Auto-immune diseases Leonard H Sigal MD, FACP, FACR P.R.I.- CD& E- Immunology Bristol-Myers Squibb Princeton, NJ Clinical Professor of Medicine and Pediatrics.

Auto-immune diseasesAuto-immune diseases

Leonard H Sigal MD, FACP, FACR

P.R.I.- CD& E- Immunology

Bristol-Myers Squibb

Princeton, NJ

Clinical Professor of Medicine and Pediatrics

UMDNJ – Robert Wood Johnson Medical School

New Brunswick, NJ

““Too little immunity” is a Too little immunity” is a problemproblem

But, what about “too much” immunity?

Recall: Critical to a proper immune response is being able to differentiate

“self” from “non-self”- the entity from the attackers

““Too much immunity”Too much immunity”

Allergy- one theory: may be due to improved hygiene and lack of ambient bacterial exposures early in life

Auto-immunity- breakdown in tolerance- genetic predisposition plus environmental exposure as trigger

AUTO-IMMUNITYAUTO-IMMUNITY Breakdown in ability to differentiate “self”

from “non-self” Tolerance is the ability to not

immunologically react to self Self-recognition (non-auto-aggressive

behavior) is part of many normal immune and homeostatic mechanisms

5 to 8% of the US population has an auto-immune disorder, may be more than one

AUTO-IMMUNITYAUTO-IMMUNITY Tolerance starts in thymus and continues

with active suppression in the periphery Developing “immunocytes” are exposed to

self-antigens and if their receptor recognizes self too well the cell is eliminated (“negative selection”); no recognition “positive selection”; mid- ground survive but anergized or controlled peripherally.

AUTO-IMMUNITYAUTO-IMMUNITY

Organ-specific: single or a fewSystemicAuto-immunity of a single organ

often means there is another organ affected

Family history is often positive

Self-recognition- Self-recognition- salubrious examplessalubrious examples

Idiotype network- regulation of antibody production

Antigen presentation: MHC and cell-surface antigen receptors interact

Ligand-receptor interactions Antigen-specific suppressor cells & factors

Why auto-immunityWhy auto-immunity?? There are “auto-aggressive” immune clones in

your body right now Under normal circumstances these are kept

under control- breakdown in control leads to auto-aggressive behavior

A breakdown in tolerance can lead to auto-immunity

In both SLE and RA, auto-antibodies may be present for up to 9 years prior to disease

What Induces Autoimmunity?What Induces Autoimmunity?

CENTRAL (prenatal) and PERIPHERAL (later) MECHANISMS

Aire- a key to tolerance induction in the Aire- a key to tolerance induction in the thymusthymus

Aire- auto-immune regulator: protein expressed in the thymus that induces thymic medullary epithelial cells to express 200 to 1200 non-thymic proteins, seemingly to allow intra-thymic processing and presentation of these proteins to lead to tolerance

Defect of Aire expression associated with APECED: autoimmune polyendocrinopathy candidiasis ectodermal dystrophy

FOXp3FOXp3

Mouse strain “scurfy”: develops an X-linked recessive auto-immune disorder with multiple organ-specific inflammation, hypergammaglobulinemia, wasting and a lymphoproliferative disorder- due to uncontrolled activation and proliferation of CD4+ T-cells.

Similar human disease phenotype: – X-linked autoimmunity, allergic dysregulation syndrome

(XLAAD) – Immune dysregulation, polyendocrinopathy,

endocrinopathy, X-linked syndrome (IPEX).

T-regs: CD4+ CD25+T-regs: CD4+ CD25+

GITR, CD62L, CTLA4 or E/7 integrin might be better markers than CD25

non T-reg T regulatorsnon T-reg T regulators

CD4+ TH1 cells (secreting gamma interferon)CD4+ TH2 cells (secrete IL-4)CD4+CD25+ TH3 cells (IL-10 and/or TGF)CD4+ TR1 cells (secrete IL-10)intraepithelial CD8+ /cells (IL-10) and

natural killer T-cells (IL-4).

