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

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Presentation on theme: "Advances in the pathogenesis and management of SLE Anne Davidson MBBS Feinstein Institute for Medical Research, Manhasset NY."— Presentation transcript:

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

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

3 Systemic autoimmunity

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

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

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

8 Immunity Mar 26;32(3): Endosome Nucleus

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 Nat Rev Rheum 6: Tissue damage

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

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

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

16 Effector T cell subset differentiation and plasticity Science Feb 26;327(5969):

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

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 fold increased

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

22 Heterogeneity among different models Inflammation Hypoxia, ER-Stress, Apoptosis Cytokine, T-cell, macrophages NZB/NZWNZM2410 NZW/BXSB pos reg. cytokine biosynthetic processimmune response-activating signal transductioncellular response to unfolded protein immune system process endoplasmic reticulum unfolded protein response regulation of cytokine productionimmune responseresponse to biotic stimulus cytokine productionimmune response-regulating signal transductionpositive regulation of NF-kappaB activity regulation of cytokine biosynthetic processcytokine productionpositive regulation of cell migration immune responseresponse to molecule of bacterial origin glycerol ether metabolic processimmune response-cell surface receptor signalingresponse to organic substance T cell activationregulation of peptidyl-tyrosine phosphorylationresponse to chemical stimulus hemopoietic or lymphoid organ developmentlymphocyte proliferationpositive regulation of cell motion response to bacteriummononuclear cell proliferationresponse to other organism Top ten Biological processes enriched in the shared network (Z-score >10)

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

24 Integrative Biology (Physiology) Molecular Nephrology approach Genetics Epigenetics Genomics Proteomics In vitro tissue culture model systems Organ culture and development Molecular interaction Animal models Clinical outcome research Molecular Phenotyping Disease Biobanks Functional Genomics Clinical research Model systems Molecular Pathology

25 Treatment

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

27 Success in SLE has been limited 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 Innate B cell Costimulation Cytokines

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

29 Ramanujam, M. A&R 62(5): Response to remission induction is strain and context dependent NZB/W IFNα induced NZM2410 Liu, J. Immunol 187;

30 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.

31 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.

32 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


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