mechanism of sle

MECHANISM OF MECHANISM OF DISEASE(SLE)DISEASE(SLE)

นพนพ..สุ�รสุฤษดิ์สุ�รสุฤษดิ์ ขาวละออขาวละออ11/11/200911/11/2009

outlines GENETIC AND EPIDEMIOLOGIC FACTORS AUTOANTIBODIES IN LUPUS SOURCE OF AUTOANTIGENS IN LUPUS TISSUE DAMAGE BY AUTOANTIBODY ROLE OF T CELLS CYTOKINES IN LUPUS IMPLICATION FOR TREATMENT

Genetic & epidemiologic factors1. Female hormones

-90% are female

-unclear how sex hormone promote

2. Drug-induced lupus

-best known : procainamide,

hydralazine, quinidine

Anisur Rahman.mechanism of disease systemic lupus erythematosus.NEJM 2008;358;9:929-939

Genetic & epidemiologic factors3. Antecedent viral-like illness : EBV

4. Ultraviolet radiation

5. Gene : 8 susceptibility loci

Anisur Rahman.mechanism of disease systemic lupus erythematosus.NEJM 2008;358;9:929-939

GENETIC

Anisur Rahman.mechanism of disease systemic lupus erythematosus.NEJM 2008;358;9:929-939

GENETIC

Abul K. Abbas. Cellular and molecular immunology 6th edition 2007

GENETIC

Mary K Crow.Developments in the clinical understading of lupus.Arthritis Research & Therapy 2009;11:245

GENETIC

Mary K Crow.Developments in the clinical understading of lupus.Arthritis Research & Therapy 2009;11:245

Autoantibodies in lupus1. Anti-dsDNA : highly specific for lupus

70% of pt. with lupus

< 0.5% of healthy/other

2. Mannik et al. detected IgG for

-Ro(ribonucleoprotein complex)-La(RNA-binding protein)

Anisur Rahman.mechanism of disease systemic lupus erythematosus.NEJM 2008;358;9:929-939

Autoantibodies in lupus-C1q

-Sm(nuclear particle)

3. Anti--actinin : kidney disease

4. Anti-nucleosome : kidney, skin disease

5. Anti-N-methyl-D-aspartate(NMDA) Rc

6. Antiplatelet Ab

Anisur Rahman.mechanism of disease systemic lupus erythematosus.NEJM 2008;358;9:929-939

Anisur Rahman.mechanism of disease systemic lupus erythematosus.NEJM 2008;358;9:929-939

Autoantibodies in lupus

Autoantibodies in lupus

Autoantibodies in lupus

การติดิ์สุ� fluorescein จากการติรวจ indirect immunofluorescent assay & specific autoantibodies ที่��เก��ยวข�อง

Autoantibodies in lupus

การติดิ์สุ� fluorescein จากการติรวจ indirect immunofluorescent assay & specific autoantibodies ที่��เก��ยวข�อง

Autoantibodies in lupus-not know why some anti-dsDNA Ab deposit preferentially in kidney-Is -Actinin a target for Pathogenic Anti-DNA Antibodies in Lupus Nephritis?-candidate Ag = 100-kd actin-binding & crosslinking protein, human -actinin 4 isoforms

Lesley J et al.Arthritis & Rheumatism 2004;50(3):866-70

Autoantibodies in lupus-ACTN1 : non muscle forms

-ACTN2 : limit to skeleton & cardiac m

-ACTN3 : limit to skeleton & cardiac m

-ACTN4 : non muscle forms

-in kidney -Actinin 4 localized in podocyte

foot processes & mesangial cells

Lesley J et al.Arthritis & Rheumatism 2004;50(3):866-70

Autoantibodies in lupus

Autoantibodies in lupus

Autoantibodies in lupus

Autoantibodies in lupus disruption of morphology of actin

cytoskeleton

Foot process effacement and fusion

proteinuria

Lesley J et al.Arthritis & Rheumatism 2004;50(3):866-70

Autoantibodies in lupus Result

-greater proportion of anti-dsDNA IgG

from pt. with renal dz bound to -actinin

than did those purified from sera of pt.

without renal dz

-pathogenic anti-dsDNA Ab cross-react

with -Actinin

Lesley J et al.Arthritis & Rheumatism 2004;50(3):866-70

-Ag ที่��กระติ��น T cell จากผู้��ป่�วย lupus มั!กเป่"น histone-derived peptides ซึ่$�งไดิ์�จาก histone (protein core of nucleosome) แติ' Ag เหล'า