Antigen Presenting Cell

MHC class I MHC class II

Adaptive/Acquired Immunity: Activation of Effector T cells

Viral antigenSelf antigen

CD4+HelperCD8+

Cytotoxic

Cytotoxic cell activityAntibodiesCytokines

Effector T cells

Foreignantigen

Processing & Loading

CD4+ Th17

Possible autoimmune activity

CD4+ CD25+Treg Foxp3

Regulatory functions

TGF + IL6

TGF

TGF IL10

IL17 IL22

CD4 cell populations of note CD4 cell populations of note

Th1 Th2 Th17 Intracellular Extracellular pathogens Extracellular

pathogens like parasites bacteria*

IFN IL4 IL17ALT IL5 IL17FTNF IL6 IL6IL2 IL9

IL10IL13

* Bacterial species implicated include : Klebsiella pneumoniae, Bordetella pertusis, Citrobacter rodentium, and Borrelia burgdorferi

T Cells Orchestrate the Adaptive and Innate Responses

CD4+T-helper cell

B-cell

Stem cellMacrophage

Tcell

Tcell

TcellT

cell

IL-2

IFN-, TN

F-

B-cell proliferationB-cell differentiation

cytokine productionAPC activityantibody production

IL-4, IL-10

IL-3

, IL

-7, G

M-C

SF

TNF-, IL-1, IL-6, IL-12

IFN-

IL-4

IL-5

TNF-

TGF-

OsteoclastRANK-L

Proliferate and differentiate to effectors

2. Abnormal Immune Response

C1q,C2,C4 HLA-D2,3,8 MBL FcR 2A,3A,2BIL-10MCP-1PTPN22

RashNephritisArthritisLeukopeniaCNS dzCarditisClottingEtc

Renal FailureAtherosclerosisPulm fibrosisStrokeDamage from RxEtc

Chr. inflam

Chr. oxid.

UV lightGenderEBVOther InfeOthers

3. AutoantibodiesImmune Complexes

C3

C3a

Ag

DC

Bcell

Tcell

Suppressivenetworks

Environment

1. Genes

5.Damage4. Inflammation

Ag

DC

Bcell

Tcell

Suppressivenetworks

Courtesy Bevra Hahn, MD

Auto-antibodies- receptor targets:Auto-antibodies- receptor targets: Receptor StimulateReceptor Stimulate BlockBlock TSH R. Graves Hashimoto’s Insulin R. Hypo- Hyperglycemia ACTH R. Addison’s Intrinsic

Factor Pernicious anemia

ACh R. Myasthenia gravis

Auto-antibodies- other targetsAuto-antibodies- other targets::

Basement membrane Goodpasture’s syndrome Uveal tract Sympathetic ophthalmia Cardiac tissue Dressler’s syndrome Exocrine glands Sjogren’s syndrome Epidermal Bullous pemphigus

hemidesmosomes Blood cells Hemolytic anemia, AITP

TREATMENT OF AUTO-TREATMENT OF AUTO-IMMUNITYIMMUNITY

If hormonal deficiency- REPLACEIf organ inflammation- SUPPRESS

Pulse corticosteroidsOral corticosteroidsCytotoxic agentsImmunomodulatory agentsPlasmapheresis

TREATMENT OF AUTO-TREATMENT OF AUTO-IMMUNITYIMMUNITY

Neutralize inflammatory cytokines: Solubilized receptor TNF

Monoclonal antibody TNF, BLyS

Antibody to receptor IL-6

Receptor antagonist IL-1Suppress antigen-specific response

Co-stimulation blockade CTLA4Ig

Counterbalancing cytokines

MP/DC

DR

TCR

Peptide

Inosinic acidInosinic acid purines

IMPDHpurines IMPDH

CD28

B CellT Cell

CD20

CD22

BCMAAPRIL

YBCR Anti-CD20

EdratideLJP394

CTLA4-Ig

Mycophenolate Mycophenolate

Anti-BLySTACI-Ig

BLyS

Anti-CD22

IFNaAnti-IFNa

Clinical Trials

Treg

X

Courtesy Bevra Hahn, MD

CD28

B7

B7

Molecular biology has given us a Molecular biology has given us a new therapeutic worldnew therapeutic world

