Pathogenetic mechanisms in atypical HUS
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1 Pathogenetic mechanisms in atypical HUS Seppo Meri University & University Hospital Helsinki, Finland Antalya, Turkey Photo: Markku Kallio
2 HUS after eating Kebab - 22 yo female - watery diarrhea one day after eating steak kebab - admitted to nephrology ward 1 week later with acute kidney injury and hemolytic anemia - symptoms: nausea, vomiting and abdominal pain oliguria, urine dipstick: 3+ blood and protein platelets 25x 10 9 /l, Hb 72 g/l, RBC fragments - NO rash/joint pain/weight loss/ bleeding/ fever or focal neurological symptoms HUS after eating Kebab: why?
3 Many human diseases are linked to complement activation Diseases affecting kidneys Others Dense deposit disease (DDD) C3 glomerulonephritis (C3GN) Hemolytic uremic syndrome (ahus and EHEC-HUS) Systemic lupus erythematosus Antibody-mediated kidney rejection Catastrophic antiphospholipid antibody syndrome (CAPS) Cold agglutinin disease (CAD) Ab Age-related macular degeneration (AMD) Paroxysmal nocturnal hemoglobinuria (PNH) Myocardial infarction Sepsis, ARDS Thrombotic thrombocytopenic purpura (TTP) Hemolytic anemia (AIHA) Rheumatoid arthritis
4 Complement activation in various human diseases Diseases affecting kidneys Others Dense deposit disease (DDD) C3 glomerulonephritis (C3GN) Hemolytic uremic syndrome (ahus and EHEC-HUS) Systemic lupus erythematosus Antibody-mediated kidney rejection Catastrophic antiphospholipid antibody syndrome (CAPS) Cold agglutinin disease (CAD) Ab Age-related macular degeneration (AMD) Paroxysmal nocturnal hemoglobinuria (PNH) Myocardial infarction Sepsis, ARDS Thrombotic thrombocytopenic purpura (TTP) Hemolytic anemia (AIHA) Rheumatoid arthritis
5 Complement activation C3 convertase Functions of complement: 1. Lysis (MAC) 2. Opsonization (C3b, C4b, C1q) 3. Chemotaxis and activation of phagocytes (C5a) 4. Inflammation (C5a, C3a, C5b-9) - mediator release from mast cells - increased permeability of blood vessels 5. Processing of immune aggregates 6. Strengthening adaptive immune responses - > Pathological consequences: inflammation, tissue damage, thrombosis MAC Autoimmune hemolytic anemia (AIHA)
6 Complement activation C3 convertase Functions of complement: 1. Lysis (MAC) 2. Opsonization (C3b, C4b, C1q) 3. Chemotaxis and activation of phagocytes (C5a) 4. Inflammation (C5a, C3a, C5b-9) - mediator release from mast cells - increased permeability of blood vessels 5. Processing of immune aggregates 6. Strengthening adaptive immune responses - > Pathological consequences: inflammation, tissue damage, thrombosis MAC Autoimmune hemolytic anemia (AIHA)
7 Factor H protects self tissues from C attack -> mutations, polymorphisms and autoantibodies predispose to disease FH DDD (MPGN2) CRP C3b PTX3 C3c C3d AMD ahus C3b Dense Deposit Disease (DDD) Age-related Macular Degeneration (AMD) Hemolytic uremic syndrome (HUS)
8 Complement inhibitors MCP = membrane cofactor protein - cofactor in C3b inactivation DAF = decay accelerating factor - promotes decay of C3bBb CD59 = protectin (MAC-inhibitor) C3b inactivator (Factor I) Factor H 1) Cofactor activity (FH, MCP, CR1) 2) Decay accelerating activity (FH, DAF, CR1)
9 MCP = membrane cofactor protein - cofactor in C3b inactivation DAF = decay accelerating factor - promotes decay of C3bBb CD59 = protectin (MAC-inhibitor) Complement inhibitors C3b inactivator (Factor I) Factor H Mutations in ahus 1) Cofactor activity (FH, MCP, CR1) 2) Decay accelerating activity (FH, DAF, CR1)
10 Self-control by factor H Factor H ic3b Vascular endothelia and blood cells are protected by polyanions: sialic acids, phospholipids and glycosaminoglycans Hyvärinen et al, Blood, 2016; Convay, Blood, 2016
11 Molecular mechanism of ahus Nonself low avidity Self high avidity FH-related ahus is caused by a failure in FH19-20 binding to cell surface C3b + sialic acid Jokiranta et al, EMBO J, 2006; Kajander et al, Proc Natl Acad Sci, 2011; Hyvärinen et al, Blood, 2016
12 Complement-mediated vascular damage in ahus PNH = paroxysmal nocturnal hemoglobinuria Meri, Eur J Int Med, 2013
13 Patient: Campylobacter Stool culture: Campylobacter jejuni HS: 50, Pen O:2 (no EHEC) - supportive treatment, no antibiotics, hemodialysis started - ADAMTS13 13%, ANCA, ANA, anti-gbm antibodies negative - discharged 2 weeks later BUT readmitted 4 days later with hemoptysis, edema and worsened renal function - X-ray: diffuse bilateral patchy shadowing. Antibiotics started, respiratory function declined. - admitted to ICU. Intubated. After i.v. prednisolone (3 days) rapid improvement -> extubated 4 days later HUS after campylobacter infection: why? Bowen et al. J Gen Intern Med 31: , 2016 Hendrikson et al, in preparation
14 Multiple causes of hemolytic uremic syndrome Genetic Unknown Microbial Factor H Factor I MCP (CD46) C3, Factor B Thrombomodulin (THBD) HUS Diacylglycerol kinase e? E. coli O157, O104 (STEC-HUS) Immune Anti-Factor H antibody
15 Self-control by factor H Factor H ic3b GM3 Vascular endothelia and blood cells are protected by gangliosides Blaum et al, Nat Chem Biol, 2015; Hyvärinen et al, Blood, 2016; Convay, Blood, 2016
16 Multiple causes of hemolytic uremic syndrome Genetic Unknown Microbial Factor H Factor I MCP (CD46) C3, Factor B Thrombomodulin (THBD) HUS Diacylglycerol kinase e? E. coli O157, O104 (STEC-HUS) Immune Anti-factor H antibody Anti-ganglioside antibodies khus
17 Complement analyses in the diagnostics of TMA/HUS 1. Total complement activity (CP, AP, LP) C3, C4, FH levels (may be normal in ahus) ADAMTS13 level (decreased in TTP) 2. Complement activation products (Bb, SC5b-9) (in specialised laboratories) 3. Mutation analyses: ahus: FH, MCP, FI, C3, B, THBD DDD and C3GN: FH, FHRs, C3 4. Autoantibody analyses DDD: anti-c3bbb (= C3 nephritic factor) ahus: anti-fh TTP: anti-adamts13 5. Shiga-toxin E. coli (culture, toxin detection) 6. Campylobacter & antiganglioside antibodies DDD, C3GN STEC-HUS khus
18 Acknowledgements Haartman Institute Sakari Jokiranta Hanna Jarva Taru Meri Anna-Helena Saariaho Aino Koskinen Markus Lehtinen Karita Haapasalo Arnab Bhattacharjee Marcel Messing Helsinki University Hospital Hannu Jalanko Christer Holmberg Elina Armstrong Riitta Lassila Seija Peltonen Kati Kaartinen Kadri Hendrikson Sari Aaltonen Viikki Biocenter Tommi Kajander Veli-Pekka Jaakola Adrian Goldman University College, London Emily Bowen Iain McDougall
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