Ätiopathogenese der Sarkoidose
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1 Sarkoidose-Symposium USZ 26. Oktober 2017 Ätiopathogenese der Sarkoidose Martin Brutsche
2 Search for hints Is it a genetic disease? 2. Is it infection? 3. Is it induced by specific exposures to organic/anorganic antigens? 4. Is it Autoimmunity 5. Summary of confusion
3 AJRCCM 2016
4
5 Linkage Analyses Susceptibility for sarcoidosis Integrin alpha(e): sarcoidosis & fibrosis (Clin Immunol 2009) Annexin A11 (GWAS > SNPs in 499 German patients and 490 controls; Nat Genetics 2008) Löfgren vs. Non-Löfgren IL7R: sarcoidosis & Löfgren (Genes Immun. 2009) C-C chemokine receptor 5 gene: Female-specific association (J Mol Med 2008)
6 BTLN2-SNP rs Nature Genetics 2005; 37: 357 Butyrophilin-like 2 (BTNL2) is involved in co-stimulation of T-Lymphocytes due to similarities to B7-1 Risk allel has truncated form resulting in increased activation of T-lymphocytes RR for sarcoidosis +60%
7 Antworten aus der Genetik Sarkoidose ist keine Erbkrankheit Genpolymorphismen für die Empfindlichkeit für die Sarkoidose Genpolymorphismen für die phänotypische Präsentation der Sarkoidose Löfgren vs. Non- Löfgren Polymorphismen weisen zu Mechanismen der Zell-vermittelten Immunantwort und Antigen- & Proteinverarbeitung Pathogenese
8 Search for hints Is it a genetic disease? 2. Is it infection? 3. Is it induced by specific exposures to organic/anorganic antigens? 4. Is it Autoimmunity 5. Summary of confusion
9 Wie verläuft die Entzündung? Aktivierung der angeborenen, zellvermittelten Immunantwort TH1-Immunantwort Abwehr von intrazellulären Keimen wie Mykobakterien, Propionibakterien Iannuzzi et al. NEJM 2007
10 Chen ES et al. AJRCCM 2010 Tissue of sarcoidosis patients: ICH, ELISA SAA is highly expressed in granulomata in sarcoidosis and not so in other granulomatous disorders BAL of sarcoidosis patients for functional studies, including in vitro-stimulation model SAA induces activation of macrophages via TLR-2
11 SAA is highly expressed in granulomas in sarcoidosis Chen ES et al. AJRCCM 2010
12 SAA is highly expressed in granulomas in sarcoidosis Chen ES et al. AJRCCM not so in other granulomatous disorders...not so in other granulomatous disorders...
13 Maertzdorf J et al. PNAS 2012 Comparison between TB and sarcoidosis Whole-blood gene expression profiling, microrna expression, and multiplex serum analytes Very similar...! Sarcoidosis is like TB, but without the presence of living microorganisms!?!
14 Maertzdorf J et al. PNAS 2012
15 Z. Song et al. J Exp Med 2005 Limited proteomics in serum for poorly soluble/protease-resistant tissue antigens (i.e. properties of granuloma-inducing sarcoidosis tissue extracts) Incl. Mycobacterium tuberculosis catalase peroxidase (mkatg) Such tissue antigens found in 9/12 (75%) sarcoidosis tissues (3/22 (14%) in control tissues (p=0.0006)
16 Z. Song et al. J Exp Med 2005
17 Mycobacterium tuberculosis catalase peroxidase (mkatg) Z. Song et al. J Exp Med 2005 mkatg-ich positive in 5/9 (55%) sarcoidosis tissues (0/14 control tissues; p=0.004) IgG antibodies to recombinant mkatg detected in sera of 12/25 (48%) sarcoidosis patients (0/11 PPD - controls; p=0.006 & 4/10 PPD + controls; p=0.72) Remnant mycobacterial catalase peroxidase might be one target of the adaptive immune response driving granulomatous inflammation in sarcoidosis
18 Search for hints Is it a genetic disease? 2. Is it infection? 3. Is it induced by specific exposures to organic/anorganic antigens? 4. Is it Autoimmunity 5. Summary of confusion
19 Regional heterogeneity in CH Deubelbeiss et al. Eur Respir J Per Inh. Significant heterogeneity p<0.001 Population density p=0.04 (negative correlation) Medical services p=0.43 Air pollution p=0.43
20 p=0.004 Associations with different methods of agriculture Deubelbeiss et al. Eur Respir J. 2010
21 p=0.009 Associations with industries (Co-inertia) Deubelbeiss et al. Eur Respir J. 2010
22 Häufigkeit von CBD Sensibilisierung 2-20% der Be Exponierten Ca. 40% von Sensibilisierten entwickeln CBD Ca. 6-7% von Sarkoidosis Patienten waren in D und Israel in Wahrheit CBD 16-30% von Sarkoidosis Patienten sind/waren Be exponiert, von diesen sind zwischen 20-40% CBD
23 Search for hints Is it a genetic disease? 2. Is it infection? 3. Is it induced by specific exposures to organic/anorganic antigens? 4. Is it Autoimmunity 5. Summary of confusion
24 Autoimmunity? PRO Associations with HLA-types (Wahlstro m J et al. J Clin Invest 2007) Presence of hypergammaglobulinemia (Hunninghake GW, Crystal RG. J Clin Invest 1981) CON Compartimalization of immune response Peripheral anergia of immune response
25 Häggmark A et al. Am J Respir Crit Care Med 2015 Antigen microarrays (3,072 protein fragments) to screen for IgG reactivity in 73 BAL samples from sarcoidosis, asthma & healthy subjects 131 targets verified on suspension bead arrays using 272 additional BAL and 141 paired sera Reactivity to 4 antigens was analyzed in 22 unprocessed BAL samples from patients with fibrosis and 269 plasma samples from patients diagnosed with myositis
26 Häggmark A et al. Am J Respir Crit Care Med 2015 Identification of 4 promising autoantigens Most patients had reactivity to either of these autoantigens
27 J. Grunewald et al. ERJ 2016 Pulmonary sarcoidosis patients (n=43, incl. 26 HLA-DRB1*03 + ) bronchoscopy & BAL TCR α and β chains of CD4+ T-cells were analysed by flow cytometry, DNA-sequenced, and 3D-molecular models of TCR-HLA- DRB1*03 complexes generated
28 TCR-Construct TCR-chains, CDR-loops, HLA-DR-chains Antigen-Pocket Vimentin-derived peptide Vim fits in pocket J. Grunewald et al. ERJ 2016
29 Autoimmunity? Possible through molecular mimicry Antigen hits the body Incomplete elimination of proteins/peptides Remnant misfolded and bacterial proteins might have resemblance to autoantigens Persistance of immune response after clearance of infection Concept of autoimmunity needs to be revisited
30 Search for hints Is it a genetic disease? 2. Is it infection? 3. Is it induced by specific exposures to organic/anorganic antigens? 4. Is it Autoimmunity 5. Summary of confusion
31 Summary Sarcoidosis is characterized by an activation of innate immunity and granuloma formation It is likely that the immune response is induced by antigen(-s) sometimes in a context of (airborne) infection Remnant/aggregated antigens form the nidus for granuloma formation Molecular mimicry might induce autoimmunity It is possible that Berylliosis is not another disease, but a sarcoidosis with known antigen
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