Immunology of Primary Sclerosing Cholangitis John M. Vierling, - - PowerPoint PPT Presentation

Immunology of Primary Sclerosing Cholangitis

John M. Vierling, M.D., F.A.C.P. Professor of Medicine and Surgery Director, Baylor Liver Health Chief of Hepatology Baylor School of Medicine Director of Advanced Liver Therapies

• St. Luke’s Episcopal Hospital

Houston, TX

Anatomy of Bile Ducts

Anatomy of Bile Ducts

Artery Portal Vein Bile Duct

Pathology Primary Sclerosing Cholangitis

ERC

Pathology of Primary Sclerosing Cholangitis

Small Ducts Medium Ducts

Pathology of Primary Sclerosing Cholangitis

Blood Vessels Pushed Away from Bile Ducts Small Ducts Medium Ducts

Antigen Response

Past

Antigen Response

Present

Antibodies (Vaccinations,

Responses to infections)

Cell Mediated Killing (Viruses,

Tumors, Rejection of transplanted

• rgans

Immunology of Primary Sclerosing Cholangitis The Three “Rs”

Your immune response has 3 functions:

Recognize Respond Remember

Immunology of Primary Sclerosing Cholangitis

Your immune response:

Recognize: Foreign antigens Avoid self antigens (autoantigens)

Immunology of Primary Sclerosing Cholangitis

Your immune response:

Respond: Innate immune response

Immediate “ready to go” response Triggered by molecules on

bacteria, viruses, tumor cells

Influences adaptive immune responses

Adaptive immune response

Immunology of Primary Sclerosing Cholangitis

Your immune response:

Respond: Adaptive immune response

Small, processed proteins (antigens) Presentation of antigens by HLA

molecules to T cells and B cells

Activation of T and B cells to antigens

Immunology of Primary Sclerosing Cholangitis

Your immune response:

Respond: Important to: Regulate both magnitude and

duration

Shut off response once it has

served it purpose

Immunology of Primary Sclerosing Cholangitis

Your immune response:

Respond: Self or autoantigens= autoimmunity Break in self-tolerance As if self were foreign

Innate Immune Response

Part One Particles:

