Systemic lupus erythematosus 서울의대류마티스내과이은영

Transcription

1 Systemic lupus erythematosus 서울의대류마티스내과이은영

2 Table of Contents Introduction Clinical aspect of SLE Basic science of SLE - overview - B cell biology - cytokine network - organ damage Summary

3 Introduction Systemic lupus erythematosus (SLE) Autoimmune disease Autoantibodies Immune complex Multi-organ involvement Heterogenous manifestations Unclear pathogenesis Unpredictable acute flare

4 Epidemiology Epidemiology Disease of women of child-bearing age Between late 10s and early 40s M : F = 1 : 9 (1 : 2 in the child & aged) Black > White Prevalence 200/100,000 (Black) 40/100,000 (Northern Europeans) Incidence /100,000 (America) /100,000 (Europe)

5 pathogenesis Genetic factor Environmental factor Immune Reaction Abnormal immune response Activation of innate immunity (dendritic cells) Activation of adaptive immunity (antigen-specific T & B cells) Inhibition of regulatory & inhibitory T cells Reduced clearance of apoptotic cells & immune complexes

6 Etiology Genetic factor Concordancy in twins 50-60% in monozygotic twins 5-10% in dizygotic twins Familial aggregation in 10% Association with gene polymorphisms Increased frequency of HLA-B7, B8, DR2, DR3 & DQw1 Complement; C4AQ0, C1q or C4 deficiency Fc γ receptor IIA low-affinity phenotype

7 Genetic factor Chromosome Loci and Genes Associated with SLE Dendritic cell function & IFN signaling IRF5, STAT4, SPP1, IRAK1, TREX1, TNFAIP3, TNIP1, PRDM1, PHRF1, TYK2, SLC15A4, and TLR8 Immune-complex processing and innate immunity ITGAM, C1QA, C2, C4A, C4B, FCGR2A, FCGR3A, FCGR3B, KLK1/3, KLRG1, and KIR2DS4 T cell function and signaling PTPN22, TNFSF4, PDCD1, IL10, BCL6, IL16, TYK2, PRL, STAT4, and RASGRP3 B cell function and signaling BANK1, BLK, LYN, BCL6, and RASGRP3 Cell cycle, apoptosis, and cellular metabolism CASP10, NMNAT2, PTTG1, MSH5, PTPRT, UBE2L3, ATG5, and RASGRP3 Transcriptional regulation JAZF1, UHRF1BP1, BCL6, MECP2, ETS1, and IKZF1 SLE-associated locus Other genes PXK, ICA1, XKR6, and SCUBE1 Tsokos GC. N Engl J Med. 2011;365(22):

8 Hormonal factor Androgen as a suppressor and estrogen as an accelerator Environmental factor Infection (viral, bacterial) EBV-homology between Sm Ag & EBNA (PPPGMRPP vs PPPGRRP) EBV viral load, serologic response, impaired CD8 response Drugs UV light Abnormalities in the regulatory mechanism of the immune response Abnormalities and dysregulation of cytokines or apoptosis

9 Clinical symptoms and signs skin Malar rash Discoid rash SCLE

10 Joint involvement 95% Hand, wrist, knee Rare deformity Avascular necrosis of bone 5-10% Most common on femoral head SLE 자체혹은 Steroid 치료와연관

11 Renal involvement Pleuritis, pericarditis CNS involvement

12 Gastrointestinal involvement lupus enteritis, lupus pancreatitis, Target sign Vascular occlusion - antiphospholipid syndrome: stroke, coronary artery disease,

13 Laboratory findings Antinuclear antibody - 핵내에있는여러항원을 targeting 하는항체 ANA-positive sera 는여러가지다른핵내항원들과반응 ds-dna small nuclear ribonucleoproteins: Ro (SS-A), La (SS-B), nrnp, & Sm enzymes: topoisomerase-1 (Scl-70) histone proteins 표준검사 : indirect immunofluorescence Hep-2 cell ANA by EIA + Hep-2 cell nucleus Serum of patients + FITC-tagging 2 Ab +

14 ANA 양성인질환이나 condition 은매우다양. Most useful in SLE; sensitive but not specific for SLE

15 Titer of ANA positivity Tan EM et al. Range of antinuclear antibodies in "healthy" individuals. Arthritis Rheum. 1997;40(9): 정상인에서 ANA 양성률 31.7% at 1:40 dilution 13.3% at 1:80 dilution 5.0% at 1:160 dilution 3.3% at 1:320 dilution Best discriminating dilution is 1:160 Sensitivity 95% in SLE Sensitivity 87% in systemic slcerosis