น�) ไมั'กระติ��น T cell จากคนป่กติ

-H2B10-33, H416-39, H471-94, H391-105,

H2A34-48, H449-63

Anisur Rahman.mechanism of disease systemic lupus erythematosus.NEJM 2008;358;9:929-939

Autoantibodies in lupus NMDA (N-methyl-D-Aspartate)

-excitatory amino acid

-released by neurons

-lupus pt. who had serum Ab against

DNA & NMDA receptors caused

cognitive impairment & hippocampal

damage

Kowal C et al.Proc Natl Acad Sci USA 2006;103:19854-9

Source of autoantigens in lupus1. cellular debris (as result of apoptosis)

-apoptotic bleb on surface of dying

cell

Ag within cell expose on surface of blebs

Anisur Rahman.mechanism of disease systemic lupus erythematosus.NEJM 2008;358;9:929-939

Source of autoantigens in lupus

Anisur Rahman.mechanism of disease systemic lupus erythematosus.NEJM 2008;358;9:929-939

Source of autoantigens in lupus2. Removal of apoptotic debris

-C1q play role in phagocytosis

-phagocytes from lupus pt. engulf less

than phagocytes from healty people

3. Deficiency of complement poor

“waste disposal”

Anisur Rahman.mechanism of disease systemic lupus erythematosus.NEJM 2008;358;9:929-939

Tissue damage by autoantibody-Two main theories1. extracellular dsDNA bind to autoAb

enter bloodstream

complexes settle in renal glomerular basement membrane

Anisur Rahman.mechanism of disease systemic lupus erythematosus.NEJM 2008;358;9:929-939

Tissue damage by autoantibody

2. Autoantibodies cross-react with proteins [Ag similar shape (shared epitopes) or similar charge]

direct pathogenic effect on cells

(-actinin)

Anisur Rahman.mechanism of disease systemic lupus erythematosus.NEJM 2008;358;9:929-939

The role of T cells B-cells are stimulated by T-cells as “T-lymphocyte help”

-B-cell division, switching Ab production -promote change in molecular sequence

of secreted AbT-cell help high affinity IgG autoAb

Anisur Rahman.mechanism of disease systemic lupus erythematosus.NEJM 2008;358;9:929-939

The role of T cells-Autoantigen-specific B cells & T cells ที่�� ผู้ลติ injurious autoAb ไมั'พบในคนป่กติ เน-�องจาก

1.removal(deletion) of autoreactive B 2.inactivation of cells(remain in body

but anergy)3.change in light chain of Ab(from

autoreactive B cell) : receptor editing

Anisur Rahman.mechanism of disease systemic lupus erythematosus.NEJM 2008;358;9:929-939

The role of T cells Regular T cell

-suppress activation of helper T cell & B cells reduction number or function or both-But Treg with active lupus reduce ability this activity(เที่�ยบก!บ inactive

or control)

Anisur Rahman.mechanism of disease systemic lupus erythematosus.NEJM 2008;358;9:929-939

The role of T cells

Anisur Rahman.mechanism of disease systemic lupus erythematosus.NEJM 2008;358;9:929-939

The role of T cells

Anisur Rahman.mechanism of disease systemic lupus erythematosus.NEJM 2008;358;9:929-939

Cytokines in lupus1. TNF- : controversial

-ในหน�พบว'า ถ้�าให� TNF- จะสุามัารถ้ delay development of lupus

Jacob CO, McDevitt HO.Nature 1988;331:356-8

-in human with RA who treated with anti-TNF- Ab พบ anti-dsDNA Ab และ lupus develop บ�างในบางราย

Charles Pj et al.Arthritis Rheum 2000;43:2383-90

Anisur Rahman.mechanism of disease systemic lupus erythematosus.NEJM 2008;358;9:929-939

Cytokines in lupus-low TNF- activity associated with increase dz. Activity

Gabay C et al.J rheumatology 1997:24;303-8

-By contrast, level of TNF- messenger RNA was high in kidney-biopsy specimens from pt. LN

Herrera-Esparza et al.Lupus 1998;7:154-8

Anisur Rahman.mechanism of disease systemic lupus erythematosus.NEJM 2008;358;9:929-939

Cytokines in lupus-Aringer et al. ร!กษาผู้��ป่�วย lupus 6 คน ดิ์�วย infiximab(monoclonal Ab of anti-TNF- Ab) พบว'า

- 3 คน ลดิ์อาการป่วดิ์, บวมัของข�อ - 60% ลดิ์ urinary protein loss ใน LN

Aringer M et al.Arthritis Rheum 2004;50:3161-90

Anisur Rahman.mechanism of disease systemic lupus erythematosus.NEJM 2008;358;9:929-939

