Pathogenetic mechanisms in atypical HUS · Hemolytic anemia (AIHA) Rheumatoid arthritis Ab....
Transcript of Pathogenetic mechanisms in atypical HUS · Hemolytic anemia (AIHA) Rheumatoid arthritis Ab....
Photo: Markku KallioAntalya, Turkey
21.10.2017
Pathogenetic mechanisms in atypical HUS
Seppo Meri
University &
University Hospital
Helsinki, Finland
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 109/l, Hb 72 g/l, RBC fragments
- NO rash/joint pain/weight loss/ bleeding/ fever or focal
neurological symptoms
HUS after eating Kebab: why?
Many human diseases are linked to
complement activation
Diseases affecting kidneys
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)
Others
Age-related macular
degeneration (AMD)
Paroxysmal nocturnal
hemoglobinuria (PNH)
Myocardial infarction
Sepsis, ARDS
Thrombotic thrombocytopenic
purpura (TTP)
Hemolytic anemia (AIHA)
Rheumatoid arthritisAb
Complement activation in various
human diseases
Diseases affecting kidneys
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)
Others
Age-related macular
degeneration (AMD)
Paroxysmal nocturnal
hemoglobinuria (PNH)
Myocardial infarction
Sepsis, ARDS
Thrombotic thrombocytopenic
purpura (TTP)
Hemolytic anemia (AIHA)
Rheumatoid arthritisAb
Autoimmune hemolytic anemia
(AIHA)
MAC
Complement activation
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
C3 convertase
Autoimmune hemolytic anemia
(AIHA)
MAC
Complement activation
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
C3 convertase
7 8 11 12 20
++ ++++
131 144FH
C3b C3c C3d
C3b
DDD(MPGN2)
aHUSAMD
Factor H protects self tissues from C attack-> mutations, polymorphisms and autoantibodies predispose to disease
Dense Deposit
Disease
(DDD)
Age-related Macular
Degeneration
(AMD)
Hemolytic uremic
syndrome
(HUS)
CRP
PTX3
Complement inhibitors
MCP = membrane cofactor protein - cofactor in C3b inactivation
DAF = decay accelerating factor - promotes decay of C3bBb
CD59 = protectin (MAC-inhibitor)
Factor H
C3b inactivator
(Factor I)
1) Cofactor activity
(FH, MCP, CR1)
2) Decay accelerating activity
(FH, DAF, CR1)
Complement inhibitors
MCP = membrane cofactor protein - cofactor in C3b inactivation
DAF = decay accelerating factor - promotes decay of C3bBb
CD59 = protectin (MAC-inhibitor)
Factor H
C3b inactivator
(Factor I)
1) Cofactor activity
(FH, MCP, CR1)
2) Decay accelerating activity
(FH, DAF, CR1)
Mutations
in aHUS
Self-control by factor H
Factor H
Hyvärinen et al, Blood, 2016; Convay, Blood, 2016
iC3b
Vascular endothelia and blood cells are protected by polyanions:
sialic acids, phospholipids and glycosaminoglycans
Jokiranta et al, EMBO J, 2006; Kajander et al, Proc Natl Acad Sci, 2011; Hyvärinen et al, Blood, 2016
Self – high avidityNonself – low avidity
FH-related aHUS is
caused by a failure in
FH19-20 binding to cell
surface C3b + sialic acid
Molecular mechanism of aHUS
Complement-mediated vascular damage in aHUS
Meri, Eur J Int Med, 2013
PNH = paroxysmal
nocturnal
hemoglobinuria
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 31:353-356, 2016
Hendrikson et al, in preparation
Factor H
Factor I
MCP (CD46)
C3, Factor B
Thrombomodulin
(THBD)
E. coli O157, O104
(STEC-HUS)
Genetic
HUS
Multiple causes of hemolytic uremic syndrome
Microbial
Immune
Anti-Factor H
antibody
Unknown
Diacylglycerol kinase e ?
Self-control by factor H
Factor H
Blaum et al, Nat Chem Biol, 2015; Hyvärinen et al, Blood, 2016; Convay, Blood, 2016
iC3b
Vascular endothelia and blood cells are protected by gangliosides
GM3
Factor H
Factor I
MCP (CD46)
C3, Factor B
Thrombomodulin
(THBD)
E. coli O157, O104
(STEC-HUS)
Genetic
HUS
Multiple causes of hemolytic uremic syndrome
Microbial
Immune
Anti-factor H
antibody
Anti-ganglioside
antibodies
Unknown
Diacylglycerol kinase e ?
kHUS
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
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