16 Pattern Patterns of ANA Specific antibody Associated disease Homogeneous Speckled Peripheral (rim) Nucleolar Centromere(discrete speckled) Anti-dsDNA Anti-Sm Anti-RNP Anti-Ro/SSA Anti-La/SSB Anti-dsDNA Anti-Scl-70 Anti-PM-Scl Anti-centromere SLE SLE MCTD Sjgoren's syndrome Systemic slcerosis SLE Systemic slcerosis Inflammatory myopathy CREST Syndrome

17 Anti-ENA ANA 의 subset, ENA(extractable nuclear antigens) 에대해반응 질환과의연관성 Anti-Ro: primary Sjogren s syndrome, SLE Anti-Scl 70: systemic sclerosis (diffuse scleroderma) Anti-centromere: systemic sclerosis (limited scleroderma) Anti-Jo-1: Polymyositis and dermatomyositis Anti-Smith: SLE Anti-RNP: mixed connective tissue disease Sensitivity 가낮기때문에, rheumatic disease 가의심되면서 ANA 강양성일때검사를내는것이바람직하다 Diagnostic information Possibility of more severe disease manifestations

18 진단기준

19 Treatment Limitation No cure Rare complete sustained remissions Therapeutic goal Control acute flares Relieve symptoms Prevent organ damages

20 Therapeutic algorithm Life-threatening? No Conservative Hydroxychloroquine,.. Yes High dose corticosteroid Cyclophosphamide Mycophenolate mofetil Improved QOL? Mycophenolate mofetil/azathioprine No Low dose corticosteroid Biologic agent No response Stem cell transplantation

21 Basic science of SLE

22 Disease course of systemic lupus erythematosus (SLE). Bertsias G K et al. Ann Rheum Dis 2010;69:

23 The Spiral of disease progress in SLE

24 Apoptosis and antigen In SLE, apoptotic cells become secondarily necrotic because of their impaired clearance. Eggleton, P Antigen Antibody Complexes. els. Nature Genetics 2000;25:135

25 Arbuckle MR, et al. N Engl J Med. 2003;349(16): 전신홍반루푸스발생전자가항체의존재 At least one SLE autoantibody was present before the diagnosis in 88% of SLE patients. ANA, anti-phospholipid, anti-ro, and anti-la in a mean 3.4 years before the Dx. Anti-ds DNA antibodies in a mean 2.2 years before the Dx. Anti-Sm and anti-nrnp in a mean 1.2 years before the Dx.

26 전신홍반루푸스의발병모델 Cytokines involved in the pathogenesis of SLE Harrison s Principles of Internal Medicine. 18 th Eds. Robbins and Cotran Pathologic Basis of Disease.8 th Eds. Nature Rev Rheumatol 2010;6:

27

28 B cell biology Role of B cells in SLE - Loss of B cell tolerance - Abnormalities in the B cell compartment - Initiation and propagation of autoimmunity - Autoantibody-independent function

29 Gene defects may affect Loss of B cell tolerance 1) B-cell activation thresholds (eg, Fc receptor [FcR]) 2) B-cell longevity (eg, B-cell activator of the tumor necrosis factor family [BAFF] transgenics) 3) apoptotic cell/autoantigen processing (eg, mer knockout)

30 Abnormalities in the B cell compartment in human SLE Healthy subject - Important tolerance checkpoint operates to censor autoreactive B cells in the mature naive compartment - 50% to 75% of newly produced human B cells are autoreactive and must be silenced by tolerance mechanisms Key checkpoints - immature B-cell stage in the BM - between new transitional emigrants and mature B cells in the periphery SLE - Defect in transitional B-cell checkpoint

31 B cell development, selection, and function

32 Abnormalities in the B cell compartment in human SLE increased calcium flux on signaling through the BCR - high or aberrant expression of costimulatory molecules (CD80, CD86, and CD40 ligand) abnormalities in B-cell homeostasis - naive B-cell lymphopenia - expansion of peripheral blood plasma cells - increased transitional B cells - expansion of activated memory B-cell subsets

33 Initiation and propagation of autoimmunity Immune dysregulation by B cells in SLE - serving as the precursors of antibody-secreting cells - taking up and presenting autoantigens to T cells - helping to regulate and organize inflammatory responses through cytokine and chemokine secretion - regulating other immune cells

34 Immune complex binding -> activation of plasmacytoid dendritic cells (DCs) by costimulation of TLRs (TLR-7, -8, or -9) and FcRs -> stimulating the secretion of large quantities of IFN-a -> activation and maturation of DCs and stimulation of T and B cells -> myeloid DCs produce BAFF, triggers more B-cell activation Binding autoantibodies -> can directly trigger activation and proliferation of autoantibodyproducing B cells - Deficiency of TLR-7 or -9 - prevent autoab production in mouse models - Mechanisms of action of antimalarials - inhibition of TLR signaling

