Autoimmunity and imunopathology - PowerPoint Presentation

Slide1

Autoimmunity and imunopathology

Tomas Milota, MD.

Department of Immunology,Department of Rheumatology,Second Medical Faculty, Charles University and Motol University Hospital, Prague

Slide2

Basic characteristics

of

immunityKey system for homeostasis

maintenance:

Protection

against

pathogens (PAMPs)AutotoleranceImmune surveillance – removal of damaged or mutated cells+ broad spectrum of non-immunological functions■ interactions with central nervous system■ interactions with endocrine system

Immunodeficiency

Autoimmunity

Malignancy

Slide3

Characteristics

of basic immune system disorders

Allergy

–

process

, when immune system in predisposed individuals exerts inflammatory response against exogenous antigens – allergens (which is tolerated in healthy individuals) upon repeated expositionsImmunodeficiency – condition, when one or more components of immune system is completely missing or is partly defective, it

is usually manifested with

recurrent infections and/or immune system

dysregulationAutoimmunity

– process, when immune system

recognizes own structures (cells and

tissues) as foreign and causes their destruction

by

cytotoxic

mechanisms

Slide4

Immunedeficiency

vs.

AutoimmunityIL-10 deficiency:Crohn diseaseNOD2 GOF mutation

:Blau syndrome

AIRE

deficiency

:

APECED syndromeFoxP3 deficiency:IPEX syndromePID with high prevalence of autoimmune complications: • selective IgA deficiency• CVID• CMC• CID • AR- HIESC3 deficiency:SLE-like

Monogenic

causes of

autoimmunity (rare)

ADA2

deficiency:Monogenic vasculitis

Polygenic

and

multifactorial

ethiology

(common

concept

)

Slide5

Exogenous

factors

Endogenous

factors

■

Infectiosn

(EBV – RS, H.py – CAG)■ UV radiation (SLE)■ Drugs (prokainamid, hydrakazin – SLE, statiny – dermato/polymyositis)■ Smoking (vasculitis – Burger disease, rheumatoid arthritis)■ Stress, trauma, chemicals

■

Genetic predisposition■ Gender

■ Age

Mo

saic

of autoimmunity

Slide6

Genetic predisposition

Monogenic

causes autoimmune diseases■ APECED (Autoimmune PolyEndocrinopathy,

Candidosis,

E

ctodermal

Dysplasia) – mutation AIRE gene (AutoImmune REgulator) – AR heredity■ IPEX (autoimmune polyendocrinopathy, enteropathy) – mutation FOXP3 (TREGs) – X linked■ CTLA4 deficiency – mutation in CTLA4 (inhibitory molecule) – AD heredity■ ALPS (Autoimmune Lymphoproliferative Syndrome) – mutation in FAS (AD), FAS-L, CASP10 (AD/AR)

Slide7

2) HLA asociace

2) MHC I association (in

polygenic/multifactorial)■ HLA B27 – spondylarthritis■ HLA B51 – Behcet disease2) MHC II association

(in polygenic/

multifactorial

)

■

HLA DQ2, HLA DQ8 – Celiac disease■ HLA DR3, HLA DR4 – Hashimoto thyreoiditis■ HLA DR3, HLA DR4, HLA DQ2, HLA DQ8 – Type 1 diabetes■ HLA DR15 – roztroušená sklerózaProtective variants:HLA DR7 - Hashimoto hyreoiditisHLA DR14 – Multiplex sclerosisHLA DR14, HLA DR15 - Type 1 diabetesHigh prevalence of Hashimoto hyreoiditis a Celiac disease in Type 1 diabetes

patients

Ka

lei

dos

cope

of

auto

immu

nity

Slide8

2) Gene polymorphisms for

cytokines and their

receptors Cytokinová rodina

Asociované onemocnění

Rodina IL-2

T1DM,

RA, IBD, MS, vitiligo

Rodina IL-12AS, IBD, PsA/PsRodina IL-23AS, Ps/PsA, IBDRodina IL-10IBD, T1DIFN ISLE, SS

Slide9

CD80,CD86 / CD28

CD40 / CD40L

OX40 L / OX40

ICOS-L / ICOS

---------------------------

PD-1L / PD-1

PD-2L / PD-2

APCTh1

T

h

17

T

h

f

T

h

2

CTLA4 /

IL-10 /

TGF beta

T

reg

IL-12

IL-4

TGF-beta

IL-6, ICOS

TGF-beta,

IL-6, IL-23

T-bet / STAT4

GATA-3 / STAT6

Bcl-6

Ror-g / STAT3

FOXP3 / STAT5

CXCR5

CXCR3

CCR6

CRTH2

IFN gamma

IL-4, 5, 13

IL-21

IL-17

IL-10, TGF beta

IFN-I

Slide10

Phases of

autoimmunity development

Genetic

predisposition

:

