Autoimmunity - Autoimmunity - autoimmune diseasesautoimmune diseases
Roland JonssonRoland Jonsson
Broegelmann Research LaboratoryBroegelmann Research Laboratory
RJ13
Autoimmunity Autoimmunity
- - - response to own tissue (antigen)
- - tissue damage a/o reduced function - spesific adaptive immune response
against own antigen
RJ13
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)
RJ13
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)
RJ13
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
RJ13
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
RJ13
- Difficult to eliminate the antigen
- Sustained immuneresponse
Result - Result - chronic inflammationchronic inflammation
Adaptive immune response Adaptive immune response – – endogenous antigenendogenous antigen
RJ13
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
RJ13
Classification ofClassification ofautoimmune diseases (2)autoimmune diseases (2)
SystemicSystemicReumatoid artrittSklerodermiSjögrens syndromPolymyosittSystemisk lupus erythematosus
RJ13
What triggers autoimmunity?What triggers autoimmunity?
- Environmental factors
- Genetic factors (espes. MHC)
RJ13
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
RJ13
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
RJ13
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
RJ13
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
RJ13
Diagnostics – prognosis inDiagnostics – prognosis inautoimmune diseasesautoimmune diseases
- Autoantibodies in diagnostics – marker
- Prognosis (timelag) until disease develops
RJ13
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)
RJ13
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)
RJ13
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
Top Related