Complements and complement deficiency

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Complements and complement deficiency

Presented by Suparat Sirivimonpan, MD.

July19, 2013

Published in: Health & Medicine, Technology
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Complements and complement deficiency

  1. 1. Complement and Complement deficiency 19-7-2013 Suparat Sirivimonpan, MD.
  2. 2. Topic outlines Complement • Complement pathway activation – Classical pathway – Alternative pathway – Lectin activation pathway • Complement receptors • Regulation of complement activation • Functions Complement deficiencies • Disorders associated with complement deficiencies • Evaluation • Management
  3. 3. The complement system • Heat labile plasma proteins • consists of several plasma proteins that work together » normally inactive » activated only under particular conditions • Important effector mechanism of innate immunity • One of the major effector mechanisms of humoral immunity Abbas.Cellular and molecular immunology 7th edition
  4. 4. The most important biological functions of the complement system 1. innate host defense: – Opsonization – initiation of an inflammatory response – clearance of apoptotic debris – direct lysis of gram negative bacteria 2. adaptive responses – B cell activation – T cell priming Kathleen E. Sullivan. Middleton's Allergy: Principles & Practice, 7th ed
  5. 5. Abbas.Cellular and molecular immunology 7th edition
  6. 6. Complement activation • Complement activator  proteolytic enzyme cascade • Complement regulatory protein • Complement receptor
  7. 7. Pathways of Complement Activation • 3 major pathways Pathways Activator 1. Classical -Ab bound to Ag (IC) -Pentraxins (CRP,SAP, PTX3) -SIGN R-1 -Apoptotic cell 2. Alternative Microbial cell surfaces (absence of Ab) ex. LPS 3. Lectin mannose residues on microbe Abbas.Cellular and molecular immunology 7th edition
  8. 8. Kathleen E. Sullivan. Middleton's Allergy: Principles & Practice, 7th ed - Alternative and lectin : effector mechanisms of innate immunity - Classical : major mechanism of adaptive humoral immunity Abbas.Cellular and molecular immunology 7th edition
  9. 9. Classic pathways Abbas.Cellular and molecular immunology 7th edition
  10. 10. Classic pathways Abbas.Cellular and molecular immunology 7th edition
  11. 11. Classic pathways C3 convertase = C4b2a Abbas.Cellular and molecular immunology 7th edition C5 convertase = C4b2a3b
  12. 12. Alternative pathways Abbas.Cellular and molecular immunology 7th edition
  13. 13. Alternative pathways Abbas.Cellular and molecular immunology 7th edition internal thioester groups C3 tickover
  14. 14. Alternative pathways Abbas.Cellular and molecular immunology 7th edition C3 convertase = C3bBb C5 convertase =C3bBb3b
  15. 15. Abbas.Cellular and molecular immunology 7th edition Classic Lectin pathways
  16. 16. Lectin pathways • MBL and ficolins associate with MBL-associated serine proteases (MASPs) • MASP proteins – structurally homologous to the C1r and C1s proteases – serve a similar function : cleavage of C4 and C2 Abbas.Cellular and molecular immunology 7th edition Subsequent events in this pathway are identical to those that occur in the classical pathway
  17. 17. Lectin pathways Abbas.Cellular and molecular immunology 7th edition C3 convertase = C4b2a C5 convertase = C4b2a3b
  18. 18. Abbas.Cellular and molecular immunology 7th edition
  19. 19. Abbas.Cellular and molecular immunology 7th edition Pores : 100 A in diameter (10 nm)
  20. 20. L. Skattum et al. Molecular Immunology 48 (2011) 1643–1655
  21. 21. Complement receptors Abbas.Cellular and molecular immunology 7th edition
  22. 22. Complement receptors Complement receptor of the immunoglobulin family (CRIg) • express on surface of macrophages in the liver (Kupffer cells) • binds C3b and iC3b • involved in the clearance of opsonized bacteria and other blood-borne pathogens Abbas.Cellular and molecular immunology 7th edition
  23. 23. Regulators of Complement Activation (RCA) Abbas.Cellular and molecular immunology 7th edition
  24. 24. MCP, CR1, DAF are produced by mammalian cells but not by microbes Abbas.Cellular and molecular immunology 7th edition
  25. 25. Abbas.Cellular and molecular immunology 7th edition iC3b, C3d, and C3dg  recognized by receptors on phagocytes and B lymphocytes
  26. 26. Abbas.Cellular and molecular immunology 7th edition
  27. 27. Protein Cell 2012, 3(7): 487–496