●

Familial occurrence● MHC● (gender, age)Environment● Infection● UV radiation● Smoking● DrugsImmune systém dysregulation:● dysbalance stimulatory / inhibitory

signals● impaired

cytokine production

SUSCEPTIBILITY

INITIATION:

Autoantibody

detection

PROPAGATION:

Unspecific

manifestation

(sub/febrilie, fatigue

)

MANIFESTATION

:

Clinically

specific

symptoms

Slide11

Disease

Incidence

Rheumatoid arthritis10 – 50 : 100 000JIA1 – 20 : 100 000Ankylosing spondylitis

6 – 7 : 100 000

Sjogren

syndrome

7 : 100 000

SLE1 – 8 : 100 000Systemic scleroderma0,3 – 2 : 100 000Myositis0,1 : 100 000Epidemiology I: gender influence

6M

16R

35R

50RJIA

SLE

RA

GCA

Slide12

Disease

M:F Ratio

SLE10 – 20x in FSjogren syndromeUp to 9x in FSystemic scleroderma

3 – 8x in F

Myositis

Up

to

3x in FJIA3 – 4x in FRheumatoid arthritis2 – 3x in FAnkylosing spondylitis2 – 3x in MEstrogenys increase expression of IFN I a IRF 5 (interferon regulating faktor 5) Overexpression

of X linked genes: C

D40L, CXCR3, OGT, FOXP3, TLR7, TLR8

, IL2RG, BTK, and IL9R

Differences

microbiome composition between males

and females

Different

changes

in cell

phenotype

of

males

and

females

during

aging

Epidemiology II:

age

influence

Slide13

Classification of

autoimmune diseases

1) According to pathophysiological mechanism: Coombse and Gell Classification

Type

Mechanism

Disease

I.

IgE mediatedIgEEGPA (Churg – Strauss)II.ADCC (Antibody Dependent Cell Cytotoxicity)IgG, IgMAIHA, ITPMyasthenia gr.Gravesova thyreoiditisIII.Imunocomplex reactions

IgGcomplementSLE

Reactive arthritisIC glomerulonephritis

IV.Delayed hypersensitivityT lymphocytes

T1DMHashimoto thyreoiditisMultiplex sclerosis

Slide14

2) According to

localisation

Organ specific:Tissue specific autoantibodies may be detectedAutonatibodies may be

diagnostic or

pathogenic

(

activating

/ inhibiting / cytotoxic)■ ENDOCRINOPATHY: Graves thyreoiditis (TRAK), Hashimoto thyreoiditis (anti TG, anti TPO), T1DM (anti GAD, anti IAA, anti IA2)■ AI CYTOPENIAS: AIHA (anti erythrocyte AAb – direct/indirect Coombs test), ITP (anti thrombocytic AAb), AI neutropenia (anti

leukocytic)■ NEUROLOGIC DISEASES: Myasthenia gravis (anti AceCh-R), Multiplex sclerosis

(no specific AAb

present)■ DERMATOLOGIC DISEASES: pemphigus (

anti desmoglein 1,3), psoriasis (no specific

AAb present)

Slide15

B) Organ localized:Organ Unspecific

AAb present Organ specific

disease■ Ulcerative colitis (ANCA)■ Crohn disease (ASCA)■ AI hepatitis (type I, II

, III

:

ASMA/F-aktin

,

LKM, SLA, + ANA, anti dsDNA)+ possible association with HCV infection in type II■ Celiac disease (anti EMA, anti TRG)■ Primary billiary cirrhosis (AMA)

Slide16

C) Systemic autoimmune diseases

Presence of UNspecific

AAb (ANA, ENA, RF, ACPA)Multiorgan manifestation■ systemic connective tissue diseases (SLE, dermato

/polymyositis,

Sjogren

syndrome,

systemic

scleroderma)■ systemic vasculitis (EGPA, GPA, MPA, PAN, OBA, Kawasaki,, Takayasu, ……)■ rheumatic diseases (Rheumatoid arthritis, JIA, spondylarthritis)

Slide17

Therapy

■ Non – steroid antiflogistics

■ Disease Modifying Antirheumatic Drugs (DMARDs)■ Glucocorticosteroids

Slide18

NSA

Mechanisms of action:

Inhibition of cyclooxygenase (COX-1 – constitutive, COX-2 inducible): unselective (ASA, ibuprofenum, diclofenacum, ketoprofenum, indometacinum), COX-2

preferential (meloxicam, nimesulid

), COX-2

selective

(

celekoxib, etorikoxib, rofekoxib) Clinical effect:Reduce production of proinflammatory cytokines – prostaglandines: analgetic, antipyretic a antiedematic effect, functional improvent of the jointsAdministration: systemic vs. localAdverse events:Gastrointestinal toxicity (peptic ulcer disease)Renal toxicity (

renal insificiency, tubul-interstitial

nephritis, papilar

necrosis)Hepatal toxicity Dermatological

toxicity (urtcaria)Platelets

disorders (thrombocytopenia)

Respiratory toxicity (nasal

polyposis

, ASA

induced

asthma)

Slide19

Glucocorticoids

Mech

anisms of action:- binding GRE (glucocorticoid response elements):- non-genomic

effect (immediate): COX-2 inhibition

,

reduction

of proinflammatory cytokine releasegenomic (delayed effect): Effect on activity of transcriptional factors (NFkB, AP-1)Clinical effect:Reduction of proinflammatory cytokines, leukocytes activity, analgetic, antipyretic and antiedematic effect, functional improvent of the joints + disease modifying effect!!!