Cytokines in lupus2. IL-10

-high level in lupus pt. correlate with

activity of disease

-stimulate of polyclonal populations of

B cells

Anisur Rahman.mechanism of disease systemic lupus erythematosus.NEJM 2008;358;9:929-939

Cytokines in lupus3. Interferon

-พบว'าระดิ์!บของ IFN- เพ�มัข$)นในผู้��ป่�วย lupus

-Baechler EC et al ไดิ์�รายงานเมั-�อป่/ 2003 ว'าพบมั� 13 gene ที่�� up-regulate in PBMC

โดิ์ย IFN จากผู้��ป่�วย lupus เมั-�อเป่ร�ยบเที่�ยบก!น cell

เดิ์�ยวก!นของ control

Anisur Rahman.mechanism of disease systemic lupus erythematosus.NEJM 2008;358;9:929-939

Cytokines in lupus-Studies of lupus-prone NZB/W F1 mice

พบ nephritis ในหน�ที่��ไดิ์� expose ก!บ IFN- ติลอดิ์

ติ!)งแติ'อาย�น�อยๆจนอาย� 15-20 สุ!ป่ดิ์าห2 มัากกว'ากล�'มั control

Mathian A et al.journal of immunity 2005;174:2499-506

Anisur Rahman.mechanism of disease systemic lupus erythematosus.NEJM 2008;358;9:929-939

Cytokines in lupus4. B-lymphocyte stimulator

-member of TNF-ligand superfamily

-promote proliferation & survival of B

-detect overexpression of stimulator in

both lupus pt. & lupus-prone mice

Anisur Rahman.mechanism of disease systemic lupus erythematosus.NEJM 2008;358;9:929-939

Cytokines in lupus-Stohl et al report

-elevated levels of soluble B-cell

stimulator in serum & on PBMC up

to 50 % of active lupus pt.

Stohl W.Arthritis Rheum 2003;48:3475-86

Anisur Rahman.mechanism of disease systemic lupus erythematosus.NEJM 2008;358;9:929-939

Cytokines in lupus-Level of B-lymphocyte stimulators

correlate with level of anti-dsDNA Ab in

serum & decreased in 9 pt. who were

treated with corticosteroids

Stohl W.Arthritis Rheum 2003;48:3475-86

Anisur Rahman.mechanism of disease systemic lupus erythematosus.NEJM 2008;358;9:929-939

Cytokines in lupus

Anisur Rahman.mechanism of disease systemic lupus erythematosus.NEJM 2008;358;9:929-939

Treatment of patients who had elevated serum BLyS levels with intensive courses of high-dose corticosteroids resulted in marked reductions in serum BLyS levels

Implications for treatmentAim at reducing autoantibody levels

1.corticosteroids reduced level of

anti-dsDNA Ab & reduced frequency

of severe flares of disease

*side effect of corticosteroids*Bootma H et al.Lancet 1995;345:1595-9

Tseng CE et al.Arthritis Rheum 2009;54:3623-32

Anisur Rahman.mechanism of disease systemic lupus erythematosus.NEJM 2008;358;9:929-939

Implications for treatment2.Rituximab : monoclonal Ab of CD20

-เป่"น Chimeric mouse/human

monoclonal IgG antibody

-กลไกของ Rituximab ในการที่3าลาย B cells

ย!งไมั'ถ้�กค�นพบแน'นอนแติ'จากการศึ$กษา in vitro

พบว'าการที่3าลาย B cells เกดิ์จาก 3 กลไกหล!กค-อ

Eisenberg R et al.Clin Immunol 2005;117(3):207-13 Thatayatikom A et al. Autoimmun Rev 2006;5(1):18-24

Implications for treatment1. Antibody-dependent cell-mediated

cytotoxicity (ADCC) และ apoptosis โดิ์ยเกดิ์การ engagement ของ FcγRIIIa (CD16) บน macrophages และ natural killer cells

2. Complement-dependent cytotoxicity 3. Intracellular signaling ที่3าให�เกดิ์ B cell

apoptosis

Eisenberg R et al.Clin Immunol 2005;117(3):207-13 Thatayatikom A et al. Autoimmun Rev 2006;5(1):18-24

Implications for treatment

Leandro MJ et al.Arthritis Rheum.2002 Oct;46(10):2673-7

Implications for treatment

Thatayatikom A et al. Autoimmun Rev 2006;5(1):18-24

Implications for treatmentCD20-35 Kd, non-glycosylated tetraspannin cell membrane-embedded phosphoprotein -พบเฉพาะใน B –lineage ติ!)งแติ'ระยะ pre-B cells, immature B cells, mature naive B cells, pre-germinal center mature B cells, GC mature B cells จนถ้$ง memory (GC) B cells-ไมั'พบใน plasma cells

