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Autoimmunity and imunopathology

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Presentation on theme: "Autoimmunity and imunopathology"— Presentation transcript:

1 Autoimmunity and imunopathology
Tomas Milota, MD. Department of Immunology, Department of Rheumatology, Second Medical Faculty, Charles University and Motol University Hospital, Prague

2 Basic characteristics of immunity
Key system for homeostasis maintenance: Protection against pathogens (PAMPs) Autotolerance Immune 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

3 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 expositions Immunodeficiency – 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 dysregulation Autoimmunity – process, when immune system recognizes own structures (cells and tissues) as foreign and causes their destruction by cytotoxic mechanisms

4 Immunedeficiency vs. Autoimmunity
Monogenic causes of autoimmunity (rare) ADA2 deficiency: Monogenic vasculitis AIRE deficiency: APECED syndrome FoxP3 deficiency: IPEX syndrome NOD2 GOF mutation: Blau syndrome PID with high prevalence of autoimmune complications: • selective IgA deficiency • CVID • CMC • CID • AR- HIES IL-10 deficiency: Crohn disease C3 deficiency: SLE-like Polygenic and multifactorial ethiology (common concept)

5 Exogenous factors Endogenous factors
■ Infectiosn (EBV – RS, – CAG) ■ UV radiation (SLE) ■ Drugs (prokainamid, hydrakazin – SLE, statiny – dermato/polymyositis) ■ Smoking (vasculitis – Burger disease, rheumatoid arthritis) ■ Stress, trauma, chemicals ■ Genetic predisposition ■ Gender ■ Age Mosaic of autoimmunity

6 Genetic predisposition
Monogenic causes autoimmune diseases ■ APECED (Autoimmune PolyEndocrinopathy, Candidosis, Ectodermal 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)

7 Kaleidoscope of autoimmunity
2) HLA asociace 2) MHC I association (in polygenic/multifactorial) ■ HLA B27 – spondylarthritis ■ HLA B51 – Behcet disease 2) 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 skleróza Protective variants: HLA DR7 - Hashimoto hyreoiditis HLA DR14 – Multiplex sclerosis HLA DR14, HLA DR15 - Type 1 diabetes Kaleidoscope of autoimmunity High prevalence of Hashimoto hyreoiditis a Celiac disease in Type 1 diabetes patients

8 2) Gene polymorphisms for cytokines and their receptors
Cytokinová rodina Asociované onemocnění Rodina IL-2 T1DM, RA, IBD, MS, vitiligo Rodina IL-12 AS, IBD, PsA/Ps Rodina IL-23 AS, Ps/PsA, IBD Rodina IL-10 IBD, T1D IFN I SLE, SS

9 Th1 Th2 Thf Th17 Treg APC IFN-I IL-12 IL-4 IL-6, ICOS
T-bet / STAT4 IFN-I CXCR3 IFN gamma IL-12 Th2 GATA-3 / STAT6 IL-4 CRTH2 IL-4, 5, 13 CD80,CD86 / CD28 CD40 / CD40L OX40 L / OX40 ICOS-L / ICOS PD-1L / PD-1 PD-2L / PD-2 Thf IL-6, ICOS Bcl-6 APC CXCR5 IL-21 TGF-beta, IL-6, IL-23 Th17 Ror-g / STAT3 CTLA4 / IL-10 / TGF beta CCR6 TGF-beta IL-17 Treg FOXP3 / STAT5 IL-10, TGF beta

10 Phases of autoimmunity development
Genetic predisposition: ● Familial occurrence ● MHC ● (gender, age) Environment ● Infection ● UV radiation ● Smoking ● Drugs Immune systém dysregulation: ● dysbalance stimulatory / inhibitory signals ● impaired cytokine production SUSCEPTIBILITY INITIATION: Autoantibody detection PROPAGATION: Unspecific manifestation (sub/febrilie, fatigue) MANIFESTATION: Clinically specific symptoms

11 Epidemiology I: gender influence
Disease Incidence Rheumatoid arthritis 10 – 50 : JIA 1 – 20 : Ankylosing spondylitis 6 – 7 : Sjogren syndrome 7 : SLE 1 – 8 : Systemic scleroderma 0,3 – 2 : Myositis 0,1 : 6M 16R 35R 50R JIA SLE RA GCA

