Pathogenesis of lupus apoptosis clearance and regulation of self tolerance. Durga Prasanna Misra

Transcription

1 Pathogenesis of lupus apoptosis clearance and regulation of self tolerance Durga Prasanna Misra

2 Format Apoptosis Apoptosis in SLE Decreased apoptosis of autoreactive cells Increased apoptosis Defective clearance Soluble factors Macrophage/M defects NET degradation defects Apoptosis AND SLE pathogenesis

3 Apoptosis 1842 described apoptosis while studying the development of tadpole of the midwife toad Programmed cell death Physiologic process Leads to generation of apoptotic bodies Clearance of apoptotic cells: No inflammation,

4 Apoptosis Vs necrosis

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7 Secondary necrotic cell-derived material (SNEC) pro-inflammatory

8 PLoS ONE 6(3): e17495.

9 Format Apoptosis Apoptosis in SLE Decreased apoptosis of autoreactive cells Increased apoptosis Defective clearance Soluble factors Macrophage/M defects NET degradation defects Apoptosis AND SLE pathogenesis

10 SLE: Role of decreased apoptosis MRL/lpr, gld/gld apoptosis of autoreactive T and B cells Altered localisation of dsdna producing B cells Mice deficient in Fas develop antinuclear antibodies J Immunol 2001; 167:

11 Format Apoptosis Apoptosis in SLE Decreased apoptosis of auto-reactive cells Increased apoptosis Defective clearance Soluble factors Macrophage/M defects NET degradation defects Apoptosis AND SLE pathogenesis

12 Evidence of apoptosis

13 Apoptosis In SLE: Does it Occur? Hepburn et al.ard 2007

14 Apoptosis In SLE: Does it Occur? Healthy control UV exposure -24 hrs UV exposure -72 hrs SLE Kuhn et al. Arthritis Rheumatol 2006

15 Apoptosis In SLE: Does it Occur? Dhir et al. Lupus 2009

16 Format Apoptosis Apoptosis in SLE Decreased apoptosis of autoreactive cells Increased apoptosis Defective clearance Soluble factors Macrophage/M defects NET degradation defects Apoptosis AND SLE pathogenesis

17 Soluble factors

18 Role of C1q in apoptotic cell clearance Patient: abnormal C1q protein J Immunol ;2011;187:

19 Anti-class a scavenger receptor autoab from SLE patients impair phagocytic clearance of apoptotic cells by M in vitro ART 2011;13:R9

20 SLE sera: HMGB1 nucleosome complexes JEM 2008;205(13):

21 Mechanisms Blocks PS on apoptotic bodies Activation of pdc via TLR9 and RAGE Activation of auto-reactive B cell via TLR2 Anti-HMGB1 antibodies correlate with lupus activity

22 Format Apoptosis Apoptosis in SLE Decreased apoptosis of autoreactive cells Increased apoptosis Defective clearance Soluble factors Macrophage/M defects Apoptosis AND SLE pathogenesis

23 Impaired Uptake of Apoptotic Cells Into Tingible Body M Green: TUNEL Red: Macrophage (CD68) A & R (1):

24 Mechanism for decreased uptake MFG-E8

25 Defects in uptake of apoptotic cells ARD 2006;65:216-21

26 Defective uptake of late apoptotic cells by SLE sera Jurkat T cell line A & R 2007;56(10):

27 Mechanism of defective uptake by SLE sera: partly thru Fc receptors A & R 2007;56(10):

28 Format Apoptosis Apoptosis in SLE Decreased apoptosis of autoreactive cells Increased apoptosis Defective clearance Soluble factors Macrophage/M defects NET degradation defects Apoptosis AND SLE pathogenesis

29 NET degradation and SLE Impaired NET degradation in a subset of SLE patients Higher antidsdna titres and ANA titres in NETnondegraders PNAS 2010;107:

30 Format Apoptosis Apoptosis in SLE Decreased apoptosis of autoreactive cells Increased apoptosis Defective clearance Soluble factors Macrophage/M defects NET degradation defects Apoptosis AND SLE pathogenesis

31 Tolerate me signals Rheumatology 2005;44:

32 TAM Receptors Nat Rev Immunol May ; 8(5):

33 TAM receptors : tolerance induction Absence of TAM receptors Accumulation of uncleared apoptotic material. Production of cytokines Severe autoimmune phenotype Nat Rev Immunol May ; 8(5):

34 Clustering of autoag on apoptotic surface structures 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

35 Danger signals from secondary necrotic cells

36 Apoptosis AND SLE

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