AUTOIMMUNITY AND AUTOIMMUNE DISEASE

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Bo Gao, Ph.D. Bo Gao, Ph.D.

DEPARTMENT OF IMMUNOLOGYINSTITUTE FOR IMMUNOBIOLOGY

2010-07-022010-07-02

Email: [email protected]

Tel: 54237379

mailto:[email protected]

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Contents:Contents:

Introduction

Organ-Specific Autoimmune Diseases

Systemic Autoimmune Diseases

Mechanisms of Induction

Treatment

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Introduction

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Autoimmunity OriginsAutoimmunity Origins

Horror autotoxicus:Horror autotoxicus: Literally, the horror of Literally, the horror of self-toxicity. self-toxicity.

A term coined by the A term coined by the German immunologist German immunologist Paul Ehrlich (1854-1915) Paul Ehrlich (1854-1915) to describe the body's to describe the body's innate aversion to innate aversion to immunological self-immunological self-destruction. destruction. Paul Ehrlich , Nobel Prize in 1908 for d

emonstrating production of antibody

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Frank Burnet 1900--1990

Nobel Prize 1960

Clone selection hypothesis

Self-reactive lymphocyte were deleted during development

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Definition of autoimmune disease

Disease caused by failure of self-tolerance and subsequent immune responses against self antigens are called autoimmune diseases.

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5 % to 7% adult affected.5 % to 7% adult affected.Two third women.Two third women. More than 40 human More than 40 human

diseases autoimmune in diseases autoimmune in origin.origin.

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Insulin-dependent diabetes mellitusInsulin-dependent diabetes mellitus

Multiple sclerosisMultiple sclerosis

Graves’s diseaseGraves’s disease

Myasthenia gravisMyasthenia gravis

Hashimoto’ diseaseHashimoto’ disease

Goodpasture’s syndromeGoodpasture’s syndrome

……

Organ-Specific Autoimmune Diseases

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Sjögren’s syndromeSjögren’s syndromeSclerodermaSclerodermaDermatomyositisDermatomyositisMixed connective tissue diseaseMixed connective tissue disease (MCTD)(MCTD)

…………..

Systemic lupus Systemic lupus ErythematosusErythematosus (SLE) (SLE)

Rheumatoid arthritis (RA)Rheumatoid arthritis (RA)


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Induction Theories for Autoimmune Disorders

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1. Ag released from hidden location (by injury Ag released from hidden location (by injury or infection)or infection)

Intraocular antigens Post-traumatic uveitis

Sperm Orchitis after vasectomy

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2. Molecular mimicry (Cross-reactions)Cross-reactions)

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DefinitionDefinition: : DDeterminants of infectious agent mimic a host aeterminants of infectious agent mimic a host antigen and trigger self-reactive T-cell clones to antigen and trigger self-reactive T-cell clones to attack host tissues. ttack host tissues.

ExamplesExamples::

RRheumatic fever due to group A heumatic fever due to group A streptococcstreptococcusus SLE due to Epstein-Barr virus cross reactive with nuSLE due to Epstein-Barr virus cross reactive with nu

clear Sm antigenclear Sm antigen Lyme aLyme artrtrhritis due to rhritis due to BBorreliaorrelia burgdorferi burgdorferi reactive w reactive w

ith LFA-ith LFA-1 1 (lymphocyte function antigen-1) (lymphocyte function antigen-1)

Molecular mimicry

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Rheumatic fever is a classic example of molecular mimicry

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“Wrong” cells induced to express MHC Class II

antigen (and act as APCs) – IDDM, Hashimoto’s

Additional signals, such as IFN-gamma IL-1 and TNF

3. Inappropriate expression of class II MHC

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4.Epitope spreading

DefinitionDefinition: : InitialInitial response to oneresponse to one self self determinant (one peptide) could expand determinant (one peptide) could expand to involve additional determinants on to involve additional determinants on the same molecule as well as additional the same molecule as well as additional self-proteins. self-proteins.

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It explains how a It explains how a response to one response to one cryptic epitope cryptic epitope can mature into a can mature into a full-blown full-blown autoimmune autoimmune response response ..