  28. 28. Function Abbas.Cellular and molecular immunology 7th edition C5a > C3a > C4a : anaphylatoxin C3b,C4b: opsonin
  29. 29. Functions (cont.) • Promote solubilization of immune complexes and their clearance by phagocytes • C3d protein binds to CR2 on B cells  facilitates B cell activation and initiation of humoral immune responses Abbas.Cellular and molecular immunology 7th edition
  30. 30. Complement deficiency
  31. 31. L. Skattum et al. Molecular Immunology 48 (2011) 1643–1655
  32. 32. L. Skattum et al. Molecular Immunology 48 (2011) 1643–1655
  33. 33. L. Skattum et al. Molecular Immunology 48 (2011) 1643–1655
  34. 34. COMPLEMENT DEFICIENCIES • Deficiencies in classical pathway components • Deficiencies in alternative pathway components • Deficiencies in lectin pathway components • Deficiencies in the terminal complement components • Deficiencies in complement regulatory proteins • Deficiencies in complement receptors
  35. 35. L. Skattum et al. Molecular Immunology 48 (2011) 1643–1655 Deficiencies in classical pathway components
  36. 36. C1q DEFICIENCY • strongest known genetic risk factor for lupus • early- onset SLE • lupus seen in C1qD individuals is less steroid responsive • increased rate of infection – compromised opsonization – mild decrease in B cell co-stimulation • initial symptoms in the C1qD patients are more often cutaneous symptoms of autoimmune disease than infections Kathleen E. Sullivan. Middleton's Allergy: Principles & Practice, 7th ed L. Skattum et al. Molecular Immunology 48 (2011) 1643–1655
  37. 37. C1r,C1s DEFICIENCY • Deficiencies of C1r and/or C1s are extremely rare • frequently combined • few cases of selective deficiencies • Glomerulonephritis and lupus have been found in C1r/C1s deficient patients • 60% develop SLE or similar disease • infections mainly due to encapsulated bacteria are frequent Kathleen E. Sullivan. Middleton's Allergy: Principles & Practice, 7th ed
  38. 38. C4 DEFICIENCY • C4A deficiency – 1–2% of general population – up to 15% of patients with SLE – risk factor for SLE – severity of the disease is often less in patients with C4A deficiency compared to complement sufficient hosts • C4B deficiency – 1–2% of population – up to 15% of patients with invasive bacterial disease : – impaired opsonization and a modestly compromised B cell response to antigen Kathleen E. Sullivan. Middleton's Allergy: Principles & Practice, 7th ed
  39. 39. C2 DEFICIENCY – most common of inherited classical complement component deficiencies in Caucasians – most common cause of death : sepsis – most common organisms : S. pneumoniae and H. influenzae – Asymptomatic Kathleen E. Sullivan. Middleton's Allergy: Principles & Practice, 7th ed
  40. 40. C3 DEFICIENCY • rarest of the 4 early component deficiencies • most severe phenotype – neutrophil dysfunction (abscesses) – humoral deficiencies (sinopulmonary disease) – complement deficiencies (sepsis, meningitis) • 1/3 : Membranoproliferative glomerulonephritis Kathleen E. Sullivan. Middleton's Allergy: Principles & Practice, 7th ed
  41. 41. L. Skattum et al. Molecular Immunology 48 (2011) 1643–1655 Deficiencies in Alternative pathway components
  42. 42. FACTOR B DEFICIENCY • A single case has been reported : meningococcemia FACTOR D DEFICIENCY • Neisserial infections : most common manifestation • Systemic streptococcal infections have also been seen • Other complement levels are typically normal Deficiencies in Alternative pathway components Kathleen E. Sullivan. Middleton's Allergy: Principles & Practice, 7th ed
  43. 43. PROPERDIN DEFICIENCY • only X-linked complement deficiency • occurs largely in Caucasians • one or more episodes of meningococcal disease • Other bacterial infections are also seen (less common) • high fatality rate in meningococcal disease in contrast to patients with terminal complement component deficiencies Deficiencies in Alternative pathway components Kathleen E. Sullivan. Middleton's Allergy: Principles & Practice, 7th ed
  44. 44. L. Skattum et al. Molecular Immunology 48 (2011) 1643–1655 Deficiencies in Lectin pathway components
  45. 45. MBL deficiency • minimally to susceptibility to infections • combination with other primary or secondary immunodeficiency  MBL deficiency has been shown to be a risk factor in particular for respiratory tract infections – ex. C2 deficiency , CVID • Also increased risk of cardiovascular disease Kathleen E. Sullivan. Middleton's Allergy: Principles & Practice, 7th ed L. Skattum et al. Molecular Immunology 48 (2011) 1643–1655 Deficiencies in Lectin pathway components
