Autoimmunity - Autoimmunity - autoimmune diseasesautoimmune diseases

Roland JonssonRoland Jonsson

Broegelmann Research LaboratoryBroegelmann Research Laboratory

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Autoimmunity Autoimmunity

- - - response to own tissue (antigen)

- - tissue damage a/o reduced function - spesific adaptive immune response

against own antigen

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Autoimmune diseaseAutoimmune disease

Autoinflammation Autoinflammation

no response against own tissue no response against own tissue (antigen)

utilize the innate immune system

reaction without any cause

granulocytes – monocytes

intense episodes with inflammation

symptoms: fever, redness, joint effusionRJ13

Examples of autoinflammatoric Examples of autoinflammatoric diseasedisease

Familial Mediterranean Fever (FMF)Familial Mediterranean Fever (FMF)

Neonatal Onset Multisystem Inflammatory Disease (NOMID)

Tumor Necrosis Factor (TNF) Receptor-Associated Periodic Syndrome (TRAPS)

Deficiency of the Interleukin-1 Receptor Antagonist (DIRA)

Behçet’s Disease RJ13

IL-12

Naiv autoreaktiv T- hjelpercelle

Autoreaktive Th1-celler som utskiller IFN- og TNF og gir inflammasjon. Kan forårsake autoimmun sykdom

Autoreaktive Th2-celler som beskytter mot utvikling av autoimmune sykdommer

Immundeviasjon

B7CD28

IL-4

Th1Th2

Immunedeviation – development of“harmless” Th2-cells protects

Autoimmune dis. Protects againstautoimmunity

Autoimmunity

CD4+ T cells: Th1: IL-2, IFN-

Th2: IL-4, IL-5, IL-13

Th3/Tr: IL-10, TGF-

Th17: IL-17

Cytokines (1)Cytokines (1)

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Th1 (IFN-):Host defense (IC pathogens) autoimmunity

Th2 (IL-4, IL-5,IL-13):Host defense (parasites), Allergy, asthma

Th17 (IL-17): Host defense(EC pathogens) Inflammation

Autoimmunity

Fates of CD4 T cells

T-reg (TGF-, IL-10)Immunosuppression

NaïveT cell

STAT4T-bet

IL-23

STAT6GATA3

RORt

IL-12

c-maf

Foxp3

TGF-

Pro-inflammatory: IL-1, IL-6, TNF-, IL-12, IL-18, (IFN-, chemokines)

Anti-inflammatory: IL-4, IL-10, IL-13, TGF-

Cytokines (2)Cytokines (2)

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Autoimmune diseasesAutoimmune diseases

• 5-7% of the population

• nearly all organsystems in the body

can be involved

• can be asymptomatic for a long time

• varieable disease expressionRJ13

Genetic Predisposition

Autoantibodies, Onset of

Autoimmunity

Pathological Injury

Clinical Disease

Disease

Clinical Presentation

Environmental Triggers

Thyreoidea: Hashimotos thyreoiditt

Binyrebark: Idiopatisk binyrebarksvikt

Nyre: Nefrotoksisk glomerulonefritt

Ventrikkel: Pernisiøs anemi

Pancreas: Diabetes mellitus, type I

Hud: Bulløse hudsykdommer

Muskel: Myasthenia gravis

Fig 26.1

Definition of autoimmune diseaseDefinition of autoimmune disease

- Autoantibodies

- Autoreactive T cells

- Autoimmune process primarily

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Witebsky’s criteria (1957)Witebsky’s criteria (1957)How to prove autoimmune disease?How to prove autoimmune disease?

1. Antibodies should be detectable

2. Autoantigens should be identified

3. Experimental induction of antibodies against the antigen

4. Induceable disease in an experimental model

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- Difficult to eliminate the antigen

- Sustained immuneresponse

Result - Result - chronic inflammationchronic inflammation

Adaptive immune response Adaptive immune response – – endogenous antigenendogenous antigen

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Type I diabetes mellitusGoodpasture’s syndromeMultippel skleroseGrave’s diseaseHashimotos thyreoiditt

Classification of Classification of autoimmune diseases (1)autoimmune diseases (1)

Autoimmun perniciøs anemiAddison’s diseaseVitiligoMyastenia gravis

OrganspesificOrganspesific

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Classification ofClassification ofautoimmune diseases (2)autoimmune diseases (2)

SystemicSystemicReumatoid artrittSklerodermiSjögrens syndromPolymyosittSystemisk lupus erythematosus

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What triggers autoimmunity?What triggers autoimmunity?

- Environmental factors

- Genetic factors (espes. MHC)

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Disease HLA Allele Relative Risk*

Rheumatoid arthritis DR4 6IDDM DR3 5

DR4 5-6DR3/DR4 20

Chronic active hepatitis DR3 14 Sjögren´s syndrome DR3 + DQ 10 Coeliac disease DQ2/DQ8 10 Dermatitis herpetiformis DR3 50 Ankylosing spondylitis B27 90-100

*Relative risk: Probability of individuals with a particular HLA allele(s) to develop a disease compared with individuals lacking that allele(s).