Eisenberg R et al.Clin Immunol 2005;117(3):207-13 Thatayatikom A et al. Autoimmun Rev 2006;5(1):18-24

Implications for treatment

Implications for treatment-not known natural ligand

-CD20 functions as a Ca(2+)-permeable

cation channel and is involved in cell

activation and growth regulation of B cells Bubien et al, 1993; Tedder et al, 1985; Tedder and Engel, 1994

Leandro MJ et al.Arthritis Rheum.2002 Oct;46(10):2673-7

Implications for treatment3.Abtimus sodium (LJP 394)

-four DNA epitopes conjugated to pharmacologically inert triethylene glycol platform-can crosslinking of membrane Ig on surface of naïve B cell in absence of T cell help anergy or apoptosis

Alarcon-Segovia D et al.Arthritis Rheum.2003 Feb;48(2):442-54

Implications for treatment 3.Abtimus sodium (cont.)

-2 mechanism to reduce circulating

anti-dsDNA Ab

2.1.form small soluble complex

2.2.induce B cell tolerance by crosslinking

anti-dsDNA surface Ig Rc on B celltrigger

B cell anergy / apoptosis

Alarcon-Segovia D et al.Arthritis Rheum.2003 Feb;48(2):442-54

Implications for treatment4.Anti-CD22(Epratuzumab)-monoclonal antibodies that prevent CD22 binding to its natural ligands-มั�การศึ$กษาแบบ open-label, single-center study ในผู้��ป่�วย SLE 14 คนที่��มั�ความัร�นแรงแบบ moderate degrees ( BILAG >2) โดิ์ยไมั'มั� concomitant immunosuppressants หร-อ steroid พบว'าร�อยละ 93 ของผู้��ป่�วยมั�อาการดิ์�ข$)น, level B cell มั�จ3านวนลดิ์ลง ป่ระมัาณร�อยละ 35 ที่�� 18 สุ!ป่ดิ์าห2และความัร�นแรงของ โรคคงที่��ระดิ์!บติ3�าๆ จนถ้$ง 6 เดิ์-อน

Dorner T et al.Arthritis Research & therapy 2006;84:R74

Implications for treatmentCD22

-135kDa glycoprotein

-B-lymphocyte-restricted membrane of

immonoglobulin superfamily

-first expressed in cytoplasm of pro-B

& pre-B cells, then on surface as mature

, expression ceasing when diff. to plasma

Dorner T et al.Arthritis Research & therapy 2006;84:R74

Implications for treatmentCD22(cont.)

-cytoplamic tail contain ITIM

-inhibition of BCR signal

-key role in B cell development &

survival(def. enhanced apoptosis)

แติ'หน�าที่��ที่��แน'นอนย!งไมั'ชั!ดิ์เจน

Dorner T et al.Arthritis Research & therapy 2006;84:R74

Implications for treatment

Implications for treatment5. Anti-IL-10

-SLE pt. produce abnormally large

amounts of IL-10

-serum levels correlate with dz activity

-IL-10 inhibits Ag presentation & Th1

lymphocyte activation

Llorente L et al.Arthritis Rheumatism 2000;43:1790-1800

Implications for treatment-In vivo function of IL-10 poorly

understood

-Chernoff AE et al และ Huhn RD et al ไดิ์� ที่3าการศึ$กษาไว� ติ!)งแติ'ป่/ 1995-6 พบว'า IL-10

สุามัารถ้ย!บย!)งการผู้ลติของ proinflammatory cytokine

จาก mononuclear cell และย!บย!)ง T cell

proliferation ไดิ์�อ�กดิ์�วย

Llorente L et al.Arthritis Rheumatism 2000;43:1790-1800

Implications for treatment-Luis LLorente et al ไดิ์�ที่ดิ์ลองป่ระเมันความัป่ลอดิ์ภั!ย และป่ระสุที่ธิผู้ลของ anti-IL-10 monoclonal Ab เป่"นคร!)งแรกที่��ใชั�ในมัน�ษย2 โดิ์ยให�สุารน�)ในผู้��ป่�วย active SLE & steroid dependent dz . ในขนาดิ์ 20mg/d IV เป่"นเวลาติ'อเน-�องก!น 21 ว!น และติดิ์ติามัติ'ออ�ก 6 เดิ์-อน พบว'าผู้��ป่�วยที่�กคนสุามัารถ้ที่นยาไดิ์�ดิ์� และไมั'พบอาการข�างเค�ยงใดิ์ๆ โดิ์ยอาการที่างข�อ และผู้วหน!งดิ์�ข$)นอย'างเห:นไดิ์�ชั!ดิ์