Replace deficiencies- IVIG, ADARepair genetic defects- ADAStem cell transplantsCytokines, receptors, antibodies- antagonist

and agonist Support patients until defect identified and

toxicity of therapy can be overcome

Abbreviations in common useAbbreviations in common use SUFFIX DESCRIPTION -mab Monoclonal antibodies -umab Human mab -ximab Chimeric mab (mixture of mouse and human

structures) -zumab Humanized mab (very short murine sequences

remain, solely in the antigen-binding regions) -cept Receptor-antibody fusion protein, often Fc

component of an IgG -kinra Interleukin receptor antagonist (-kin is suffix for

interleukin; -ra for receptor antagonist)-nakinra IL1 receptor antagonist

-tinib Inhibitor of a tyrosine kinase

SYSTEMIC INFLAMMATORY SYSTEMIC INFLAMMATORY SYNDROMESSYNDROMES

Systemic lupus erythematosus (SLE) Rheumatoid arthritis (RA) Juvenile rheumatoid arthritis (JRA)- aka

Juvenile idiopathic arthritis (JIA) Juvenile dermatomyositis Kawasaki disease Seronegative spondylarthropathies (SNSA)

SYSTEMIC LUPUS SYSTEMIC LUPUS ERYTHEMATOSUSERYTHEMATOSUS

Multi-system inflammatory disease Episodic features in kidneys, brain, skin,

joints, serosa Broad range of severity Steady improvement in outcomes with the

evolution of better treatment Poor outcome: CNS or renal disease; lower

socio-economic status; “externalizedlocus of control”

SYSTEMIC LUPUS SYSTEMIC LUPUS ERYTHEMATOSUS-CriteriaERYTHEMATOSUS-Criteria

Constitutional Skin: malar rash,

discoid lesions, photosensitivity

Oral/nasal muco-cutaneous lesions

Joints and Muscle Nephritis

Brain: seizures, psychosis Pleurisy/pericarditis Cytopenias Positive ANA Immunoserologies:

dsDNA, Sm, anti-cardiolipin

Need “4 of the 11” criteria

SYSTEMIC LUPUS SYSTEMIC LUPUS ERYTHEMATOSUSERYTHEMATOSUS

Most common cause of death used to be: active disease

Now, it is consequences of STEROIDS: early: infection late: accelerated atherosclerosis

Consequences of cyclophosphamide: malignancy

Consequences of dialysis, hypertension, etc.end-organ damage

Crow MK, A&R, 2003

IFN

IL-10

TGFTGF

TsTs

Miyara et al, J Immunology, 2005

Treg (Foxp3 CD4+ T) are Depleted in Patients with Active SLE

The Path to AutoAntibodies

Tissue

C’

Th BAPC/pDC Y

Treg TsuppPhago

TGFTGF in Normals in Normals

NK

IL-2

NK

CD8

BTGF

T

AB

Treg CD4

Patients with SLE Make Patients with SLE Make Abnormally Low Levels of Abnormally Low Levels of

TGFTGF

0

50

100

150

200

250

300

350

400

PBL NK T

Normal

SLETGFpg/ml

Human cells stimulated with anti-CD2

Ohtsuka et al, JI 1998

* *

SYSTEMIC LUPUS SYSTEMIC LUPUS ERYTHEMATOSUSERYTHEMATOSUS

Therapy tailored to the organ system(s) affected, severity/type of damage

NSAIDsHydroxychloroquineCorticosteroidsCyclophosphamideAzathioprineBiologics in trials- BLyS, CTLA4Ig

Rheumatoid arthritisRheumatoid arthritis

1% of population; seems to be decreasing in incidence

Synovitis, primarily of small joints of hands and feet

Symmetric- could this be neural input?Rheumatoid factorAnti-CCP (cyclic citrullinated peptide) prior

to disease

Rheumatoid arthritis- focus?Rheumatoid arthritis- focus?