12 Epidemiology II: age influence
Disease M:F Ratio SLE 10 – 20x in F Sjogren syndrome Up to 9x in F Systemic scleroderma 3 – 8x in F Myositis Up to 3x in F JIA 3 – 4x in F Rheumatoid arthritis 2 – 3x in F Ankylosing spondylitis 2 – 3x in M Estrogenys increase expression of IFN I a IRF 5 (interferon regulating faktor 5) Overexpression of X linked genes: CD40L, CXCR3, OGT, FOXP3, TLR7, TLR8, IL2RG, BTK, and IL9R Different changes in cell phenotype of males and females during aging Differences microbiome composition between males and females

13 Classification of autoimmune diseases
1) According to pathophysiological mechanism: Coombse and Gell Classification Type Mechanism Disease I. IgE mediated IgE EGPA (Churg – Strauss) II. ADCC (Antibody Dependent Cell Cytotoxicity) IgG, IgM AIHA, ITP Myasthenia gr. Gravesova thyreoiditis III. Imunocomplex reactions IgG complement SLE Reactive arthritis IC glomerulonephritis IV. Delayed hypersensitivity T lymphocytes T1DM Hashimoto thyreoiditis Multiplex sclerosis

14 2) According to localisation
Organ specific: Tissue specific autoantibodies may be detected Autonatibodies 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)

15 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)

16 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)

17 Therapy ■ Non – steroid antiflogistics ■ Glucocorticosteroids ■ Disease Modifying Antirheumatic Drugs (DMARDs)

18 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 joints Administration: systemic vs. local Adverse 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)

19 Glucocorticoids Mechanisms of action:
- binding GRE (glucocorticoid response elements): - non-genomic effect (immediate): COX-2 inhibition, reduction of proinflammatory cytokine release genomic (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!!!

20 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 disease Osteoporis (densitometric screening necessary!!!) Atherosclerosis Impaired glucose metabolism Negative impact on CNS (insomnia, emotional lability, psychosis) Adrenocortical insuficiency Ostatní: eye cataract, hirsutism, aseptic osteonecrosis, cushingoid habitus, glaukoma, sekundary amenorhea,…..

21 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)

22 Conventional synthetic (csDMARDs):
Mechanism of action Antiproliferative: methotrexate, leflunomide, azathioprine, cyclophosphamide) Inhibition of Ca dependent signalization (cytokines resposnible to activation and proliferation: Cyclosporin A Inhibition of endosome: antimalarics Unknown mechanism: sulfasalazin Adverse event: - hepatotoxicity, myelotoxicity, nephrotoxicity, GIT toxicity, retinopathy (Plaquenil), pneumonitis (methotrexate), cystitis (cyclophosphamide) Remedy Dosage regimen Hydroxychloroquine 200 (400) mg dayly Sulfasalazine 500 – 2000 (3000) mg dayly Methotrexate 5 – 20 (25) mg weekly + Ac. folicum Leflunomide 10 – 20mg daly Cyclosporin A 2,5 – 3,2mg/kg/day Azathioprine 1 – 3mg/kg/day

23 Biologické (bDMARDs) monoclonal antibody: Chimeric (infliximab), humanized (certolizumab) or human (adalimumab, sekukinumab) or fuze proteins (etanercept, abatacept) block proinflamatoy cytokine or its receptor (anakinra), costimulatory molecules (abatacept) Target Remedy Anti IL-1R anakinra Anti IL-1beta canakinumab Anti TNF alpha infliximab, etanercept, adalimumab, certolizumab, golilumab Anti IL-6RA tocilizumab, sarilumab Anti IL- 17A sekucinumab, ixekizumab CTLA4 abatacept Anti BAFF belilumab 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

24 Th1 Th2 Thf Th17 Treg APC IL-1 IFN-I IL-12 TNF-α IL-4 IL-6, ICOS
T-bet / STAT4 IL-1 IFN-I CXCR3 Anakinra Canakinumab IFN gamma IL-12 TNF-α Ustekinumab (+IL-23) Th2 GATA-3 / STAT6 Etanercept Adalimumab Cetolizumab Golilumab IL-4 CRTH2 IL-4, 5, 13 Tocilizumab CD80,CD86 / CD28 CD40 / CD40L OX40 L / OX40 ICOS-L / ICOS PD-1L / PD-1 PD-2L / PD-2 Thf IL-6, ICOS Bcl-6 APC CXCR5 IL-21 TGF-beta, IL-6, IL-23 Th17 Ror-g / STAT3 Ustekinumab (+IL-12) Risankizumab Abatacept CTLA4 / IL-10 / TGF beta CCR6 Sekucinumab Bimekizumab Ixekizumab IL-17 TGF-beta Treg FOXP3 / STAT5 IL-10, TGF beta

25 Thank you for attention!

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