  46. 46. MASP2 DEFICIENCY (mannose-binding protein-associated serine protease 2) • combination of autoimmune symptoms and recurrent respiratory infections • more severe course of disease in MASP-2-deficient patient as compared to MBL-deficient individuals Ficolin-3 deficiency • first case of ficolin-3 deficiency was described – recurrent respiratory infections since early childhood and later in life cerebral abscesses and several episodes of pneumonia Kathleen E. Sullivan. Middleton's Allergy: Principles & Practice, 7th ed L. Skattum et al. Molecular Immunology 48 (2011) 1643–1655 Deficiencies in Lectin pathway components
  47. 47. L. Skattum et al. Molecular Immunology 48 (2011) 1643–1655 Deficiencies in terminal complement components - only with meningococcal infection with high recurrence rate -rarely fatal (ǂ Properdin) -C9 deficience : CH50 is diminished but not absent
  48. 48. L. Skattum et al. Molecular Immunology 48 (2011) 1643–1655 Deficiencies in complement regulatory proteins& complement receptor
  49. 49. WAO Journal 2012; 5:182–199) 3 forms of HAE (1) HAE-1 - C1-INH deficiency : low antigenic and functional C1- INH levels (2) HAE-2 - C1-INH dysfunction : normal (or elevated) antigenic but low functional C1-INH levels (3) HAE-3 - normal C1-INH antigenic and functional levels
  50. 50. Curr Allergy Asthma Rep (2012) 12:273–280 HAE type 1,2
  51. 51. Type 3 HAE • HAE with normal C1-INH • very rare disease • The symptoms are very similar to HAE-1/2 • A subset of HAE-3 patients exhibits mutations in factor XII • The genetic abnormality of most HAE-3 patients has not yet been defined • Diagnosis requires a family history of angioedema WAO Journal 2012; 5:182–199)
  52. 52. HAE : diagnosis should be suspected : • history of recurrent angioedema, esp. if hives are absent • with (1) positive family history (2) onset of symptoms in childhood/adolescence (3) recurrent abdominal pain attacks (4) occurrence of upper airway edema (5) failure to respond to antihistamines, glucocorticoid, or epinephrine; and (6) presence of prodromal signs or symptoms before swellings • Suspicion of HAE-1/2 should prompt laboratory workup WAO Journal 2012; 5:182–199)
  53. 53. HAE - Extremities, face, or genitalia are most often involved - Angioedema typically progresses for 1–2 days and resolves in another 2–3 days - Common precipitants are illness, hormonal fluctuations, trauma, and stress - Infections have rarely been reported in HAE in spite of the associated hypocomplementemia - very low levels of C4 ,C2 : enough for CP-dependent protection against infection Kathleen E. Sullivan. Middleton's Allergy: Principles & Practice, 7th ed L. Skattum et al. Molecular Immunology 48 (2011) 1643–1655
  54. 54. HAE : work up • blood levels of C4, C1-INH protein, and C1- INH function • if abnormally low  repeat to confirm the diagnosis (Evidence grade: D, strength of recommendation: strong) • normal results may need to be checked during an attack of angioedema WAO Journal 2012; 5:182–199) C4 -C4 level is useful for screening -cannot be relied upon to confirm or exclude Dx - repeat C4 during an attack  ↑probability - False negative  measurement of C4d
  55. 55. HAE-1/2 : work up • The C1-INH antigenic level – low in HAE-1 and acquired C1-INH deficiency patients – normal in HAE-2 patients • The C1-INH functional activity – low in HAE-1 and HAE-2 and acquired C1-INH deficiency patients • In rare patients  Gene analysis – SERPING1 gene : HAE-1/2 – factor XII genes : HAE-3 WAO Journal 2012; 5:182–199) • C3 levels : normal • CH50 is not useful
  56. 56. WAO Journal 2012; 5:182–199)
  57. 57. Treatment • All attacks that result in debilitation/dysfunction and/ or involve the face, the neck, or the abdomen should be considered for on-demand treatment • Treatment of attacks affecting the upper airways is mandatory • treated attack as early • Every patient with HAE-1/2 should be considered for home therapy and self-administration training, once the diagnosis of C1-INH deficiency is confirmed WAO Journal 2012; 5:182–199)
  58. 58. WAO Journal 2012; 5:182–199)
  59. 59. WAO Journal 2012; 5:182–199) Plasma-derived C1-INH (pdC1-INH) recombinant C1 INH B 2 receptor antagonist kallikrein inhibitor
  60. 60. L. Skattum et al. Molecular Immunology 48 (2011) 1643–1655 Deficiencies in complement regulatory proteins