Llorente L et al.Arthritis Rheumatism 2000;43:1790-1800

Implications for treatment-นอกจากน�)ผู้��ป่�วยที่�กคนย!งสุามัารถ้ลดิ์ขนาดิ์ของ prednisolone ลงไดิ์� -หล!งจากติดิ์ติามัติ'ออ�ก 6 เดิ์-อน ย!งสุามัารถ้ควบค�มัอาการของ โรคไดิ์�

Llorente L et al.Arthritis Rheumatism 2000;43:1790-1800

Implications for treatment

Llorente L et al.Arthritis Rheumatism 2000;43:1790-1800

Implications for treatment

Llorente L et al.Arthritis Rheumatism 2000;43:1790-1800

Implications for treatment5.Anti-TNF--TNF- is important proinflammatory cytokine with pleiotropic properties-activation of cascade of inflammatory events lead to tissue destruction-markeddly increased & appear to be bioactive in active SLE pt.

Aringer M et al.Arthritis & Rheumatism 2004;50(10):3161-69

Implications for treatment-find TNF- in renal tissue in all types

of lupus glomerulonephritis and ass.

with renal disease activity

-NZB/NZW mice application high dose

TNF- shown to delay dz onset in this

lupus-prone mouse

Aringer M et al.Arthritis & Rheumatism 2004;50(10):3161-69

Implications for treatment-but in kidney MRL/lpr Lupus-prone

mice contain high levels of TNF and

serum levels of TNF in these mice

correlate with disease activity, similar

to finding in human

Aringer M et al.Arthritis & Rheumatism 2004;50(10):3161-69

Implications for treatment-In human RA & Crohn’s disease : TNF blockage lead to formation of ANA 30-40%, anti-dsDNA 15% of pt., which occasionally ass. with transient drug-induced lupus-like syndrome-because of controversy data, blockage of TNF not be considered to be option ; trial

Aringer M et al.Arthritis & Rheumatism 2004;50(10):3161-69

Implications for treatment-Aringer M et al ไดิ์�รายงานการให�ยา TNF- 4300 mg infliximab (chimeric anti-

TNF- Ab)ในผู้��ป่�วย 6 คน ที่��เป่"น active SLE(4

with nephritis, 3 with arthritis

ที่��ดิ์-)อติ'อการร!กษาดิ์�วยวธิ�อ-�นๆ) เพ�มัเข�าไป่จากการร!กษาเดิ์มัที่�� มั�อย�'แล�ว เชั'น ร'วมัก!บ azathioprine or MTX

Aringer M et al.Arthritis & Rheumatism 2004;50(10):3161-69

Implications for treatment-Aringer M et al. ไดิ์�สุร�ป่ว'า infliximab ไมั'ที่3า ให�เพ�มั adverse event ที่��สุ!มัพ!นธิ2ก!บ SLE

activity แมั�ว'าจะพบระดิ์!บของ anti-dsDNA และ ระดิ์!บของ anti-cardiolipin จะเพ�มัข$)นก:ติามั

ที่!)งน�)ย!ง ไดิ์�เสุนอแนะให�มั�การศึ$กษาเพ�มัเติมัในระดิ์!บ large

controlled trials ติ'อไป่

Aringer M et al.Arthritis & Rheumatism 2004;50(10):3161-69

Implications for treatment6.Anti-CD40 ligand

-phase I/II studies in humans with LN

demonstrated reduction of anti-

dsDNA Ab but not of protective Ab

Sidiropoulos PI.Lupus 2004;13(5):391-7

Implications for treatment-reduction of anti-DNA associated

with increase serum complement

levels & reduce glomerular inflammation

Sidiropoulos PI.Lupus 2004;13(5):391-7

7.CTLA-4-Ig

Anisur Rahman.mechanism of disease systemic lupus erythematosus.NEJM 2008;358;9:929-939

CONCLUSION1. Genetic & many factors link to lupus2. Lupus-associated genes contribute to

one or more mechanisms of lupus pathogenesis

3. At the present we find many autoantibodies which have different prevalence in SLE

CONCLUSION4. Most studies of autoantibody-mediated

tissue damage have focused on

role of anti-dsDNA Ab in pt. with LN

5. Antigen-driven is process which Ag

binds Ig on surface o B cells and can

occur only in B lymphocytes that are

being stimulated by T cells(T lymph.help)

CONCLUSION6. Apoptotic blebs are source of

autoantigen

7. Many cytokines that found in SLE

and new treatment which correlate

with these cytokines may use for

treatment SLE pt. in future

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