1. Autoimmunity - autoimmune diseases
Roland Jonsson
Broegelmann Research Laboratory
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2. Autoimmunity - - response to own tissue (antigen)
- tissue damage a/o reduced function
- spesific adaptive immune response against own antigen
Autoimmune disease
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3. Autoinflammation 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 effusion
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4. Examples of autoinflammatoric disease 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
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5. Naiv autoreaktiv T- hjelpercelle
Autoimmunity
CD28 B7
Naiv autoreaktiv T- hjelpercelle
IL-4
IL-12
Immundeviasjon
Th1
Th2
Autoreaktive Th1-celler som utskiller IFN-g og TNF og gir inflammasjon. Kan forårsake autoimmun sykdom
Autoreaktive Th2-celler som beskytter mot utvikling av autoimmune sykdommer
Immunedeviation – development of
“harmless” Th2-cells protects
Autoimmune dis. Protects against autoimmunity

6. Cytokines (1) CD4+ T cells: Th1: IL-2, IFN- Th2: IL-4, IL-5, IL-13
Th3/Tr: IL-10, TGF-
Th17: IL-17
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7. Fates of CD4 T cells Th1 (IFN-g):Host defense Th2 (IL-4, IL-5,IL-13):
(IC pathogens)
autoimmunity
STAT4
T-bet
IL-12
Th2 (IL-4, IL-5,IL-13):
Host defense
(parasites),
Allergy, asthma
STAT6
GATA3
Naïve
T cell
c-maf
Th17 (IL-17): Host defense
(EC pathogens)
Inflammation
Autoimmunity
RORgt
TGF-b
IL-23
Foxp3
T-reg (TGF-b, IL-10)
Immunosuppression

9. Cytokines (2) Pro-inflammatory: IL-1, IL-6, TNF-,
IL-12, IL-18, (IFN-, chemokines)
Anti-inflammatory:
IL-4, IL-10, IL-13, TGF-
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10. Autoimmune diseases 5-7% of the population
nearly all organsystems in the body
can be involved
can be asymptomatic for a long time
varieable disease expression
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11. Di sease Clinical Presentation Environmental Triggers
Pathological Injury
Genetic Predisposition
Autoantibodies, Onset of Autoimmunity
Clinical Disease

12. Fig 26.1
Thyreoidea: Hashimotos thyreoiditt
Binyrebark: Idiopatisk binyrebarksvikt
Nyre: Nefrotoksisk glomerulonefritt
Pancreas: Diabetes mellitus, type I
Ventrikkel: Pernisiøs anemi
Muskel: Myasthenia gravis
Hud: Bulløse hudsykdommer

13. Definition of autoimmune disease
Autoantibodies - Autoreactive T cells - Autoimmune process primarily
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14. Witebsky’s criteria (1957) How to prove autoimmune disease?
Antibodies should be detectable
Autoantigens should be identified
Experimental induction of antibodies against the antigen
4. Induceable disease in an experimental model
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15. Adaptive immune response – endogenous antigen
- Difficult to eliminate the antigen
- Sustained immuneresponse
Result - chronic inflammation
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16. autoimmune diseases (1)
Classification of
autoimmune diseases (1)
Organspesific
Type I diabetes mellitus
Goodpasture’s syndrome
Multippel sklerose
Grave’s disease
Hashimotos thyreoiditt
Autoimmun perniciøs
anemi Addison’s disease
Vitiligo
Myastenia gravis
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17. autoimmune diseases (2)
Classification of
autoimmune diseases (2)
Systemic
Reumatoid artritt
Sklerodermi
Sjögrens syndrom
Polymyositt
Systemisk lupus erythematosus
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18. What triggers autoimmunity?
- Environmental factors
- Genetic factors (espes. MHC)
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19. HLA-association immunologic diseases
Disease HLA Allele Relative Risk*
Rheumatoid arthritis DR4 6
IDDM DR3 5 DR
DR3/DR4 20
Chronic active hepatitis DR3 14
Sjögren´s syndrome DR3 + DQ 10
Coeliac disease DQ2/DQ8 10
Dermatitis herpetiformis DR3 50
Ankylosing spondylitis B
Specific HLA antigens have been associated with various human diseases, for instance the B27 antigen confers a fold increased risk for ankylosing spondylitis, and DR3 a 10-fold risk for SS. In addition to what is mentioned on this slide, the DR2 antigen confers a 3 fold increased risk for lupus, and a 4-fold risk for multiple sclerosis.
Increased frequencies of both HLA-DR2 and DR3 have been found in primary SS, in contrast to secondary SS where for instance patients with secondary SS and rheumatoid arthritis have increased HLA-DR4.
*Relative risk: Probability of individuals with a particular HLA allele(s)
to develop a disease compared with individuals lacking that allele(s).