  61. 61. CD59 DEFICIENCY AND PNH • CD59 is expressed on most hematopoietic cells and endothelial cells where it confers protection from intravascular complement mediated lysis • phenotypic resemblance to PNH – recurrent episodes of hemoglobinuria due to intravascular hemolysis • The diagnosis of PNH is made by flow cytometry for CD59 or CD55 (DAF) • DAF deficiency does not have a hemolytic phenotype – CD59 is the more important than CD55 Kathleen E. Sullivan. Middleton's Allergy: Principles & Practice, 7th ed
  62. 62. L. Skattum et al. Molecular Immunology 48 (2011) 1643–1655 Deficiencies in complement receptor
  63. 63. Evaluation
  64. 64. Evaluation assess patients with recurrent sepsis/systemic infection or sepsis on the background of autoimmune disease (or a family history of autoimmune disease) CH50 AH50 MBL levels Patients with a single meningococcal infection, either meningitis or meningococcemia, probably deserve an evaluation in non-endemic areas CH50 AH50 patients with meningococcal disease with an unusual serotype (serotypes X, Y, Z, W135 or 29E), on background of a positive family Hx, or recurrent meningococcal disease CH50 AH50 Patients with lupus CH50 Kathleen E. Sullivan. Middleton's Allergy: Principles & Practice, 7th ed
  65. 65. Evaluation assess patients with Membranoproliferative glomerulonephritis and HUS -CH50 -AH50, -C3 level (factor H, I, MCP mutation analyses ) recurrent angioedema in the absence of allergic reactions, patients with a family history of angioedema patients with angioedema preceded by a reticular rash, patients with angioedema after trauma -C4 levels -C1 inhibitor antigen and functional levels Kathleen E. Sullivan. Middleton's Allergy: Principles & Practice, 7th ed
  66. 66. Evaluation • Deficiencies of all the cascade components lead to a CH50 of 0 or near 0 – With the exception of C9 deficiency • Low levels of CH50 or AH50 results should be repeated due to – mishandling of the serum is an extremely common – C’ consumption due to active immune complex disease – diminished hepatic production : liver disease, immaturity of hepatic production seen in young infants – Less common : regulatory protein defects leading to consumption of C3 such as factor D, factor H, and factor I deficiency Kathleen E. Sullivan. Middleton's Allergy: Principles & Practice, 7th ed
  67. 67. Evaluation • abnormal CH50 or AH50 has been confirmed  serum levels of certain components (C3 and C4 primarily) Kathleen E. Sullivan. Middleton's Allergy: Principles & Practice, 7th ed
  68. 68. Management • completely dependent on the type of defect – susceptibility to infectious agents – course of the disease • Treat infection, Autoimmune, associated diseases L. Skattum et al. Molecular Immunology 48 (2011) 1643–1655
  69. 69. Management • Prevention – Replacement of the missing component • C1-INH concentrate is the only product that is licensed and is used in a regularly fashion • FFP – Antibiotic prophylaxis – Vaccination • Encapsulated bacteria : S. pneumoniae and H. influenzae • meningococcal vaccine (tetravalent serogroup A, C, Y and W-135) – Hygienic measures L. Skattum et al. Molecular Immunology 48 (2011) 1643–1655
  70. 70. Take home message • The complement system : essential component of innate immunity – opsonize microbes – promote the recruitment of phagocytes to site of infection – in some cases to directly kill the microbes • One of the major effector mechanisms of humoral immunity • Also crucial role in the preservation of the immunological homeostasis • 3 pathways : Classical , Alternative, Lectin – Activator, Regulatory protein
  71. 71. Take home message • Complement deficiencies are uncommon • infection susceptibility and disease susceptibility depend on which factor is missing • consequence can vary from almost none (C9 deficiency) to very serious infections (C3 deficiency) – C3 deficiency : severe, recurrent, often lethal bacterial infections • SLE , meningococcal disease : two most common phenotypes associated with complement deficiencies
  72. 72. Take home message • CP deficiencies : encapsulated bacteria • AP and terminal pathway deficiencies : Neisseria species • Complement deficiency does in general not confer increased susceptibility to fungal, parasitic or viral infections • The diagnosis of most complement deficiencies begins with the demonstration of a markedly low CH50 or AH50 • The identification of complement deficiency states is important to ensure optimal prevention and treatment

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