Disease causation- the big picture

1. Advances in the pathogenesis and management of SLE Anne Davidson MBBSFeinstein Institute for Medical Research, Manhasset NY

2. Chance/Fate Environment Genetic risk Innate and adaptive immune responses Disease phenotype Amplification Target organ damage Disease causation- the big picture

3. Systemic autoimmunity

4. Neut and Basoph SLE is associated with aberrant clearance of nucleic acid containing debris Virus Innate FCR Adaptive

5. DNA Ro DNA LL37 J Exp Med. 1994;179:1317-30 The source of nucleic acids in SLE

6. Genetic defects can cause an overload of IC or apoptotic particles Fc receptor polymorphisms Altered nuclease digestion eg Trex1 mutation Inefficient clearance eg complement deficiencies Excess cell death

7. Neut and Basoph SLE is associated with aberrant clearance of nucleic acid containing debris Virus Innate FCR Adaptive

8. Endosome Nucleus Immunity. 2010 Mar 26;32(3):305-15

9. SLE associated genes with definitive statistical evidence on GWAS

10. Many lupus associated genes are involved with both the induction, and response to, type 1 IFNs

11. Recognition of intracellular nucleic acids by innate receptors is pro-inflammatory Tissue damage Nat Rev Rheum 6:146 2010

12. Other genetic contributors to SLE IRF5 IRAK1 ITGAM TLR7 TNFAIP3 DNAseI TREX1 FcγR C4, C1q MHC BANK BLK PTPN22 IL10 PCDCD1 FcRIIB TLR7

13. Knowledge gained from genetic studies • Pathogenic pathways identified (TLRs, IFNs, lymphocyte activation). • May pave the way to personalized interventions • e.g. can be used to identify those at risk of drug toxicity • Only a small contribution to genetic risk has been identified using GWAS. • Other approaches will be required to identify rare alleles with a higher degree of susceptibility risk.

14. B cell fate decisions Extrafollicular Short-lived PC Blimp1 BAFF/APRIL High affinity Short-lived PC IL-12, CD40, TLR9 IFNa High affinity EBI2 Bcl6 Naive Complement Receptor IRF4, Blimp1 Low affinity Long-lived PC IFNa,TLR4 (MyD88) GC BAFF/APRIL Stromal factors Low affinity BAFF Memory PC Tolerance checkpoints

15. The germinal center is a specialized microenvironment 1 (CD4 T cells) 2 4 EF focus 3

16. Effector T cell subset differentiation and plasticity Science. 2010 Feb 26;327(5969):1098-102.

17. Preformed rafts Replacement of  with Fc Use of Syk instead of ZAP70 Ca2+ IL-2 IL-17 NEJM 365: 2110. 2012 Abnormal T cell signaling in SLE

18. Local organ damage

19. SLE is associated with damage to multiple organs

20. Endothelial dysfunction occurs in SLE Reduced circulating progenitors Increased circulating endothelial microparticles Anti-endothelial antibodies Differentiation and repair defects in mice Increased cardiovascular risk – a major cause of mortality 10 yr risk for a coronary event or stroke is 7.5-17 fold increased

21. Tissue injury is due to inflammation, hypertension, stress, hypoxia and tissue remodeling/fibrosis

22. Heterogeneity among different models NZB/NZW NZM2410 NZW/BXSB Hypoxia, ER-Stress, Apoptosis Inflammation Cytokine, T-cell, macrophages Top ten Biological processes enriched in the shared network (Z-score >10)

23. Proteinuric mice vs human SLE nephritis CD45 VCAM-1 CXCL10 CCL5 IL1 CD68 ITGAM EGF Fn1 C Berthier and M Kretzler

24. Treatment

25. Therapeutic targets suggested by an enhanced understanding of biology Genetics + Trigger INNATE Bas Neut Anti-TNF ADAPTIVE Anti-IL-21/IL-17

26. Innate B cell Costimulation Cytokines DNAse I – failed Anti-IFN - ongoing LJP toleragen – failed Rituxan - failed Atacicept – toxicity Belimumab – modest success Anti-CD22 - ongoing Anti-CD40L – failed (toxicity) Abatacept – failed? Anti-IL6 – toxicity Anti-TNF - toxicity Success in SLE has been limited

27. Challenges in developing therapies for SLE Stage New cell types New pathways Recruitment of multiple inflammatory molecules Irreversible tissue injury/fibrosis Heterogeneity Homeostatic mechanisms

28. Response to remission induction is strain and context dependent NZB/W IFNα induced NZM2410 Liu, J. Immunol 187;1506-13. 2011. Ramanujam, M. A&R 62(5):1457-68. 2010.

29. Conclusions – the biology of SLE is complex • SLE is a multigenic disease that involves loss of tolerance involving both innate and adaptive immune pathways. • Multiple triggers are likely to be involved in disease initiation and perpetuation. • Continuous exposure to excess nucleic acid containing material amplifies the disease process. • Chronic inflammation can set up aberrant activation pathways and maintain the inflammatory phenotype of long-lived effector cells.

30. The future looks bright • There are many new therapeutic opportunities directed at both systemic autoimmunity and local inflammation. • Improvements in clinical trial design together with integration of genetic and biomarker information are being addressed using large patient cohorts. • These strategies, together with discovery based approaches using appropriate animal models should translate into a decrease in morbidity and mortality in SLE patients in the coming decades.

31. Acknowledgements Microarrays Weijia Zhang Erwin Bottinger Mount Sinai NY Systems biology Celine Berthier Matthias Kretzler University of Michigan and ERCB Renal Pathology Mike Madaio Medical College of Georgia Gene expression • Ram Bethunaickan Mouse therapies • Zheng Liu • Weiqing Huang Mice • Haiou Tao • Ingrid Solano Rheuminations