-cell targeting?)
  o Immunosuppressive drugs
  o Blocking antibodies
  o Therapeutic antibodies

Question 5

PTMG

Answer 5

PTMG – passive transfer MG
- Injecting anti-AChR IgG1 into rat (mAb 35) leading to fast onset of disease

Question 6

EAMG

Answer 6

• experimental active MG
• injection torpedo AChRs that elicit and immune reponse in the rat
• leading to the formation of anti-topedo Abs of which 1% is cross-reactive to native AChR –> MG like pathology

Question 7

Ab structure

Answer 7

drawing

Question 8

Function of Ab type

Answer 8

drawing

Question 9

hypersensitivity reactions

Answer 9

1. Allergies
   a. IgE
   i. Asthma
2. Cytotoxic – Ab-dependent
   a. IgM and IgG
   b. Complement – MAC
   i. MG
   ii. Rheumatoid arthritus
3. Immune complex
   a. IgG
   b. Complement
   c. Neutrophils
   i. Lupus
4. Delayed-type hypersensitivity, cell-mediated immune memory response, AB-independent
   a. T-cells
   i. MS