T cellMacrophageSynoviocyte (fibroblastoid)B cell

GeneticsAnti-CCP2

Rheumatoid arthritis- therapiesRheumatoid arthritis- therapiesNSAIDs, COX2sCorticosteroidsMethotrexate, leflunomideCyclosporine (T cell target)Anti-CD3; total nodal irradiationAnti-TNFsCo-stimulation modulationB cell assassination; B cell activation blockade

JUVENILE JUVENILE IDIOPATHIC IDIOPATHIC ARTHRITIS (JIA)-ILAR 1995ARTHRITIS (JIA)-ILAR 1995

Seven categories: Systemic OligoarthritisPolyarthritis (RF-)Polyarthritis (RF+)Psoriatic arthritisEnthesitis-related arthritis- related to SNSAsOther arthritis

JUVENILE RHEUMATOID JUVENILE RHEUMATOID ARTHRITIS (JRA)/ ARTHRITIS (JRA)/

IDIOPATHIC ARTHRITIS (JIA)IDIOPATHIC ARTHRITIS (JIA)

Unknown etiology Unknown immune focus in joints, eyes, etc. Age < 16 years at onset Genetic pre-disposition Multiple cytokines involved,

e.g. TNF, IL-1, IL-6

Macrophage Activation Macrophage Activation Syndrome- Syndrome- complication of systemic JRAcomplication of systemic JRA

Acute onset- high fever, lymphadenopathy, acute hepatitis, profound cytopenias, DIC

Can be post-viral, NSAIDs, Methotrexate Can mimic JRA flare Hematophagocytosis by well-differentiated

macrophages in bone marrow Rx?: steroids, IVIG, cyclosporin

Macrophage activation syndromeMacrophage activation syndrome

Myelocyte within activated macrophage, and multiple adherent red blood cell and myeloid precursors.

Macrophage activation syndromeMacrophage activation syndrome

Neutrophilic bands and metamyelocyte within an activated

macrophage.

JUVENILE IDIOPATHIC JUVENILE IDIOPATHIC ARTHRITIS- New management ARTHRITIS- New management Methotrexate Etanercept Infliximab Adalimumab Leflunomide Abatacept (CTLA4-Ig) Anakinra not very effective Anti-IL-6 effective; not yet approved

DERMATOMYOSITISDERMATOMYOSITIS

Multi-system inflammatory diseaseAdults and childrenAcute and chronic inflammation of

striated muscle and skin

SERONEGATIVE SERONEGATIVE SPONDYLOARTHROPATHIESSPONDYLOARTHROPATHIES Ankylosing spondylitis Psoriatic arthritis Psoriatic spondyloarthropathy Inflammatory joint disease associated with

inflammatory bowel disease Reactive arthritis

(no longer called Reiter syndrome)

SERONEGATIVE SERONEGATIVE SPONDYLOARTHROPATHIESSPONDYLOARTHROPATHIESNo serum rheumatoid factor Inflammation of spine and sacroiliac

jointsPrimary focus of inflammation is the

enthesisHLA-B27: independent linkage with

aortic disease (and anterior uveitis)

SNSA- therapySNSA- therapy

NSAIDs, COX2SulfasalazineTNF blockade

SYSTEMIC INFLAMMATORY SYSTEMIC INFLAMMATORY SYNDROMES-VasculitisSYNDROMES-Vasculitis

Classified by size of vessel affectedLarge: Takayasu Medium: PAN; Churg-Strauss Medium: Wegener; Goodpasture Small: Henoch-Schonlein Purpura

Pathogenesis is unclear: immune complex; auto-antibody; cellular reactivity

COMBINATIONS OF FEATURES COMBINATIONS OF FEATURES GREATLY ENHANCE GREATLY ENHANCE

PROBABILITY OF PROBABILITY OF VASCULITISVASCULITISFeverGlomerulonephritisPalpable purpuraPeripheral neuropathyEstablished auto-immune diseaseIschemia, e.g. gut, heart, brain

especially in young patients

DIAGNOSING DIAGNOSING VASCULITIDESVASCULITIDES

Based on collection of current findings Consider historical features May be overlap in syndromes Always try to substantiate diagnosis by

biopsy of affected tissue(s)

