Week 4 Flashcards
tline the activation of the Classical complement pathway
- Binding of C1q to complexed IgG or IgM results in conformational change in C1 complex
- Activation of C1r then C1s (Serine esterase)
- C1s cleaves C4 to C4b and C4a
- C4b binds to C2 and is then cleaved by C1s, generating classical pathway C3 convertase (aka C4b2a)
Outline the activation of the Lectin pathway of the complement system
- Mannose-binding lectin (MBL) binds to bacterial carbohydrate moieties (Mannose)
- The bound MBL then activates proteases called MASPs
- Cleavage of C4 and C2 then proceeds analogous to the classical pathway
Outline the activation of the alternative pathway of the complement system
-C3 undergoes spontaneous hydrolysis (Auto-activation)
Outline the functions (+ regulation?) of the complement system
- Host defence against infection
- Opsonization
- Chemotaxis and leucocyte activation
- Lysis of bacteria cells
- Interface between innate and adaptive immunity
- Disposal of waste: Clearance of immune complexes and apoptotic cells
- Regulation: C1 inhibitors, Factor I, CD59 all inhibit the process
Describe the links between uncontrolled complement activation and haematological disease
- Haemolytic uraemic syndrome (HUS): results from fluid phase dysregulation
- Paroxysmal nocturnal haemoglobinuria (PNH): results from membrane-bound dysregulation
- Coomb’s test is a measure of complement activation
Describe the pathophysiology of paroxysmal nocturnal haemoglobinuria (PNH)
- Deficiency in the glycosylphosphatidylinositol (GPI) anchor found on marrow stem cells
- This deficiency leads to a deficiency of GPI-linked proteins (Such as the membrane inhibitor of reactive lysis (MIRL) aka CD59)
- Red cells that descend from these stem cells also lack GPI and GPI-linked proteins, so become sensitive to lysis by complement. (especially MIRL/CD59, DAF/CD55)
Clinical features of paroxysmal nocturnal haemoglobinuria (PNH)?
- Chronic intravascular haemolysis
- Anaemia
- Nitric oxide depletion
- Thrombosis at unusual anatomical sites
- Bone marrow failure (BMF) and cytopenia
Treatment of PNH-anaemia?
- Iron and folate supplements
- Blood transfusion
- Inhibition of haemolysis (Steroids or Complement inhibitors)
- Eculizumab: mAb: C5 inhibitor.
Describe how gene therapy is being used in the treatment of SCD
- A psuedotyped lentivirus is used to inject wild-type Beta globin genes into HSCs, along with control sequences such as LCRs
- Lentiglobin BB305 has shown promising results
- Vector derived haemoglobin production improves clinical picture
Give an example of a novel approach for the treatment of sickle cell
-Prevention of vaso-occlusion by P-selectin inhibitor Crizanlizumab
- 6 month old baby presents with low Hb, low reticulocytes, impaired growth, and craniofacial and cardiac abnormalities. Normal WCC and platelets
- What is the most likely diagnosis?
-Diamond Blackfan anaemia (Congential pure red cell aplasia)
- 8 year old child presents with anaemia, neutropenia and thrombocytopenia, dysplasia of the radius
- What is the most likely diagnosis?
-Fanconi Anaemia (Bone marrow failure syndrome)
Give 3 causes of acquired red cell aplasia
- Parvovirus B19
- EPO therapy
- Autoimmune disorder
What is the main treatment for acquired Pure red cell aplasia (PRCA)?
- Thymectomy
- Immunosuppression
- Supportive blood product transfusions
-What enzymopathy is the most common cause of hereditary Chronic non-spherocytic haemolytic anaemia (CNSHA)? Bonus Q what other enzymopathies causes this?
-Pyruvate kinase deficiency //Also G6PD deficiency and Glucose 6-phosphate isomerase