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5. Polyclonal B cell activation by CMV, EBV, and some G-negative bacteria

- T-cell-independent - Large amounts of IgM produced

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6.Role of Infection in Autoimmunity

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7. Gene factors in autoimmunity

Multiple sclerosis – particular alleles of Multiple sclerosis – particular alleles of HLA-DR HLA-DR ((DRB1*1501DRB1*1501, , DRB5*0101DRB5*0101))

Systemic lupus – lack of C1q and C4Systemic lupus – lack of C1q and C4

Genetically determined low expression of Genetically determined low expression of given self-antigen in the thymusgiven self-antigen in the thymus

Mutation (usually deletion) of autoimmune Mutation (usually deletion) of autoimmune regulator-1 gene (AIRE-1)regulator-1 gene (AIRE-1)

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AssociatioAssociation between n between HLA and HLA and susceptibilsusceptibility to ity to autoimmuautoimmune diseasene disease

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8.Estrogens and Autoimmunity

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9.Other factors favoring autoimmunity

Lymphocytes abnormalitiesLymphocytes abnormalities Cytokine Imbalance (↑IL-2 in SLE)Cytokine Imbalance (↑IL-2 in SLE) Disturbances of apoptosis ( Disturbances of apoptosis ( Deficiencies Deficiencies in in

Fas, complement, CTLFas, complement, CTLAA-4)-4) Toxins, Drugs, Chemicals (including food), Toxins, Drugs, Chemicals (including food),

UV, StressUV, Stress

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THERAPY OF AUTOIMMUNE DISEASESTHERAPY OF AUTOIMMUNE DISEASES

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ImmunosuppressionCorticosteroids, azathioprine, cyclophosamide

Removal of thymus Plasmapheresis

Short-term relief(Grave’s disease, RA, SLE)

Reduce symptoms

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TNF-alpha blockers (RA, Crohn’s dis., psoriasis) e.g., Enbrel, Remicade, Humira IL-1 receptor antagonist (RA) Ab’s against IL6R and IL-15R Statins, shown to lower CRP (RA, MS)

Reduce inflammation

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Block MHC with similar peptideBlock MHC with similar peptide or antibody or antibody AAnti-CD4nti-CD4 Blockage of IL-12Blockage of IL-12 activityactivity

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T cell vaccines (against activated Ag-specific T cells)

Monoclonal antibodies against a variety of target antigens

Oral induction of tolerance (MS)

So far, efforts have been more successfulin mice than humans

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Disease in which the body does not Disease in which the body does not produceproduce enough enough insulin insulin. .

IInsulin-nsulin-ddependent ependent ddiabetes iabetes mmellitus (IDDM)ellitus (IDDM)

It is a It is a “ T cell” Disease“ T cell” Disease..

T cells attack and destroy pancreatic beta T cells attack and destroy pancreatic beta cellscells..

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Insulin-dependent diabetes mellitus (IDDM)Insulin-dependent diabetes mellitus (IDDM)

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Insulin-dependent diabetes mellitus (IDDM)Insulin-dependent diabetes mellitus (IDDM)

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Multiple SclerosisMultiple Sclerosis

MS patients can have autoantibodies and/or self reactive T cells which are responsible for the demyelination

Myelin sheath of nerves targetedCNS attacked by inflammatory lesionsStarts in 20-40 yr. old peopleCharacterized by weakness, paralysis and ocular symptoms

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Myasthenia GravisMyasthenia Gravis

Disease marked by progressive Disease marked by progressive weakness and loss of muscle controlweakness and loss of muscle control

Classified as a “B cell” DiseaseClassified as a “B cell” DiseaseAutoantibodies against nicotinicAutoantibodies against nicotinic

acetylcholine receptors acetylcholine receptors Eventually destroys it

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Myasthenia GravisMyasthenia Gravis

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Graves’s diseaseGraves’s disease

Autoantibody mimics TSH, leads to constantthyroid stimulation

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Th1 cells and autoantibodies specificfor thyroid Ag’s infiltration of thyroid

by L, M, and PC’s hypothyroidism

Chronic inflammation and enlargement

Hashimoto’s thyroiditis

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Normal thyroid gland

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Hashimoto’s thyroiditis

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Hashimoto’s thyroiditis (From Robbins Basic Pathology ,2003 ）

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Goodpasture’s syndrome

Antibodies to membrane antigens in kidney and alveoli in lungs

Specificity – part of type IV collagen

Complement activation, cell damage, inflammation

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The anti-basement membrane antibody in Goodpasture’s syndrome forms an even layer on the glomerular basement membrane.

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Systemic Lupus Erythematosus Systemic Lupus Erythematosus (SLE)(SLE)

Typical patient: young Typical patient: young woman with butterfly rashwoman with butterfly rash

Symptoms unpredictable Symptoms unpredictable (relapsing/remitting)(relapsing/remitting)

Multisystem (skin, kidneys, Multisystem (skin, kidneys, joints, heart)joints, heart)

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• Autoantibodies!Autoantibodies!

