Complement Flashcards
Compare and contrast innate and adaptive immune systems and where complement belongs
Innate:
- Present in earlier organisms and humans
- Relies on receptors and molecules recognizing pathogen patterns
- Receptor structure is encoded in the germline, consistent across humans
- Consistent response upon pathogen recognition, regardless of occurrence frequency
Adaptive:
- Present in higher vertebrates
- Relies on unique lymphocyte receptors to identify specific pathogens
- Individual-specific receptors for each person
- Remembers past pathogens, enabling faster and stronger responses with reexposure (memory)
Innate Immunity
- Pre-existing cellular and biochemical defense mechanisms
- Responds rapidly and consistently to infections
- Components include physical/chemical barriers, phagocytic cells, natural killer cells, and soluble proteins (e.g., complement, CRP)
What is the role of complement?
- Soluble proteins produced mainly by the liver
- “Complements” antibodies, enhancing opsonization and bacterial killing
- Sequential cascade activation upon pathogen presence, culminating in pathogen killing
- Cascade amplifies response
Describe how complement proteins are activated
- Most proteins activated by proteolysis
- Many proteins are proteases
- Activated proteins cleave and activate next proteins in cascade
^[note: does larger fraction typically activate?]
Describe the classical complement pathway
- most recent evolutionarily, despite name
- C1, C4, C2, C3, C5, C6, and C7 (though not in that order)
- “Membrane attack complex” formed from C6, C7, C8, and C9: forms pore in membrane, disrupts ion balance, and results in pathogen cell death
- In total, 3 pathways activate C3: 3 pathways of complement activation
Discuss similarities between complement pathways and discuss their regulation
Notes on the pathways
- all pathways culminate in cleavage of C3, resulting in formation of MAC, binding to C3b receptors to engulf and destroy pathogen, and recruitment of inflammatory mediators to site of infection
- all pathways occur on the cellular membrane ^[which?]
Complement Activation
- Includes complement proteins, receptors, and regulatory proteins
- Regulation of C3 on cell surfaces: very important, prevents activation on self cells rather than foreign cells
- Antibodies activate classical pathway: IgM, IgG1»IgG3
Discuss the functions of complement
- Membrane attack complex
- Active intermediaries (C3a, C4a, C5a) - anaphylatoxins, inflammatory cell recruitment (chemoattract properties) ^[?]
- Opsonization - Complement deposition aids phagocytosis
- Complement receptors augment B cell activation (especially if no T help)
- Complement receptors assist B cells in transporting non-cognate antigens to lymph nodes, where the reactive B or T cell can interact with it
Discuss the role of complement in BCR formation
B Cell Co-receptor
- Essential for formation of BCR
- B cell activation through BCR amplified by signals from CD19, CD21, and CD81
- CD21 (complement receptor) activated by complement-coated pathogens
- Deficiency in CD19 and CD81 associated with common variable immunodeficiency (CVID) causing low antibody production
List and briefly the roles of key complement regulator proteins
- Regulatory proteins: C1 inhibitor, Factor H, Factor I, CD59
- c1 inhibitor targets begining of cascade, and keeps C1 contolled
- H and I targets middle of cascade, targets products of cascade, binds and prevent activation – controlling C3 deposits ^[questions]
- CD59 at end of cascade, inhibits final assembly
Discuss how complement levels are evaluated in diagnosis
- Serum testing for complement component levels
- C3 and C4 levels tested in practice
- intact not activated byproducts
- Patterns of C3 and C4 levels indicate pathway activation
- C4 down: mild classical pathway activation
- C3 and C4 down: classical activation, formation of antibody complex
- C3 down: alternate pathway activation ^[wb lectin?]
Measuring Complement in the Diagnostic Lab
- Detecting complement in tissue biopsies
- C3 frequently detected; C1q found in diseases strongly activating classical pathway
- Laboratory looks at levels of “intact” C3 and C4 – therefore when the numbers are low this means that the
complement has been activated
Discuss the purpose of detecting complement in biopsies
- Finding complement in biopsies of kidneys or skin mean that the complement pathway has been activated and can help to work out what the pathology is
- C3 is the complement protein most often looked for (and found) in these cases but for diseases that activate the classical complement pathway strongly C1q can also be found in biopsies
Describe oathogenesis of hereditary angioedema
- Hereditary angioedema due to C1 inhibitor loss: unprovoked and massive swelling
- bradykinin increase, due to C1 inhibitor loss, increasing precursors, increasing vascular permeability and vasodilation
- complement serves as diagnostic pathway as C1 INH also controls the pathway: expect C4>C2, C3 decrease
Describe paroxysmal nocturnal haemaglobinuria
- rare, acquired, life threatening
- characterised by red cell destruction and clotting risk
- somatic mutations in protein involved in GPI tails synthesis, responsible for anchoring proteins into membrane
- Thus CD59 cannot attach, and complement attacks
- medicine blocks C5, prevents MAC formation: but is expensive and makes patients immunocompromised (vaccinations)
Discuss effect of polymorphisms in Factor H
- complex chronic inflammation
- Genetic defects in Factor H genes associated with atypical hemolytic uremic syndrome and certain glomerulonephritis types
- treated with monoclonal antibody therapy
Discuss effect of defects in complement genes on SLE risk
Genetic defects in genes for C1q, C1r, C1s, C4 or C2
associated with risk of SLE
- complements have a side role in getting rid of dead and dying cells
- poor clearance leads to increase in self-antigens and autoimmunity
What is the effect of complement defects on Neisseria susceptibility?
- Complement defects increase susceptibility to Neisseria meningitidis infections
- rule out C9 defect, as increases vulnerability to subsequent infection
- defective C9 = poor MAC
- Patients with complement defects require lifelong antibiotics to guard against Neisserial infections