HLA-association immunologic diseases

1. crossreactivity2. defect cleaning from apoptotic

cells3. ”hidden” selfantigen4. modified autoantigen5. viral infections6. selection in the thymus7. immunoregulatory defects

Theories around development of Theories around development of autoimmune diseaseautoimmune disease

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TCR

MHC

Viruspeptid Kontakt-residuer

Selvpeptid

Samme TCR kryssreagerer på et selvpeptid med lignende

kontaktresiduer

TCR

MHC

En naiv T-celle med en bestemt TCR reagerer på viruspeptid. Ekspansjon av

effektorcelle

Kontakt-residuer

Molekylær etterligning

22.5

Crossreactivity

Th1: IL-2, IFN-

Th2: IL-4, IL-5, IL-13

Th3/Tr: IL-10, TGF-

Th17: IL-17

Cytokines - imbalanceCytokines - imbalance

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Risk for autoimmune disease Risk for autoimmune disease controlled by the environment – controlled by the environment –

and genetic factors, esp. MHCand genetic factors, esp. MHC

- Twinstudies

- Familystudies

- Inbred mousestrains

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A pedigree including monozygotic twins and their mother with pSS

Bolstad et al., J Rheumatol 2000;27:2264-2266.Bolstad et al., J Rheumatol 2000;27:2264-2266. AIB 02

Autoimmune diseases Autoimmune diseases transferrable over the placenta – transferrable over the placenta –

NB! IgGNB! IgG

- Myastenia gravis- Grave’s disease- Thromocytopenic purpura- Neonatal lupus o/e congenital heartblock- Pemphigus vulgaris

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Diagnostics – prognosis inDiagnostics – prognosis inautoimmune diseasesautoimmune diseases

- Autoantibodies in diagnostics – marker

- Prognosis (timelag) until disease develops

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Criteria for Classification of Criteria for Classification of Rheumatoid ArthritisRheumatoid Arthritis

1. Morning stiffness2. Arthritis of three or more

joint areas3. Arthritis of hand joints4. Symmetric arthritis5. Rheumatoid nodules6. A. Serum rheumatoid factor

B. Anti-CCP (anti-cykl. citrull. prot.)7. Radiographic changes RJ13

Waaler-Rose test

Erik Waaler(1903-1997)

Kimsenter

Pannus som vokser innover og eroderer brusk og ben

Økt synovialvæske: autoantistoffer, immun-komplekser og RA-celler.

Ben

Brusk

SynovialvevNormal Revmatoid artritt

Ben

Brusk Betent villøst synovialvev, med infiltrerende lymfocytter, makrofager, plasmaceller.

Normal, enkeltlaget synovialhinneRA

Kollagen type IV

Fig 26.5

B cellsGCFDC

MCP-leddene

PIP-leddene

Halsvirvler

Fingre

Skulder

Vristledd

Fot

Ankel

Kne

Joints affected in RA

Fig 26.6

Criteria for Classification of Criteria for Classification of Systemic Lupus ErythematosusSystemic Lupus Erythematosus

1. Malar rash

2. Discoid rash

3. Photosensitivity

4. Oral ulcers

5. Arthritis

6. Serositis

7. Renal disorder

8. Neurologic disorder

9. Hematologic disorder

10. Immunologic disorder

e.g. anti-DNA, anti-Sm

11. Antinuclear antibody

(homogenous, speckled,

peripheral or nucleolar)

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Genetic Predisposition

Autoantibodies, Onset of

Autoimmunity

Pathological Injury

Clinical Disease

SLE

Clinical Presentation

Environmental Triggers

Immunkompleks glomerulonefritt

Anemi

Proteinuri, hematuri

Pericarditt

Feber

Pleuritt

Leddsmerter

Eksantem

Sår i munnhulen

Fig 26.2

SLE

1. Serum As tilsettes permeabiliserte celler

4. Ubundet sekundær As vaskes bort

5. Kjernefarging avleses ved immunfluorescens, FITC gir grønn farge.

Positiv ANA

Negativ ANA

2. ANA binder kjernen, ubundet As vaskes bort

3. FITC konjugert sekundærantistoff mot humant Ig tilsettes

Positiv ANA

Fig 26.3

ANA test

Anti-dsDNA Ab Anti-ssDNA AbAnti-Histone Ab

Fig 26.4

Criteria for Classification of Criteria for Classification of Sjögren’s syndromeSjögren’s syndrome

1. Ocular symptoms2. Oral symptoms3. Ocular signs4. Histopathologic features5. Salivary gland involvement6. Autoantibodies

(anti-Ro/SSA or anti-La/SSB)

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Tårekjertler: Keratokonjunctivitis siccaSpyttkjertler: Xerostomi, munnsår

Luftveier: Bronkitt, lungebetennelse

Sjögren’s syndrome

Exocrine glands that are affected:

Fig 26.9

Activated B cells

Immunogenetic Predisposition

?Sialotropic virus

Hormonal predisposition

Impaired Secretion

AutoreactiveCD4+ T cell

Epithelial cell

B cell activation

Dry eyes/mouth/nose/

Etc.Extraglandular

disease

Autoantibodies:ANA

Anti-Ro/LaRF, Anti-M3R

Additional trigger or

susceptibility factor?

Lymphoma

Chemokines, cytokines,MMPs

Elevated INF-, IL-6, IL-10, TNF-, etc.IL-2,

IFN- , IL-10

Adapted from Price and Venables, 1995

Susceptibility & triggers?

Activation, apoptosis, autoantigen release,antigen presentation

Lymphocytic infiltration, decreased apoptosis?

Clinical Features