RESULTS OF VASCULAR RESULTS OF VASCULAR INFLAMMATIONINFLAMMATION

STENOSIS & OCCLUSION ISCHEMIA / INFARCTIONDILATATION & RUPTURETURBULENT FLOW / BLEED

VASCULITIDES OF OF OLDER OLDER PEOPLEPEOPLE

Giant cell arteritis Polyarteritis nodosa (PAN) Wegener granulomatosis Cryoglobulinemia Leukocytoclastic vasculitis

SIGNS AND SYMPTOMS OF GCASIGNS AND SYMPTOMS OF GCA> 50 years of age 100%ESR:       >100 60%Headache 70%Tenderness of arteries 50%Jaw claudication 50%Bruits 40%Visual symptoms:   10-15%

Diplopia           Vision loss           Ultimate blindness

Weight Loss 40%Fever 20%

POLYMYALGIA RHEUMATICAPOLYMYALGIA RHEUMATICAShoulder and hip girdle painPerceived weakness, but normal strengthMorning stiffness, but not obvious synovitisOver age 50 Dramatic and rapid response to steroidsOverlap with GCA; up to 40% of PMR have GCA

(may be delayed) and up to 65% of GCA have PMRRecent studies suggest the shoulder and hip pain is

due to a mild synovitis of those joints

GIANT CELL ARTERITISGIANT CELL ARTERITIS

Disrupted internal elastic lamella

Not merely “temporal Not merely “temporal arteritis”arteritis”

ANEURYSMS

Classical Polyarteritis Nodosa :Classical Polyarteritis Nodosa :Medium-sized vesselMedium-sized vessel involvement.

Absence of vasculitis of arterioles, venules andcapillaries. Renal diseaseRenal disease may occur, but notnot

glomerulonephritis.glomerulonephritis.

Microscopic Polyangiitis:Microscopic Polyangiitis: Involvement of "microscopic" vessels "microscopic" vessels (arterioles, venules, and capillaries), with or without medium-size with or without medium-size vessel vessel involvement.

Glomerulonephritis is commonGlomerulonephritis is common and pulmonary capillaritis may occur.

Few or no "immune deposits," no granulomasFew or no "immune deposits," no granulomas - distinct from HSP, cryoglobulinemic vasculitis, lupus, serum

sickness.

Polyarteritis NodosaPolyarteritis NodosaSkin: Small (purpura) and medium (gangrene) vessels,

subcutaneous nodules, livedo reticularis, ischemic atrophy

Renal: Rapid renal failure as a consequence of multiple infarcts

Gastrointestinal: abdominal pain, bleeding, bowel perforation, and malabsorption.

Cardiac and pulmonary: Cardiomegaly, pericarditis, coronary artery involvement leading to ischemia and infarction,

Reproductive: Orchitis in males.

WEGENER'S GRANULOMATOSISWEGENER'S GRANULOMATOSIS

• Idiopathic systemic inflammatory disease

with an unusual propensity to affect the

respiratory tract and kidneys.respiratory tract and kidneys.

• Small and medium-sized vessels.vessels.

• Tissue damage often associated with necrosis necrosis and and granuloma formation.granuloma formation.

• Active disease is often associated with

antibody formation to proteinase 3 (Pr3)antibody formation to proteinase 3 (Pr3).

Wegener GranulomatosisWegener Granulomatosis

Wegener GranulomatosisWegener Granulomatosis

ANCA:ANCA: anti-neutrophil cytoplasmic anti-neutrophil cytoplasmic

antibodiesantibodies

Myeloperoxidase, Lactoferrin, Proteinase-3

elastase, cathepsin C

WG

MPA

CG

UC

CryoglobulinemiaCryoglobulinemiaImmunoglobulin and other molecules associate in

blood; immune complexes then settle on blood vessel wall and cause inflammation.

