COMPLEMENT A Most Incomplimentary Role in Autoimmunity Rheumatology Lunch Rounds

COMPLEMENT: A Most Incomplimentary Role in Autoimmunity Rheumatology Lunch Rounds St. Michael’s Hospital Tuesday, January 21st 2003 Christine Cserti, PGY3 OUTLINE     Case The Complement Cascade The Complement Conundrum: Pathophysiology: – cause or effect? – Complement Activation & Consumption – Autoantibodies to Complement – Hypocomplementemic Genetics   Applications Summary CASE: Miss S.T.  19 yo Native Canadian female with newly-diagnosed systemic lupus erythematosus (SLE) Context: – Forewarning, asynchronous, non-specific symptoms evolving fulminantly… – Hyperestrogenic de-repression…   Unplanned pregnancy, T1-terminated – Iatrogenic insult…  Antibiotic treatment of STD/PID – Inherited predilection…  Maternal and paternal second/third degree relatives with lupus Systemic Lupus Erythematosus  Constitutional MSK – Fatigue, malaise, fever, weight loss  – arthralgias [90%]: non-erosive, periarticular +/- tendinous inflammation, usually PIPs, MCPs, wrists, knees; Jaccoud’s arthropathy – myalgias; inflammatory myositis; steroid-induced myopathy (+/- bone demineralization pain?)  Mucocutaneous/Ocular – Oral or nasal septal ulcers [30%], xerostomia – Dermatologic [80%]: photosensitivity [50%], malar rash, discoid rash [25%], alopecia [50%], urticaria, angioedema, bullae, panniculitis, Raynaud’s [30%], livedo, digital purpura, palpable (LCV) purpura – Keratoconjunctivitis sicca, anterior uveitis/iridocyclitis, central retinal artery or vein occulsion, ischemic optic neuropathy, HTN changes  Serosal Renal – [50%]: pleural, pericardial, peritoneal  – Mesangial, membranous, (focal or diffuse) proliferative nephropathy: nephritic & nephrotic Systemic Lupus Erythematosus  Hematologic – Anemia (chronic inflammatory or AIH), ATP, APLAS (VDRL & LA or ACA), leukopenia/lymphopenia  CNS – Non-psychiatric disturbances, seizures, CVA (thrombotic vasculopathy), migraine/vascular HA, organic brain syndrome/dementia, coma  Pulmonary – Pleurisy, leukosequestration, inflammatory pneumonitis, IPF, pulmonary HTN, phrenic N palsy  Cardiac – Pericarditis, myocarditis, Libman-Sacks endocarditis, thrombotic vasculitis, coronary vasculitic or atherosclerotic MI  Gastrointestinal – Peritonitis, mesenteric vasculitis, pancreatitis, nonspecific inflammatory liver disease  Laboratory – ANA + [90-95%]: speckled, diffuse, or peripheral – Anti-dsDNA [30-70%], anti-RNP, anti-Sm [30%], anti-Ro, anti-La, hypocomplementemia CASE: Miss S.T.  Serologically: – ANA+ – Anti-dsDNA+ – profound hypocomplementemia  Tx – – – – steroid pulse to high-dose steroid maintenance cyclophosphamide (cycle 1) hydroxychloroquine supportive care & ancillary prophylaxis  Persistent hypocomplementemia: – ?disease activity – ?underlying hypocomplementemic genetics – ?nephrotic hypocomplementemia The Complement Cascade  Direct participant & bridge between innate & adaptive immune response: Hub = C3 Internal thioester binds covalently to hydroxyl groups on -CHO’s & -NH3 groups on proteins The Complement Conundrum in SLE  Cause? – Homozygous deficiency of the earliest proteins of the classical pathway is causally associated with susceptibility to developing SLE  Effect? – Complement consumption – AutoAb to complement proteins develop as part of autoantibody response Complement Activation in SLE  Historical primacy  Laboratory significance: – Diagnostic – IC-mediated pathologic predominance (AIHA, GMN, antiC1q) – Disease activity   C3 & C4 – antigenic concentrations CH50 (complement hemolysis 50%) test – functional measure of pathway until MAC   Classical pathway: – consumption of C1, C4, C2 Alternative pathway: – consumption of C3, factor B Caveat on Disease-Activity “Complement Concordance”  Complement is a poor surrogate of disease activity (and thus often “discordant”) in many patients because of : – Inter-individual variability in baseline complement levels   Genetic polymorphisms Unknown factors – Acute phase synthesis vs activation-related catabolism – Serum vs tissue? – Autoantibodies Complement Activation in SLE  Histopathologically demonstrable deposition; sufficient… but necessary? (C5a) The CR1 Story – Complement receptor type 1, aka “immune adherence receptor” or CD35 – Ligand for C3b, C4b, iC3b – On the covert particulate-pathogen carriers, headed to the mononuclear phagocytic systems (eg- RBCs)  – Cofactor for Factor I (inactivating C3 to iC3b then C3dg + C3c) – On B cells & APCs: Predominate in overwhelming complement activation Autoantibodies to complement in SLE  Clinically irrelevant bystanders – Anti iC3b  Clinically malignant – – – – – C3 nephritic factor Anti-C1 inhibitor autoAb Anti-CR1 Anti-C4b2a C3 classical pathway convertase Ez Anti-C1q     1/3 of SLE pts & all HUV pts Disease severity correlate Cause or effect? As the clearance agent for autoantigenic complexes, is it so surprising that it so provokes autoantibody formation? Murine Models of GeneTargeting Techniques… Primary/Inherited Hypocomplementemia in SLE Induction  Of the homozygous hereditary complement deficiencies, the more proximal the CP protein in question, the more prevalent, severe, genderequitable, & earlier the onset the SLE: C1q or r/s -/- 90% 55% pGMN 50% Skin 90% Inc C’s ANA+ 75% DNA-, ENA+ Milder renal disease in 50%, anti Ro & La + 1% of all SLE Mostly cutaneous C4 (AB) -/-/-/- 75% cf MZ:DZ general SLE concordance rates of 24%:2% & female preponderance  Protective effect of these proteins? C2 -/(most common) C3 -/- 10-30% 14% (rare) Recurrent pyogenic infections, GMN 23% Primary/Inherited Hypocomplementemia in SLE Induction  Complement prevents SLE through: – processing and clearing of  immune complexes – Covalent insinuation (C1q to Fc, C4b & C3b to Ag) = effective solubilization & enhanced binding options to other ligands  apoptotic cells – Via C1q & other proteins – establishing self-tolerance for autoantigens by silencing B-cells  crippled during inflammation Mechanistic Pathophysiology of Complement in SLE  Early cascade crucial in averting autoimmunity Activated, distal cascade is: – Pro-inflammatory – Consumptive – Self-surrendering to autoimmune attack  Applications  Monitoring:    – To assess disease activity or infection risk C1q level (or antiC1q-IgG) C2a C3a, iC3b, C3dg, C4d, C5a, C1r-C1s-(Cinh2), TCC (sC5b-9)  Treatment Options of the Future: – NOT STRAIGHFORWARD! – Role in preventing ischemic reperfusion injury events – Anti-complement treatment:  – Complement reconstitution:  Monoclonal anti-C5a antibodies: phase I trials (RA, SLE, & others!) Primitive, Antigenic, ?Fuel to the Fire – C1q via BMT – C1q-Ab immunoabsorption Summary  Hereditary complement deficiency states: – associated with increased risk of SLE – contribute marginally to the incidence of SLE in the population – pathogenetically elucidating  Complement: – Protective PROXIMALLY (C1q, C4) – Damaging DISTALLY (C5, MAC) – Immunologically consumed and self-annihilated  Classical pathway complement component measurement important in: – Diagnosis – Immune-complex mediated manifestation surveillance (GMN) References        Barilla-LaBarca ML, Atkinson JP. Rheumatic syndromes associated with complement deficiency. Current Opinion in Rheumatology 15: 55-60, 2003 Botto M, Walport MJ. C1q, Autoimmunity and Apoptosis. Immunobiology 205: 395-406, 2002 Molina H. Update on complement in the pathogenesis of systemic lupus erythematosus. Current Opinion in Rheumatology 14: 492-7, 2002 Sturfelt G. The complement system in systemic lupus erythematosus. Scandinavian Journal of Rheumatology 31: 129-32, 2002 Walport MJ. Advances in Immunology: Complement (First of Two Parts). New England Journal of Medicine 344(14): 1058-66, April 5 2001 Walport MJ. Advances in Immunology: Complement (Second of Two Parts). New England Journal of Medicine 344(15): 1140-4, April 12 2001 Walport, MJ. Complement and systemic lupus erythematosus. The Scientific Basis of Rheumatology. London, UK. 24-26 June 2002 Arthritis Res 2002 4(Suppl 3):S279-S293 http://arthritis-research.com/content/4/S3/S279