• Antinuclear Ab present in all patients with Antinuclear Ab present in all patients with SLE... but found in other autoimmune SLE... but found in other autoimmune diseases toodiseases too

EtiologyEtiology


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They cause tissue injury!They cause tissue injury!

Form immune complexesForm immune complexes

Cause destruction, phagocytosis of cellsCause destruction, phagocytosis of cells

Multisystem effects:Multisystem effects:

Kidney (renal failure)Kidney (renal failure)

Skin (“butterfly rash”)Skin (“butterfly rash”)

CNS (focal neurologic deficits)CNS (focal neurologic deficits)

Joints (arthritis)Joints (arthritis)

Heart (pericarditis, endocarditis) Heart (pericarditis, endocarditis)

What’s so bad about having these What’s so bad about having these autoantibodies?autoantibodies?


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Variable! Some have few symptoms, rare patients die Variable! Some have few symptoms, rare patients die within months.within months.

Most patients: relapses/remissions over many years.Most patients: relapses/remissions over many years.

Acute flare-ups controlled with steroidsAcute flare-ups controlled with steroids

80% 10-year survival80% 10-year survival

Most common cause of death: renal failure Most common cause of death: renal failure


prognosisprognosis

4949Slide 7.24

Lupus nephritis. There are two focal necrotizing lesions at 11 and 2 o’clock. (H&E stain.) (Dr. Helmut Rennke)


5050Slide 7.25

Lupus nephritis, diffuse proliferative type. Note the marked increase in cellularity throughout the glomerulus. (H&E stain.) (Dr. Helmut Rennke)


5151Slide 7.26

Immunofluorescence micrograph stained with fluorescent anti-IgG from a patient with diffuse proliferative lupus nephritis. One complete glomerulus and part of another one are seen. Note the mesangial and

capillary wall deposits of IgG.

5252Slide 7.28

Lupus nephritis showing a glomerulus with several “wire loop” lesions representing extensive subendothelial deposits of immune complexes. (Periodic acid-Schiff [PAS] stain.)

5353Slide 7.29

Systemic lupus erythematosus involving the skin. A, An H&E-stained section shows liquefactive degeneration of the basal layer of the epidermis and edema at the dermoepidermal junction. B, An immunofluorescence micrograph stained for IgG reveals deposits of immunoglobulin along the dermoepidermal junction.

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Rheumatoid ArthritisRheumatoid Arthritis

Symmetric, mostly small-joint arthritisSymmetric, mostly small-joint arthritis

Systemic symptoms (skin, heart, Systemic symptoms (skin, heart, vessels, lungs)vessels, lungs)

Rheumatoid factorRheumatoid factor

Cytokines (especially TNF) cause Cytokines (especially TNF) cause damagedamage

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Circulating IgM antibodyCirculating IgM antibody

Directed against patient’s OWN IgG!Directed against patient’s OWN IgG!

Forms IgM-IgG immune complexes, Forms IgM-IgG immune complexes, which deposit in joints and cause which deposit in joints and cause badnessbadness

Present in 80% of patientsPresent in 80% of patients


EtiologyEtiology

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T cells release cytokines:T cells release cytokines:activate macrophages activate macrophages (causing destruction)(causing destruction)cause B cells to make cause B cells to make antibodies against jointantibodies against jointMost important of these Most important of these cytokines: TNFcytokines: TNF

Cytokines cause inflammation Cytokines cause inflammation and tissue damageand tissue damage

EtiologyEtiology

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Symmetric; characteristic hand featuresSymmetric; characteristic hand features

Chronic synovitis with Chronic synovitis with pannuspannus formation: formation:

synovial cell proliferationsynovial cell proliferation

inflammationinflammation

granulation tissuegranulation tissue

Joint diseaseJoint disease

Mainly small joints Mainly small joints (hands), but also knees, (hands), but also knees, elbows, shoulderselbows, shoulders

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Weakness, malaise, feverWeakness, malaise, fever

VasculitisVasculitis

Pleuritis, pericarditisPleuritis, pericarditis

Lung fibrosisLung fibrosis

Eye changesEye changes

Rheumatoid nodules on forearmsRheumatoid nodules on forearms

Systemic diseaseSystemic disease

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Variable!Variable!

A few patients stabilizeA few patients stabilize

Most patients have chronic course wiMost patients have chronic course with progressive joint destruction and dith progressive joint destruction and disabilitysability

Lifespan shortened by 10-15 yearsLifespan shortened by 10-15 years


prognosisprognosis

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AUTOIMMUNITY AND AUTOIMMUNE DISEASE