Linked to underlying abnormality of plasma cells- making antibody that self-associates, causing complexes

Can be associated malignancy or underlying inflammatory disease, e.g. Sjogren syndrome

– BUT, “idiopathic” is common and no clear explanation until… a few years ago discovery of association with Hepatitis C infection

– Now known that essentially all of these “idiopathic” cases are due to Hepatitis C infection

CryoglobulinemiaCryoglobulinemia

BEHÇET SYNDROMEBEHÇET SYNDROMEAdamantiades-BehcetAdamantiades-Behcet

May have been described first by Hippocrates in the 5th century BC, in his 3rd Epidemion.

First modern formal description published in 1922 by Hulusi Behçet, Turkish dermatologist.

Sometimes called "Adamantiades’ syndrome" or "Adamantiades-Behçet syndrome".

Males:females = 1:1; more female in US, Japan, Korea, “the West”

Increasing prevalence with increased awareness– Turkey 300/100,000; US/EU 10-17/100,000

BEHÇET SYNDROMEBEHÇET SYNDROME

HLA-B51The Silk Road

BEHÇET SYNDROMEBEHÇET SYNDROME

Mucosal lesions- very painful aphthous ulcers Cutaneous lesions- erythema nodosum, acneiform,

folliculitis Ocular- panuveitis, anterior uveitis, retinal vasculitis Arthritis/arthralgia CNS and PNS disease- meningomyelitis, brainstem,

organic confusional syndromes, changes of personality, psychosis

GI inflammation- intestinal ulcerations Deep vein thrombosis/superficial thrombophlebitis Other organs: lungs, kidneys, epididimytis

BEHÇET SYNDROMEBEHÇET SYNDROME

BEHÇET SYNDROMEBEHÇET SYNDROME

Hypopyon

BEHÇET SYNDROMEBEHÇET SYNDROME

BEHÇET SYNDROMEBEHÇET SYNDROME

Pathergy sign

VASCULITIDES OF OF YOUNGER PEOPLEYOUNGER PEOPLE

Takayasu aortitis Henoch-Schonlein purpura (HSP) Leukocytoclastic vasculitis (LCV) Kawasaki syndrome Serum sickness-immune complex-mediated Goodpasture syndrome

TAKAYASU ARTERITISTAKAYASU ARTERITISYoung womenDisease of aorta and its first branchesLoss of pulse (“Pulseless disease”), stroke,

hypertensionCan affect pulmonary circulation, as wellProgression in up to half of patients even though

thought to be in remission; may occur silently

• Even when thought to be quiescent ~40% of patients

still have active inflammation at surgery

Takayasu arteritisTakayasu arteritis

HENOCH-SCHONLEIN HENOCH-SCHONLEIN PURPURAPURPURA

Palpable purpura

Glomerulonephritis

Arthritis

Abdominal pain

Malesfemales; mean age 5 yrs.

Preceding URI in 2/3 (1-3 weeks).

HENOCH-SCHONLEIN HENOCH-SCHONLEIN PURPURAPURPURA

Small vessels, esp. Post-capillary venules.

All lesions about same stage in evolution.

Bx with i.F. TYPICALLY IgA deposits in skin and kidney

Usually single episodes < 4 weeks duration.

40% recurrence rate after period of wellness.

May be permanent renal damage

Henoch-Schonlein purpuraHenoch-Schonlein purpura

KAWASAKI DISEASE- CriteriaKAWASAKI DISEASE- Criteria

Fever 100% 5 days or more, remittent

Conjunctivitis 85 Bilateral

Lymphadenopathy 70 Cervical >1.5 cm

Lips/oral mucosa 90 Strawberry tongue

Dry, red vertical fissures Red oropharynx

Extremities 70 Erythema of palms/soles Convalescent fingertip

desquamation

KAWASAKI DISEASE-KAWASAKI DISEASE-other featuresother features

Cardiac- most serious complicationPericarditis, arrhythmias,

infarction Myocarditis- Heart failure, aneurysms

CNS- irritability is almost universalconsider aseptic meningitis,

focal lesions, seizures- CNS vasculitis

Goodpasture SyndromeGoodpasture Syndrome

Typically young men presenting with pulmonary-renal syndrome: hemoptysis AND renal failure

