Pathogenetic mechanisms in atypical HUS · Hemolytic anemia (AIHA) Rheumatoid arthritis Ab....

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Photo: Markku Kallio Antalya, Turkey 21.10.2017 Pathogenetic mechanisms in atypical HUS Seppo Meri University & University Hospital Helsinki, Finland

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