20. Theories around development of
autoimmune disease
1. crossreactivity
defect cleaning from apoptotic
cells
3. ”hidden” selfantigen
4. modified autoantigen
5. viral infections
6. selection in the thymus
7. immunoregulatory defects
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22. Samme TCR kryssreagerer på et selvpeptid med lignende kontaktresiduer
Molekylær etterligning
TCR
TCR
Viruspeptid
Selvpeptid
Kontakt-
residuer
Kontakt-
residuer
MHC
MHC
En naiv T-celle med en bestemt TCR reagerer på viruspeptid. Ekspansjon av effektorcelle
Samme TCR kryssreagerer på et selvpeptid med lignende kontaktresiduer
Crossreactivity
22.5

24. Cytokines - imbalance Th1: IL-2, IFN- Th2: IL-4, IL-5, IL-13
Th3/Tr: IL-10, TGF-
Th17: IL-17
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26. Risk for autoimmune disease controlled by the environment –
and genetic factors, esp. MHC
- Twinstudies
- Familystudies
- Inbred mousestrains
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27. A pedigree including monozygotic twins and their mother with pSS
AIB 02
Bolstad et al., J Rheumatol 2000;27:

28. transferrable over the placenta –
Autoimmune diseases
transferrable over the placenta –
NB! IgG
- Myastenia gravis
- Grave’s disease
- Thromocytopenic purpura
- Neonatal lupus
o/e congenital heartblock
- Pemphigus vulgaris
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29. Diagnostics – prognosis in
autoimmune diseases
- Autoantibodies in diagnostics – marker
- Prognosis (timelag) until disease develops
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30. Criteria for Classification of
Rheumatoid Arthritis
1. Morning stiffness
Arthritis of three or more
joint areas
3. Arthritis of hand joints
4. Symmetric arthritis
5. Rheumatoid nodules
A. Serum rheumatoid factor
B. Anti-CCP (anti-cykl. citrull. prot.)
7. Radiographic changes
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32. Waaler-Rose test
Erik Waaler
( )

34. B cells GC FDC Revmatoid artritt Normal Synovialvev
Pannus som vokser innover og eroderer brusk og ben
Ben
Ben
Brusk
Betent villøst synovialvev, med infiltrerende lymfocytter, makrofager, plasmaceller.
Brusk
Kimsenter
Økt synovialvæske: autoantistoffer, immun-komplekser og RA-celler.
Normal, enkeltlaget synovialhinne RA
B cells GC
FDC
Kollagen type IV
Fig 26.5

35. Joints affected in RA Halsvirvler Skulder PIP-leddene Vristledd
Fot
Ankel
Kne
Halsvirvler
MCP-leddene
PIP-leddene
Skulder
Vristledd
Fingre
Fig 26.6

36. Criteria for Classification of Systemic Lupus Erythematosus
8. Neurologic disorder
9. Hematologic disorder
Immunologic disorder
e.g. anti-DNA, anti-Sm
Antinuclear antibody
(homogenous, speckled,
peripheral or nucleolar)
1. Malar rash
2. Discoid rash
3. Photosensitivity
4. Oral ulcers
5. Arthritis
6. Serositis
7. Renal disorder
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37. SLE Clinical Presentation Environmental Triggers Pathological Injury
Genetic Predisposition
Autoantibodies, Onset of Autoimmunity
Clinical Disease

38. SLE Feber Eksantem Sår i munnhulen Pleuritt Pericarditt
Leddsmerter
Eksantem
Sår i munnhulen
SLE
Pericarditt
Immunkompleks glomerulonefritt
Proteinuri, hematuri
Anemi
Fig 26.2

43. ANA test 1. Serum As tilsettes permeabiliserte celler
2. ANA binder kjernen, ubundet As vaskes bort
3. FITC konjugert sekundærantistoff mot humant Ig tilsettes
4. Ubundet sekundær As vaskes bort
Negativ ANA
Positiv ANA
Positiv ANA
5. Kjernefarging avleses ved immunfluorescens, FITC gir grønn farge.
ANA test
Fig 26.3

45. Anti-dsDNA Ab
Anti-ssDNA Ab
Anti-Histone Ab
Fig 26.4

46. Criteria for Classification of
Sjögren’s syndrome
1. Ocular symptoms
2. Oral symptoms
3. Ocular signs
4. Histopathologic features
5. Salivary gland involvement
Autoantibodies
(anti-Ro/SSA or anti-La/SSB)
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47. Sjögren’s syndrome Exocrine glands that are affected:
Tårekjertler: Keratokonjunctivitis sicca
Spyttkjertler: Xerostomi, munnsår
Luftveier: Bronkitt, lungebetennelse
Fig 26.9

52. Activated B cells

53. susceptibility factor?
Immunogenetic
Predisposition
Susceptibility &
triggers?
?Sialotropic virus
Hormonal
predisposition
Activation, apoptosis,
autoantigen release,
antigen presentation
Epithelial cell
Elevated
INF-,
IL-6,
IL-10,
TNF-,
etc.
Chemokines,
cytokines,
MMPs
Lymphocytic
infiltration,
decreased apoptosis?
Autoreactive
CD4+ T cell
IL-2,
IFN- ,
IL-10
B cell
activation
Additional
trigger or
susceptibility factor?
Autoantibodies:
ANA
Anti-Ro/La
RF, Anti-M3R
Impaired
Secretion
Clinical
Features
Dry eyes/
mouth/nose/
Etc.
Lymphoma
Extraglandular
disease
Adapted from Price and Venables, 1995