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Understanding the Complement System: Functions and Dysregulation in Diseases

Explore the functions of the complement system, its role in various diseases, and the impact of dysregulation. Learn about complement deficiencies and markers of disease activity in SLE patients.

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Understanding the Complement System: Functions and Dysregulation in Diseases

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  1. Complementand SLE Marten Trendelenburg Stv. Chefarzt Klinik für Innere Medizin Universitätsspital Basel

  2. The complementsystem + lots of regulators !

  3. Functions of complement • Opsonisation • Acceleratedphagocytosis • Inactivation/neutralisation • Aggregation • Lysis of bacteria, cells, viruses • Membrane attackcomplex (MAC) • Viruseswithenvelope • Chemotaxis • C3a, C4a, C5a • Induction of humoral immune response • Antibodies • Possiblydamaginginflammatoryreactions • Not wellunderstood (coagulation etc.)

  4. C3 and C4: Single components and their split products C4 C3

  5. CH50: Classical pathway C4 C3

  6. Complementactivityorscreening

  7. Complementdeficiencies and disease • Classicalpathway: SLE, bacterialinfections • Lectinpathway: Bact. infections in childhood, SLE ? Others ? • C1 Inhibitor: Angioedema, SLE ? • Alternative Pathway: BacterialInfections • Terminal Pathway: Meningococcalinfection Dysregulation and/orconsumption

  8. The alternative pathway

  9. Diseasesassociatedwithhereditarydysregulation of complement Bogdanović R et al.,Nephron 1997 Kalman S et al., J Nephrol 2007 Ozen A et al., N Engl J Med 2017 Huber X et al., Medicine 2017 Loss and gain of functionmutations Atypicalhemolyticuremicsyndrome (aHUS) Age-relatedmaculardegeneration (AMD) C3 glomerulopathy Paroxysmal NocturnalHemoglobinuria (PNH) Others: Intestinal lymphangiectasia ?

  10. Diseaseswithsigns of complementactivation (selected) Infections ! incl. meningitis and Acute Post-StreptococcalGlomerulonephritis (APSGN) Cryoglubulinemia Autoimmune hemolysis (coldagglutinindisease etc.) Neuromyelitis optica (NMO) Someparaproteinemias Systemiclupuserythematosus (SLE) … …

  11. Complement C1q Binding site for IgG and IgM Important for fight against bacterial infections (pro-inflammatory), … … but also against autoimmunity (anti-inflammatory)

  12. C1q deficiency and SLE SLE patients with C1q deficiency have significantly more frequent discoid rash and oral ulcers than conventional SLE patients Stegert M et al., Mol Immunol 2015

  13. SLE: Low C1q (hypocomplementemia) versus C1q deficiency Cryoglobulins Some MGUS/paraproteins Coombs positive hemolyticanemia/coldagglutinins IgG RF/IgG anti-rat IgG (unpublished) Anti-phospholipidantibodies (NETs ?) Anti-C1q antibodies

  14. Low ‘complement’ asmarker of diseaseactivity • Complement consumption does occur in SLE (e.g. as judged by C3dg/larger C3 molecules) • Association with disease activity: C3 > CH50 > C4 (own data, unpublished) • Low CH50, C3 or C4 partially correlate with the SLEDAI as they are part of it. • C4 isstronglyinfluencedby C4 genecopynumbers (but thisseems not tobethemajorissue in SLE) • C3 and C4 display an increase in synthetic rate in response to inflammatory stimuli, which may compensate for hypercatabolism. • Measurement of complement levels in serum may not reflect accurately what is occurring in tissues • Autoantibodies to complement proteins may be associated with profound activation of the complement pathway in vivo, and the level of complement activation may be associated with the levels of these autoantibodies rather than by disease per se.

  15. Autoantibodiesagainstcomplementcomponents Anti-C1q antibodies (SLE, maybeothers) Anti-C1 inhibitorantibodies (acquiredangioedema) Anti-Factor H antibodies (aHUS, AMD, C3 glomerulopathy) Anti-C3bBb antibodies (nephriticfactor, C3 Nef): C3 glomerulopathy Others

  16. Trendelenburg M et al., Nephrol Dial Transpl 2006

  17. Anti-C1q in the follow-up Bock M. et al., PLoS One 2015

  18. Conclusions Complement activation can occur by extrinsic triggers as well as due to intrinsic dysregulation. Complement is involved in many diseases. Its role is understood best in rare diseases but complement is likely to be of importance for frequent diseases as well (AMD, Alzheimer, schizophrenia, cardiovascular, …) Anti-C1q antibodies are an excellent marker of disease activity in patients with SLE

  19. Receiver operating characteristics (ROC) Trendelenburg M et al., Nephrol Dial Transpl 2006; Bigler C. et al., Am J Kidney Dis 2008

  20. C1r C1s C4a C2b MAC Complement and Hemostasis Platelet Primary Hemostasis C1-Inh. Platelet vWF C1q C1r C1s XIIa DAF C4 C4b XI XIa TF C2 C4b C2a IX IXa VIIa VII antiThro C3b Secondary Hemostasis C3 C3a C3b F. I C4b antiThro X Xa X C2a C5 Thromb Prothrom F II C5a C5b Prot. S

  21. SLE Anti-C1q C1q Apoptose

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