Environmental factors including drugs. Jyoti Ranjan Parida
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1 Environmental factors including drugs Jyoti Ranjan Parida
2 Scheme of presentation Pathogenesis of autoimmune disease Evidence for environmental influence Environmental factors Proposed -Role of Sunlight -Role of Exogenous hormones -Role of EBV -Role of Drugs -Role of others Summary
3 Scheme of presentation Pathogenesis of autoimmune disease Evidence for environmental influence Environmental factors Proposed -Role of Sunlight -Role of exogenous hormones -Role of EBV -Role of Drugs -Role of others Summary
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5 Scheme of presentation Pathogenesis of autoimmune disease Evidence for environmental influence Environmental factors Proposed -Role of Sunlight -Role of exogenous hormones -Role of EBV -Role of Drugs -Role of others Summary
6 Genes & environment
7 Gullah population ANA No difference SLE in African Americans 25-OH vitamin D levels- AA
8 Genome-wide methylation studies in lupus
9 Scheme of presentation Pathogenesis of autoimmune disease Evidence for environmental influence Environmental factors Proposed -Role of Sunlight -Role of exogenous hormones -Role of EBV -Role of Drugs -Role of others Summary
10 Environmental factors In SLE
11 Scheme of presentation Pathogenesis of autoimmune disease Evidence for environmental influence Environmental factors Proposed -Role of Sunlight -Role of exogenous hormones -Role of EBV -Role of Drugs -Role of others Summary
12 Sunlight Photosensitivity 73% of patients Phototherapy Rx aggravate/precipitate LE Precipitate systemic disease de novo Aggravate existing disease Epidemiological : seasonal variation
13 UV light: Auto-antigen externalization Unirradiated keratinocytes Irradiated keratinocytes Fixed and stained with PI and FITC-anti Ro (52KDa) Yellow= Co-localization Casciola_Rosen LA et al. J Exp Med 1994, Cell death and differentiation 1999
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16 Scheme of presentation Pathogenesis of autoimmune disease Evidence for environmental influence Environmental factors Proposed -Role of Sunlight - Role of exogenous hormones -Role of EBV - Role of Drugs - Role of others Summary
17 OCP and SLE risk
18 SELENA Trial (Safety of Estrogen in Lupus: National Assessment)
19 A Trial of Contraceptive Methods in SLE A single-blind clinical trial
20 Scheme of presentation Pathogenesis of autoimmune disease Evidence for environmental influence Environmental factors Proposed -Role of Sunlight -Role of exogenous hormones -Role of EBV -Role of Drugs -Role of others Summary
21 Similarities between SLE and IM
22 Latent stage : 80 viral promoter silenced, 9 gene expressed EBNA 1,2,3A,3B,3C : Master transcription factor Glycine + Alanine repeat domain not digested by proteosome
23 EBV and SLE Link prevalence in children with SLE (99.6% Vs 70%) EBV infected B cell X 10 in SLE EBV viral load X 40 times EBV DNA in serum (42% vs 3%) Abnormal expression of 4 viral mrna in SLE (BZLF 1, LMP 1,2 EBNA 1) Defective EBV specific T cell immune response in SLE EBV specific CD8 T cell: Incapable of IFN production amount of EBV specific CD8 with compensatory in CD4
24 Viral load and genes of EBV in SLE
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26 Impaired release of cytotoxic granules and Role of PD1
27 Longitudinal monitoring of EBV replication following SLE flare onset
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30 Binding to EBNA 1
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32 Scheme of presentation Pathogenesis of autoimmune disease Evidence for environmental influence Environmental factors Proposed -Role of Sunlight -Role of EBV - Role of Drugs - Role of others Summary
33 Drug induced Lupus Definition Development of lupus-like symptoms (commonly fever, musculoskeletal, serositis) Temporal relation to continuous (>1 month) drug exposure Induction period- 1 month to >1 decade Resolves with cessation of the offending drug Reintroduction not associated with memory of prior exposure
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36 Epigenetics DNA methylation, histone modification and gene expression
37 SLE: Epigenetics
38 Genomic 5-Methyl-2 -deoxycy-tidine Content Procainamide: Inhibits DNMT
39 LFA expression with procainamide and hydralazine and its analogues
40
41 ERK and DNMT pathway
42 Anti-TNF agents Prevalence of ANA: Infliximab(40.7% 82.3%),Eternacept (11-15%), Adalimumab (50%) Prevalence of ATIL: Infliximab(0.19% 0.22%),Eternacept ( 0.18%), Adalimumab (0.10%) Baseline ANA may be done
43 Anti-TNF agents
44 Anti-TNF agents: MOA Cytokine shift from Th1 to Th2 Interfere with apoptosis by CD44 expression cytotoxic T-cells function, leading to elimination of autoantibody-producing B-cells bacterial infections polyclonal B-lymphocyte activation and autoantibody production anti-dna positivity following infection with Etanercept normalized after antibiotics
45 Scheme of presentation Pathogenesis of autoimmune disease Evidence for environmental influence Environmental factors Proposed -Role of Sunlight -Role of EBV - Role of Drugs - Role of others Summary
46 Seasonal Variation of SLE Flare- Hong kong
47 Silicon Breast Implant and SLE Sweden Retrospective study No effect NHS Prospective study
48 Effect of Smoking- Meta analysis OR 1.50 (95% CI ) Current smoker VS Non smoker Mechanisms proposed 1. Toxin mediated cell necrosis - Ag load 2. Cigarette byproducts autoreactive B cell number 3. Alter estradiol metabolism OR 0.98 (95% CI ) Ex- smoker VS Non smoker Quitting smoking helps!!!!
49 Effect of Alcohol- Meta analysis Moderate alcohol OR (95% CI) Subgroup A - < 5 yr of intake Subgroup B - > 5 yr of intake ( ), P> ( ), P<0.05 Moderate drinking Protective
50 BALES (Baltimore Lupus Environmental Study) Significant association of ingestion of alfalfa sprouts with the development of lupus
51 Vitamin D Deficiency
52 Evidences for Vit D deficiency VDR gene polymorphism Gullah population Inverse relation between disease activity and 25 (OH) vit D level Data difficult to interpret due to limited sun exposure No hard evidence for routine Vit D prescription in SLE
53 Occupational Genes and Environment in Systemic Lupus Erythematosus (GenES) study
54 Summary Both Genetics and Epigenetics have their share UV light Keratinocyte apoptosis EBV Molecular mimicry and Epitope spreading Drug (Procainamide and Hydralazine) Epigenetics Anti TNF agents- Th2 skewing Other factors Interesting but weak association
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