Caused by auto-antibodies that uniquely bind to basement membranes of lung and kidney, causing alveolitis and glomerulonephritis

Serum from patients can cause a similar syndrome to develop in serum-recipient monkeys

Goodpasture SyndromeGoodpasture Syndrome

Goodpasture SyndromeGoodpasture Syndrome

anti-GBM antibodies directed against noncollagenous (NC1) globular domain of the 3 chain of type IV GBM collagen

VASCULITIS- TreatmentVASCULITIS- Treatment

Which organ system? How severe? Rate of damage? Potential reversibility?

VASCULITIS- TreatmentVASCULITIS- Treatment

Corticosteroids Daily or Pulse Cytotoxic agents, e.g. Methotrexate

Azathioprine Cyclophosphamide

Immunomodulatories Mycophenolate mofetil

Cyclosporine

ImmunomodulationImmunomodulationGeneral PrinciplesGeneral Principles

If we accept the premise that many systemic inflammatory diseases are auto-

immune, manipulation of the immune response may help control the disease

Identification of which immune mechanism is causative/contributory is crucial

Immunomodulation-Immunomodulation- Immediate control of diseaseImmediate control of disease

Pulse IV corticosteroids can be very useful in getting some diseases under control immediately

Plasmapheresis has limited usefulness auto-antibody- (Goodpasture) or immune-complex-mediated (systemic JRA?) diseases

IVIG- ITP, dermatomyositis

Immunomodulation: PresentImmunomodulation: Present

IVIG: Regulatory idiotypes vs. Saturating Fc receptors? vs. Induction of IL-10

Steroids: Lympholysis Cytotoxics: Kill inflammatory cells Pheresis: Removal of effector cells

and “evil humors”

MOLECULAR BIOLOGIC MOLECULAR BIOLOGIC AGENTSAGENTS

Interfere with TNFSoluble receptor- Etanercept

Interfere with TNFMonoclonal antibody- Infliximab

Adalimumab Interfere with IL-1

Receptor antagonist- Anakinra Interfere with T cell costimulation Abatacept

Immunomodulation: FutureImmunomodulation: Future

Interfere with antigen-specific responses- costimulation blockade*

Regulatory “anti-inflammatory” cytokineMonoclonal antibody and soluble

receptors for effector moleculesReceptor antagonists

*- Abatacept- BMS -please recall my conflict of interest

Immunomodulation: FutureImmunomodulation: Future

Enzyme blockade- e.g. TACE, ICE*Kinase blockade, e.g. p38 MAP kinase-

intracellular messengers to nucleus Induce tolerance- oral tolerance is the

Holy Grail

*TNF or IL-1 activating-converting enzyme- frees TNF or IL-1 from membrane-bound form- makes it a circulating pro-inflammatory cytokine

Molecular biology has given us a Molecular biology has given us a new therapeutic worldnew therapeutic world

Repair immunodeficiencies- IVIG, ADARepair genetic defects- on hold for nowStem cell transplantsCytokines, receptors, antibodies- antagonist

and agonist Support patients until defect identified and

toxicity of therapy can be overcome

Confused?Confused?

leonard.sigal@bms.com JCR: Journal of Clinical Rheumatology

– Basic Science for the Clinician

Immunology Today Nature Immunology Reviews Science- introductory pieces Annual Review of Immunology Current Opinions in Immunology

Auto-immune diseasesAuto-immune diseases

Leonard H Sigal MD, FACP, FACR

P.R.I.- CD& E- Immunology

Bristol-Myers Squibb

Princeton, NJ

Clinical Professor of Medicine and Pediatrics

UMDNJ – Robert Wood Johnson Medical School

New Brunswick, NJ