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Infection and Autoimmunity

a Two-Way Relationship

Prof. Ricard Cervera

The screen versions of these slides have full details of copyright and acknowledgements 1

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Ricard Cervera, MD, PhD, FRCP

Consultant

Department of Autoimmune Diseases

Hospital Clinic, Barcelona

Survey of Autoimmune Diseases1995-2005

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A two-way relationship

Infection

Autoimmunity• Virus and autoimmunity

• Antiphospholipid syndrome and infections:

molecular mimicry

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• Myxovirus

• Reovirus

• Varicella

• Rubella

• Parainfluenza

Virus autoimmunityVirus autoimmunity

Fresco R., Virus-like particles in SLE,

N Engl J Med 1970, 283: 1231

• Parotiditis

• Epstein-Barr

• Oncornavirus

• Retrovirus

HCV





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• HCV is a single-chain RNA v irus

• It was identif ied in 1989 as the main cause of “no-A/no-B” hepatitis

• Prev alence of HCV inf ection in dev eloped countries: 1-2%

• Its high genomic heterogeneity prov ides a great capability

to elude the immune sy stem

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Mixed

cryoglobulinemia

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Etiology

Meta-analysis (<1989)





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Etiology

Etiological studies (>1989)

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Clinical Serological

muscles

articular

skin

PNS

renal

pulmonar y

thyroid glandmucosesAAN

antiML

AMA

anti-LKM1

AAF

antithyroi d

FR Cryoglob

Ramos-Casals et al., Med Clin (Barc) 2001

Autoimmune manifestation

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- Mixed cryoglobulinemia

- Sjögren’s syndrome

- Systemic lupus erythematosus

- Polyarteritis nodosa

- Antiphospholipid syndrome

HCV and autoimmune disease





10

0 20 40 60 80 100

SNP

Hepatic

Pulmonar

Vasc cut

Raynaud

Articular

Parotidomeg

Xeroftalmia

Xerostomia

HCV+ HCV-

García-Carrasco M, Ramos-Casals M, Cervera R et al. Hepatitis C virus infection in “primary” Sjögren’s syndrome:prevalence and clinical significance in a series of 90 patients; Ann Rheum Dis 1997; 56:173-5

1%1%

14%*14%*

VHC+

*p < 0.001

Sjögern’s syndrome and HCV

Prevalence Clinical charateristics

p < 0.001

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0 10 20 30 40 50 60 70 80

Hipocompl

Crioglob

Anti-La

Anti-Ro

FR

AMA

AntiCPG

AntiML

AAN

HCV+ HCV-

Ramos-Casals M, García-Carrasco M, Cervera R et al. Hepatitis C virus infection mimicking primary Sjögren’s syndrome; Clinical and immunologic description of 35 cases. Medicine (Baltimore) 2001 ;80 :1-8

35 SS HCV patients

Immunology

EEC criteria 1993

European criteria for primary SS

17 patients

11 patients

7 patients

No. of patients0 2 4 6 8 10 12 14 16 18

6

5

4 17 patients

11 patients

7 patients

Patients (%)

Immunologicalfeatures

p < 0.001

p < 0.001

p = 0.03

p = 0.02

p = 0.03

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0 20 40 60 80 100

Crioglob

Hipocompl

antiDNA

ANA

Hepatic

Nefropat

Serositis

Arthritis

Cutánea

Imm

un

olo

gic

al f

ea

ture

s

Patients (%)

HCV+ HCV-

p < 0.001

Ramos-Casals M, Font J, García-Carrasco M, Cervera R et al., Hepatitis C virus infection mimicking systemic lupus erythematosus; Study of hepatitis C virus infection in a series of 134 Spanish patients with systemic lupus erythematosus. Arthritis Rheum 2000

1%1%

11%*11%*

VHC+

*p < 0.001

Systemic lupus erythematosus and HCV

Prevalence Clinical charateristics

p = 0.001

p < 0.001

p = 0.002

p = 0.02





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Ramos-Casals M, Font J, García-Carrasco M, Cerv era R, et al. Hepatitis C virus infection mimicking systemic

lupus erythem atosus; Study of hepatitis C virus infection in a series of 134 Spanish patients with systemic

lupus erythematosus, Arthritis Rheum 2000

3 patients 6 patients 9 patients

RIBA & RNA neg

ANA > 1/160

AntiDNA > 30

No hepatic involv.

Renal involv.

ANA > 1/160

AntiDNA > 30

Anti-Sm +

Articular invol.

Cytopeni as

ANA 1:40 - 1:80

AntiDNA < 15

Cryoglobulins

Subsets of SLE-HVC patients

False + ELISA-3 SLE + HCV HCC + Lupus-like

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Deny 1992 n=1

Semenkova 1995 n=1

Galeazzi 1996 n=1

Hortelano 1997 n=3

Debat 1997 n=1

Sautter 1997 n=1

Cacoub 2000 n=9

Della Rossa 2000 n=1

Ramos-Casals et al., Med Clin (Barc), 2001

Polyvarteritis nodosa and HCV

Case reports Prevalence studies

Author Year Country n ELISA RIBA PCR

Cacoub et al.

1992 France 507 (14%)

6(12%)

Carson et al.

