Transcript (SLE).
Systemic lupus erythematosus 2016년 10월 28일 서울의대 류마티스내과 이은영 Table of Contents • Introduction • Clinical aspect of SLE • Basic science of SLE - overview - B cell biology - cytokine network - organ damage • Summary Introduction • Systemic lupus erythematosus (SLE) – Autoimmune disease • Autoantibodies • Immune complex – Multi-organ involvement – Heterogenous manifestations – Unclear pathogenesis – Unpredictable acute flare 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 – 1.8-7.6/100,000 (America) – 3.3-4.8/100,000 (Europe) 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 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 • 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):2110-21 • 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 Clinical symptoms and signs • skin Malar rash Discoid rash SCLE • Joint involvement – 95% – Hand, wrist, knee – Rare deformity • Avascular necrosis of bone – 5-10% – Most common on femoral head – SLE 자체 혹은 Steroid 치료와 연관 • Renal involvement • Pleuritis, pericarditis • CNS involvement • Gastrointestinal involvement – lupus enteritis, lupus pancreatitis, … Target sign • Vascular occlusion - antiphospholipid syndrome: stroke, coronary artery disease, … Laboratory findings • Antinuclear antibody - 핵 내에 있는 여러 항원을 targeting하는 항체 – ANA-positive sera는 여러가지 다른 핵내 항원들과 반응 – ds-DNA small nuclear ribonucleoproteins: Ro (SS-A), La (SS-B), nRNP, & Sm enzymes: topoisomerase-1 (Scl-70) histone proteins + Hep-2 cell nucleus • 표준 검사: indirect immunofluorescence Hep-2 cell – ANA by EIA Serum of patients + FITC-tagging 2 Ab + • ANA 양성인 질환이나 condition은 매우 다양. • Most useful in SLE; sensitive but not specific for SLE Titer of ANA positivity • Tan EM et al. Range of antinuclear antibodies in "healthy" individuals. Arthritis Rheum. 1997;40(9):1601-11. – 정상인에서 ANA 양성률 • • • • 31.7% at 1:40 13.3% at 1:80 5.0% at 1:160 3.3% at 1:320 dilution dilution dilution dilution – Best discriminating dilution is 1:160 • Sensitivity 95% in SLE • Sensitivity 87% in systemic slcerosis Patterns of ANA Pattern Specific antibody Associated disease Homogeneous Anti-dsDNA SLE Speckled Anti-Sm Anti-RNP Anti-Ro/SSA Anti-La/SSB SLE MCTD Sjgoren's syndrome Systemic slcerosis Peripheral (rim) Anti-dsDNA Nucleolar Anti-Scl-70 Anti-PM-Scl SLE Systemic slcerosis Inflammatory myopathy CREST Syndrome Centromere(discrete speckled) Anti-centromere Anti-ENA • ANA의 subset, ENA(extractable nuclear antigens)에 대해 반응 • 질환과의 연관성 – 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 • Sensitivity가 낮기 때문에, rheumatic disease 가 의심되면서 ANA 강양성일 때 검사를 내는 것이 바람직하다 – Diagnostic information – Possibility of more severe disease manifestations • 진단기준 Treatment • Limitation – No cure – Rare complete sustained remissions • Therapeutic goal – Control acute flares – Relieve symptoms – Prevent organ damages Therapeutic algorithm Life-threatening ? No Conservative Hydroxychloroquine, .. Yes High dose corticosteroid Cyclophosphamide Improved QOL ? No Low dose corticosteroid Mycophenolate mofetil Mycophenolate mofetil/azathioprine No response Biologic agent Stem cell transplantation Basic science of SLE Disease course of systemic lupus erythematosus (SLE). Bertsias G K et al. Ann Rheum Dis 2010;69:1603-1611 The Spiral of disease progress in SLE Apoptosis and antigen • In SLE, apoptotic cells become secondarily necrotic because of their impaired clearance. Eggleton, P. 2006. Antigen–Antibody Complexes. eLS. Nature Genetics 2000;25:135 전신 홍반 루푸스 발생전 자가항체의 존재 • 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. Arbuckle MR, et al. N Engl J Med. 2003;349(16):152633. 전신 홍반 루푸스의 발병모델 Cytokines involved in the pathogenesis of SLE Harrison’s Principles of Internal Medicine. 18th Eds. Robbins and Cotran Pathologic Basis of Disease.8th Eds. Nature Rev Rheumatol 2010;6:339-47. 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 Loss of B cell tolerance • Gene defects may affect 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) 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 B cell development, selection, and function 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 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 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 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 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 Roles of pro- and anti-inflammatory cytokines in SLE B-cell growth factors Ligands Receptors BAFF-R BLyS APRIL BCMA TACI Increased B-cell survival Costimulation of B-cell prolferation Ig class switch recombination Enhanced APC function Germinal center formation Regulation of B-cell tolerance Issacs JD, et al. EULAR 2007, Barcelona #SP0069 Heterotrimer Proteoglycans Sequester APRIL at cell surface to improve TACI and/or BCMA signalling? Mediate plasma cell trafficking 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 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 In SLE, all pathways lead to endogenous nucleic acids-mediated production of interferon (IFNα). Bertsias G K et al. Ann Rheum Dis 2010;69:1603-1611 • 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) Mechanisms of organ damage in SLE 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 Biomarkers in SLE Overall disease activity Genes PTPN22, IRF-5, STAT-4, type I interferon, IFIT1, OAS1, LY6E, ISG15, Mx1, FCγIIa polymorphysm Interleukins IL-22, IL-6, IL-10, IL-12, IL-18, IL-2 receptor α Chemokines RANTES, CXCL-11, CCL-19, MCP-1, CXCL-13, IP-10 Other molecules CD27, Reticulocyte-C4d, BLys Lupus diagnosis E-C4d, anti-ds DNA, ANA, Antinucleosome Organ specific Renal involvement -serum Antinucleosome, Anti-C1q, α-actinin, anti-α-actinin, Adrenomedulin Urine Endothelial-1, Lipocalin-2, U-MCP-1, Migration inhibition factor, Adiponectin, VCAM-1, P-selectin, CXCL-16, FOXP3, TWEAK, Osteoprotegerin Neural Antihistone, Anti-N, AECA, MMP-9, Anti-NMDA, Anti-NR2, Anti-P ribosome Skin Anticyclic citrullinated peptide 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.