Slide20

Administration: ■ systemic (

parenteral, peroral) vs. local (intraarticular

)■ pulse therapy (500 – 1000mg Solu-medrol) – high dose (40 – 60 mg Prednisone) – medium dose (20 mg Prednison) – low dose (5 – 10mg Prednisone)Adverse events

Infections (secondary

immunodeficiency

)

Higher

risk of peptic ulcer diseaseOsteoporis (densitometric screening necessary!!!)AtherosclerosisImpaired glucose metabolismNegative impact on CNS (insomnia, emotional lability, psychosis)Adrenocortical insuficiencyOstatní: eye cataract, hirsutism, aseptic osteonecrosis, cushingoid habitus, glaukoma, sekundary amenorhea,…..

Slide21

Disease modifying

drugs (DMARDs

)■ Conventional synthetic (csDMARDs)- methotrexate, leflunomide, antimalarics, ciclosporine

,…■ Biologic (

bDMARDs

)

-

anti TNF alpha (infliximab, etanercept, adalimumab,……), anti IL-17 (ixekizumab, sekukinumab,…..), anti IL-1(anakinra, canakinumab,….) apod.■ Targeted synthetic (tsDMARDs):- tofacitinib (JAK-1, JAK-3 inhibitor), baricitinib (JAK-1, JAK-2 inhibitor)

Slide22

Conventional synthetic (

csDMARDs):

Mechanism of actionAntiproliferative: methotrexate, leflunomide, azathioprine, cyclophosphamide)Inhibition of Ca dependent signalization

(cytokines resposnible to

activation

and

proliferation

: Cyclosporin AInhibition of endosome: antimalaricsUnknown mechanism: sulfasalazinRemedyDosage regimenHydroxychloroquine200 (400) mg daylySulfasalazine500 – 2000 (3000) mg daylyMethotrexate5 – 20 (25) mg weekly + Ac. folicum

Leflunomide10 – 20mg daly

Cyclosporin A2,5 – 3,2mg/kg/day

Azathioprine1 – 3mg/kg/day

Adverse event:

- hepatotoxicity, myelotoxicity, nephrotoxicity, GIT toxicity,

retinopathy (Plaquenil), pneumonitis (methotrexate), cystitis (

cyclophosphamide

)

Slide23

Biologické (bDMARDs)

monoclonal antibody:

Chimeric (infliximab), humanized (certolizumab) or human (adalimumab, sekukinu

mab)or fuze

proteins

(

etaner

cept, abatacept)block proinflamatoy cytokine or its receptor (anakinra), costimulatory molecules (abatacept)TargetRemedyAnti IL-1RanakinraAnti IL-1betacanakinumabAnti TNF alphainfliximab,

etanercept, adalimumab, certolizumab,

golilumabAnti IL-6RAtocilizumab,

sarilumabAnti IL- 17Asekucinumab,

ixekizumabCTLA4abatacept

Anti BAFFbelilumab

Adverse

events

(Anti TNF

alpha):

Hiher risk of infections (TBC, hepatitida B)

Autoimmmune

complications

(

vaskulitiy

,

iSLE

,

sarkoidosis

,

demyelinizing

disorder

of

CNS and PNS)

Panyctopenia

,

hepatal

damage

Slide24

CD80,CD86 / CD28

CD40 / CD40L

OX40 L / OX40

ICOS-L / ICOS

---------------------------

PD-1L / PD-1

PD-2L / PD-2

APCTh1

T

h

17

T

h

f

T

h

2

CTLA4 /

IL-10 /

TGF beta

T

reg

IL-12

IL-4

TGF-beta

IL-6, ICOS

TGF-beta,

IL-6, IL-23

T-bet / STAT4

GATA-3 / STAT6

Bcl-6

Ror-g / STAT3

FOXP3 / STAT5

CXCR5

CXCR3

CCR6

CRTH2

IFN gamma

IL-4, 5, 13

IL-21

IL-17

IL-10, TGF beta

IFN-I

TNF-

α

IL-1

Anakinra

Canakinumab

Etanercept

Adalimumab

Cetolizumab

Golilumab

Ustekinumab

(+IL-23)

Ustekinumab

(+IL-12)

Risankizumab

Tocilizumab

Sekucinumab

Bimekizumab

Ixekizumab

Abatacept

Slide25

Thank you

for attention

!