Bacteria Viruses Bacterial DNA

Fragments

• f dead cells

Antibodies bound to proteins

Special Proteins

Attract inflammatory cells Intensify inflammation Increase destructive

adaptive immune response

Innate Immune Response

Part Two Natural Killer Cells Recognize and Kill

Infected cells Cells under stress Tumor cells

NK

Antigen Presenting Cell

CD4 Th0 CD4 Th1 CD4 Th2 CD8 CD8 CTL

B7- CD28 B 7

• C

D 2 8

Antigens

Adaptive Immune Response

Immunogenetics in PSC

NK

Antigen Presenting Cell

CD4 Th0 CD4 Th1 CD4 Th2 CD8 CD8 CTL

Antigens

HLA

C B A

Class II III I

DP DQ DR

Immunogenetics in PSC

NK

Antigen Presenting Cell

CD4 Th0 CD4 Th1 CD4 Th2 CD8 CD8 CTL

Antigens

HLA

C B A

Class II III I

DP DQ DR Susceptibility

HLA

C B A

C’4, 2, C4AQ0, MICA, HSPs, TNFα/β

Immunogenetics in PSC

Class II III I

DP DQ DR

Antigen Antigen

IL-2

NK

Antigen Presenting Cell

CD4 Th0 CD4 Th1 CD4 Th2 CD8 CD8 CTL

B7- CD28 B7-CD28

IL-4 IFNγ

Antigens

Adaptive Immune Response

Innate Immune Response

IL-2 IFNγ

NK

Antigen Presenting Cell

CD4 Th0 CD4 Th1 CD4 Th2 CD8 CD8 CTL

B B

MAC

IL-4

B7- CD28 B 7

• C

D 2 8

IL-4 IFNγ

Antigens

Adaptive Immune Response

Antibodies (Autoantibodies) Cell-Mediated Killing

HLA

C B A

Complement, MICA, HSPs, TNFα/β

Immunogenetic Associations in PSC

Class II III I

DP DQ DR

Susceptibility OR

• B8-TNFA*2-MICA*008-DRB3*0101-DRB1*0301-DQA1*0501 DQB1*0201

2.69

• DRB3*0101-DRB1*1301-DQA1*0103-DQB1*0603

3.80

• DRB5*0101-DRB1*1501-DQA1*01102-DQB1*0602

1.52

• MICA*008

5.0 Resistance

• DRB4*-DRB1*0401-DQA1*0301-DQB1*0302

0.26

• DRB4*-DRB1*0701-DQA1*0201-DQB1*0303

0.15

• MICA*002

0.12

Donaldson PT, Norris S. Autoimmunity 2002; 35: 555-64; Neri, et al: Dig Liver Dis 2003;35: 571-6; Sheth S, et al. Hum Genet 2003; 113: 286-92; ter Borg PC, et al: Neth J Med 2004; 62: 326-31; ERi R, et al: Genes Immun 2004; 5: 444-50; Yang X, et al: J Hepatol 2004; 40: 375-9

Is PSC an Autoimmune Disease?

Comparison of Classical Autoimmunity and PSC

• Females more than males

No

• Afflicts children & adults

Yes

• HLA susceptibility associations

Yes

• Autoantigen(s)

No

• Autoantibodies or cell-mediated reactions to

No autoantigens

• Associated with other “immune diseases”

Yes

• Responds to immunosuppression treatment

No

Classical Autoimmunity PSC

• Small Bowel Overgrowth
• Genetically susceptible rats

Peptidoglycan-polysaccahride (PG-PS PAMP)

Rat Model of Small Bowel Bacterial Overgrowth

Lichtman SN, et al: J Clin Invest 1992; 90: 1313-22

Mutanolysin Palmitate

Immune Mechanisms in Sclerosing Cholangitis

Spontaneous Sclerosing Cholangitis in Mdr2-/- Mouse

Fickert et al., Gastroenterology 2002; 123: 1238

D

Immune Mechanisms in Sclerosing Cholangitis

Spontaneous Sclerosing Cholangitis in Mdr2-/- Mouse

Fickert P, et al. Gastroenterology 2004; 127: 261-74.

Genetic cause of bile leak

between bile duct lining cells

Bile triggers innate immune

inflammation and adaptive immunity

Innate immune cells produce

inflammatory chemicals

These chemicals activate

cells to form scar around the bile duct

As the scar thickens, blood

vessels pushed away from the bile duct

Shrinkage of the lining cells of the

bile duct due to lack of oxygen and nutrition supplied by

Immune Reactions in PSC

Bile Duct Lining Cell

CD44 Fas MHC II

ICAM-1

CD40 MHC I LFA-3

Chemicals that Cause Inflammation and Scarring

Fas IL-6R

Chemicals that Attract Inflammatory Cells to Cholangiocytes

CD1d B7 B7

↑ HSP

E-cadherin TNFαR

Growth Factors for Cells Producing Scar

CCRs CXCRs

Particles from Bacteria Inflammatory Molecules

VCAM-1

CCL28

CCL28

Innate Immune Signalling Blood Flow

Rolling Adherent Diapedesis Inflammatory Cells Originally Activated in the Gut

Possible Sequence of Events in Primary Sclerosing Cholangitis

Adaptive Immunity + Innate Immunity Ulcerative or Crohn’s Colitis Bacterial Molecules Into Portal Vein Cytokines, Chemokines, Fibrosing Inflammation Bile Regurgitation Displacement Of Arterial Vessels Abnormal Cholangiocyte Functions Immune and Other Genetic Susceptibilities Atrophy

• f

Cholangiocytes

Immunology of Primary Sclerosing Cholangitis

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