35 Autoantibody-dependent and independent mechanisms Recruit CXCR5+ follicular T helper (TFH) cells to GC -> influence of B cells on TFH cells via ICOSL and OX40L costimulation -> hyperactive GC, breakdown of B-cell tolerance, autoab production, lupus-like phenoytype

36

37 Cytokines involved in SLE Activation of antigen-specific CD4+ T cell Activation of B cells by cytokines TNF-α (Tumor necrosis factor-α) IFN type 1, 2 (Interferon type 1, 2) BLyS (B lymphocyte stimulator) IL-6, IL-10 (Interleukin-6, 10) IL-2, TGF (Transforming growth factor) Decreased induction of regulatory & inhibitory T cells

38 Roles of pro- and anti-inflammatory cytokines in SLE

39

40 B-cell growth factors Ligands BLyS APRIL Heterotrimer Receptors BAFF-R BCMA TACI Proteoglycans Increased B-cell survival Costimulation of B-cell prolferation Ig class switch recombination Enhanced APC function Germinal center formation Regulation of B-cell tolerance Sequester APRIL at cell surface to improve TACI and/or BCMA signalling? Mediate plasma cell trafficking Issacs JD, et al. EULAR 2007, Barcelona #SP0069

41 Interferon-alpha in SLE Family of type I IFNs: IFN-α, IFN-β - induced by DNA and RNA virus infection (through intracellular nucleic acid receptors or after engagement of TLR: TLR3 for double-stranded RNA, TLR7 or -8 for single-stranded RNA, or TLR9 for demethylated CpG-richDNA) - mainly by plasmacytoid dendritic cells (pdcs) Function of IFN-α - differentiation of monocytes into dendritic-like cells - induction of natural killer and natural killer T cells - promotion of IFN-γ production - support for B-cell differentiation into class-switched antibody producing cells - occasionally induce apoptosis -> produce self antigen

42 Insights from gene expression studies Microarray - increased levels of type I IFN induced genes in lupus PBMCs (MX1, the OAS family, and IFIT1) - both type I IFNs and type II IFN (IFN-γ) fluctuation of IFN levels in individual patients - ELISA platforms for measuring IFN-α have not been useful - fluctuations in IFN-inducible gene expression in PBMC over time, in some cases, with close parallel to fluctuations in disease activity scores or response to therapy

43 In SLE, all pathways lead to endogenous nucleic acids-mediated production of interferon (IFNα). Bertsias G K et al. Ann Rheum Dis 2010;69:

44 Advances in research into mechanisms of IFN pathway activation in SLE - Genetic contributions to type I interferon production and response (IRF5, TRF7, TNFAIP3, STAT4,..) - Molecular pathways mediating production of IFN-α (Fc receptor, TLR7, TLR9, anti RBP,.. ) - IFN-α in murine lupus model (pristane administration)

45 Mechanisms of organ damage in SLE

46 Biomarkers of SLE Previous: ex) GFR, serum creatinine, ESR, CRP defined as a genetic, biologic, biochemical, or event related correlate with disease pathogenesis or manifestations can be evaluated qualitatively and/or quantitatively in laboratories should be (1) biologically active and pathophysiologically relevant (2) be simple to use in routine practice (3) accurately and sensitively change with disease activity

47 Biomarkers in SLE Overall disease activity Genes Interleukins Chemokines Other molecules Lupus diagnosis Organ specific Renal involvement -serum Urine Neural Skin PTPN22, IRF-5, STAT-4, type I interferon, IFIT 1, OAS1, LY6E, ISG15, Mx1, FCγIIa polymorphysm IL-22, IL-6, IL-10, IL-12, IL-18, IL-2 receptor α RANTES, CXCL-11, CCL-19, MCP-1, CXCL-13, IP-10 CD27, Reticulocyte-C4d, BLys E-C4d, anti-ds DNA, ANA, Antinucleosome Antinucleosome, Anti-C1q, α-actinin, anti-α-actinin, Adrenomedulin Endothelial-1, Lipocalin-2, U-MCP-1, Migration inhibition factor, Adiponectin, VCAM-1, P-selectin, CXCL-16, FOXP3, TWEAK, Osteoprotegerin Antihistone, Anti-N, AECA, MMP-9, Anti-NMDA, Anti-NR2, Anti-P ribosome Anticyclic citrullinated peptide

48 Summary B cell is a critical player in the pathogenesis of SLE. B cells contribute to SLE pathogenesis by antibody-dependent and independent mechanisms. Although the primary triggers of SLE and the IFN pathway remain undefined, many studies showed crucial roles of IFN pathway in SLE pathogenesis. To understand these cytokine abnormalities may be beneficial in figuring out the pathogenesis of SLE and developing effective targeting therapeutics.