1993 USA 5611 (20%)

3 (5%)

3 (5%)

Hortelano et al.

1997 Spain 64 (67%)

Prevalence of infection of VHC

in patients with polyvarteriti s nodosa

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Leroy 1998 n=1

Buskila 1998 n=1

Mangia 1999 n=1

Cacoub 2000 n=3

García-Carrasco et al., Rev Esp Reumatol 2002

Antiphospholipid syndrome and HCV

Case reports Prevalence studies

Authorand

referenceYear Country n

ELISA

n (%)RIBA

PCRn (%)

Munōz-Rodríguezet al.

1999 Spain 88 2 (2) - 0 (0)

Dalekos et al.

2000 Greece 24 0 (0) - -

Total - - 112 2 (2) - -

Prevalence of infection of VHC

in antiphospholi pid syndrome





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J Hepatol 1999; 30: 770-773

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J Hepatol 1999; 30: 770-773

18J Hepatol 1999; 30: 770-773





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Metaanalysis of patients with EAS%

Prevalence of HCV systemic

autoimmune disease

0

5

10

15

20

25

SS SLE Behcet APS PAN SSc

2%

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HCV triple tropismHCV

Salivary gland HepatocytesLymphocytes

Ramos-Casals et al., Am J Pathol 2001

Sjögern’s Cryoglobulinemi a Chronic hepatitis

cirrhosis

Hepatocell ular carcinomaB-cell lymphoma

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Virus autoimmunity

HIV





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Autoimmune diseases

in HIV patients

• Systemic lupus erythematosus

• Antiphospholipid syndrome

• Autoimmune thrombocytopenia

• Vasculitis

• Inflammatory myopathies

• Thyroiditis

• Primary biliary cirrhosis

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Autoim Rev 2002; 1: 329-337

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Autoim Rev 2002; 1: 329-337





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Autoim Rev 2002; 1: 329-337

26Autoim Rev 2002; 1: 329-337

27Clin Infect Dis 2004; 38: 1009-1016





28Clin Infect Dis 2004; 38: 1009-1016

Antiphospholi pid syndrome

(APS)-related features

in 82 patients with chronic

viral diseases (hepatitis C

virus and/or HIV infection)

29Clin Infect Dis 2004; 38: 1009-1016

Comparison of charact eristics of patients

with antiphospholip id syndrome (APS) and hepatitis C virus (HCV)

infection and those with APS and HIV infection, excluding patients

with HCV-HIV coinfection

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Comparison of clinical features of patients

with antiphospholip id syndrome (APS)-relat ed viral

infection(s) and un-select ed patients with APS

Clin Infect Dis 2004; 38: 1009-1016





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Infection

Autoimmunity

- Virus and autoimmunity

- Antiphospholipid syndrome and infections:

molecular mimicry

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APS and infections

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APS and infections

General characteristics





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APS and infections

Manifestations of antiphospholipid syndrome

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APS and infections

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APS and infectionsAssociated infections





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Molecular mimicry

J Rheumatol 2000; 27: 238-240

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40

41

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CAPS registry:

precipitating factors (I)

Infections 36 (24%)

Respiratory tract 15 (10%)

Cutaneous 6 (4%)

Urinary tract 6 (4%)

Gastrointestinal 3 (2%)

Sepsis 2 (1%)

Other 4 (3%)





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Molecular mimicry

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J Clin Immunol 2004; 24: 12-23

Molecular mimicry

45J Clin Immunol 2004;

24: 12-23

Prevalence of aCL antibodies in bacterial, rickettsial,

yeast, parasite and spirochetal infections





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Location of the ββββ2GPI-related peptides identified

by the peptide phage display library

47J Clin Immunol 2004; 24: 12-23

Antiphospholip id Abs detected in diverse infections and β2GPI

peptide homologies shared with structures in these pathogens

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Antiphospholip id Abs detected in diverse infections and β2GPI

peptide homologies shared with structures in these pathogens

J Clin Immunol 2004; 24: 12-23





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Molecular mimicry

J Clin Immunol 2003

50J Clin Immunol 2003

Molecular mimicry

Results:

• Anti-peptide C Abs were significantly correlated

with recurrent abortions (35.8% vs. 19.8%, p < 0.005)

• Anti-P274-280 Abs were associated with toxemia

(12.4% vs. 5.6%, p < 0.03) and with recurrent abortions

(25.7% vs. 15.2%, p < 0.02)

• Anti-P244-264 were associated

with cardiac valve abnormalities

(19.0% vs. 11.5%, p < 0.05)

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Eular Prize 2005

Yehuda Shoenfeld

Pier Luigi Meroni

Ricard Cervera





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Liam Smeeth, Ph.D., Sara L. Thomas, Ph.D.,

Andrew J. Hall, Ph.D., Richard Hubbard, D.M.,

Paddy Farrington, Ph.D, and Patrick Vallance, M.D.

N Engl Med 2004;351:2611-8

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Infection

Autoimmunity

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“Everything is autoimmune

until proven otherwise”

“Everything is autoimmune

until proven otherwise”

Yehuda Shoenfeld





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Infection

Autoimmunity

““Everything is autoimmune

and infectious –

until proven otherwise””

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