Presentation on theme: "Auto-immune diseases Leonard H Sigal MD, FACP, FACR"— Presentation transcript:
1 Auto-immune diseases Leonard H Sigal MD, FACP, FACR P.R.I.- CD& E- ImmunologyBristol-Myers SquibbPrinceton, NJClinical Professor of Medicine and PediatricsUMDNJ – Robert Wood Johnson Medical SchoolNew Brunswick, NJ
2 “Too little immunity” is a problem 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
3 “Too much immunity”Allergy- one theory: may be due to improved hygiene and lack of ambient bacterial exposures early in lifeAuto-immunity- breakdown in tolerance- genetic predisposition plus environmental exposure as trigger
4 AUTO-IMMUNITYBreakdown in ability to differentiate “self” from “non-self”Tolerance is the ability to not immunologically react to selfSelf-recognition (non-auto-aggressive behavior) is part of many normal immune and homeostatic mechanisms5 to 8% of the US population has an auto- immune disorder, may be more than one
5 AUTO-IMMUNITYTolerance starts in thymus and continues with active suppression in the peripheryDeveloping “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.
6 AUTO-IMMUNITY Organ-specific: single or a few Systemic Auto-immunity of a single organ often means there is another organ affectedFamily history is often positive
8 Why auto-immunity?There are “auto-aggressive” immune clones in your body right nowUnder normal circumstances these are kept under control- breakdown in control leads to auto-aggressive behaviorA breakdown in tolerance can lead to auto- immunityIn both SLE and RA, auto-antibodies may be present for up to 9 years prior to disease
9 What Induces Autoimmunity? CENTRAL (prenatal) and PERIPHERAL (later) MECHANISMS
10 Aire- a key to tolerance induction in the thymus 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 toleranceDefect of Aire expression associated with APECED: autoimmune polyendocrinopathy candidiasis ectodermal dystrophy
11 FOXp3Mouse 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).
12 T-regs: CD4+ CD25+GITR, CD62L, CTLA4 or E/7 integrin might be better markers than CD25
14 Adaptive/Acquired Immunity: Activation of Effector T cells Antigen Presenting CellForeignantigenViral antigenSelf antigenProcessing & LoadingMHC class IMHC class IITGF + IL6TGFCD4+HelperCD4+Th17CD8+CytotoxicCD4+CD25+TregFoxp3IL IL22Effector T cellsPossibleautoimmuneactivityAntibodiesCytokinesCytotoxic cell activityTGF IL10Regulatoryfunctions
15 CD4 cell populations of note Th Th Th17Intracellular Extracellular pathogens Extracellularpathogens like parasites bacteria*IFN IL IL17ALT IL IL17FTNF IL IL6IL2 IL9IL10IL13* Bacterial species implicated include : Klebsiella pneumoniae, Bordetella pertusis, Citrobacter rodentium, and Borrelia burgdorferi
16 T Cells Orchestrate the Adaptive and Innate Responses Proliferate and differentiate to effectorsOsteoclastCD4+T-helper cellRANK-LTcellTcellIL-2IL-4, IL-10TcellTcellB-cellIFN-g, TNF-aIL-3, IL-7, GM-CSFIFN-gIL-4IL-5TNF-aTGF-bMacrophageStem cellB-cell proliferationB-cell differentiationcytokine productionAPC activityantibody productionTNF-a, IL-1, IL-6, IL-12
22 Y MP/DC Clinical Trials Treg X T Cell B Cell Anti-IFNa Edratide LJP394 PeptideCD28TCRXYAnti-CD20BCRCD20CTLA4-IgAnti-CD22CD22T CellB CellCD28B7IMPDHIMPDHInosinic acidpurinesInosinic acid purinesBCMAAPRILBLySMycophenolateMycophenolateAnti-BLySTACI-IgCourtesy Bevra Hahn, MD
23 Molecular biology has given us a new therapeutic world Replace deficiencies- IVIG, ADARepair genetic defects- ADAStem cell transplantsCytokines, receptors, antibodies- antagonist and agonistSupport patients until defect identified andtoxicity of therapy can be overcome
24 Abbreviations 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
26 SYSTEMIC LUPUS ERYTHEMATOSUS Multi-system inflammatory diseaseEpisodic features in kidneys, brain, skin, joints, serosaBroad range of severitySteady improvement in outcomes with the evolution of better treatmentPoor outcome: CNS or renal disease; lower socio-economic status; “externalized locus of control”
27 SYSTEMIC LUPUS ERYTHEMATOSUS-Criteria ConstitutionalSkin: malar rash, discoid lesions, photosensitivityOral/nasal muco- cutaneous lesionsJoints and MuscleNephritisBrain: seizures, psychosisPleurisy/pericarditisCytopeniasPositive ANAImmunoserologies: dsDNA, Sm, anti- cardiolipinNeed “4 of the 11” criteria
28 SYSTEMIC LUPUS ERYTHEMATOSUS Most common cause of death used to be: active diseaseNow, it is consequences of STEROIDS: early: infection late: accelerated atherosclerosisConsequences of cyclophosphamide: malignancyConsequences of dialysis, hypertension, etc. end-organ damage
33 Patients with SLE Make Abnormally Low Levels of TGF pg/ml**Ohtsuka et al, JI 1998Human cells stimulated with anti-CD2
34 SYSTEMIC LUPUS ERYTHEMATOSUS Therapy tailored to the organ system(s) affected, severity/type of damageNSAIDsHydroxychloroquineCorticosteroidsCyclophosphamideAzathioprineBiologics in trials- BLyS, CTLA4Ig
35 Rheumatoid arthritis1% of population; seems to be decreasing in incidenceSynovitis, primarily of small joints of hands and feetSymmetric- could this be neural input?Rheumatoid factorAnti-CCP (cyclic citrullinated peptide) prior to disease
36 Rheumatoid arthritis- focus? T cellMacrophageSynoviocyte (fibroblastoid)B cellGeneticsAnti-CCP2
37 Rheumatoid arthritis- therapies NSAIDs, COX2sCorticosteroidsMethotrexate, leflunomideCyclosporine (T cell target)Anti-CD3; total nodal irradiationAnti-TNFsCo-stimulation modulationB cell assassination; B cell activation blockade
38 JUVENILE IDIOPATHIC ARTHRITIS (JIA)-ILAR 1995 Seven categories:SystemicOligoarthritisPolyarthritis (RF-)Polyarthritis (RF+)Psoriatic arthritisEnthesitis-related arthritis- related to SNSAsOther arthritis
39 JUVENILE RHEUMATOID ARTHRITIS (JRA)/ IDIOPATHIC ARTHRITIS (JIA) Unknown etiologyUnknown immune focus in joints, eyes, etc.Age < 16 years at onsetGenetic pre-dispositionMultiple cytokines involved, e.g. TNF, IL-1, IL-6
40 Macrophage Activation Syndrome- complication of systemic JRA Acute onset- high fever, lymphadenopathy, acute hepatitis, profound cytopenias, DICCan be post-viral, NSAIDs, MethotrexateCan mimic JRA flareHematophagocytosis by well-differentiated macrophages in bone marrowRx?: steroids, IVIG, cyclosporin
41 Macrophage activation syndrome Myelocyte within activated macrophage, and multiple adherent red blood cell and myeloid precursors.
42 Macrophage activation syndrome Neutrophilic bands and metamyelocyte within an activated macrophage.
43 JUVENILE IDIOPATHIC ARTHRITIS- New management MethotrexateEtanerceptInfliximabAdalimumabLeflunomideAbatacept (CTLA4-Ig)Anakinra not very effectiveAnti-IL-6 effective; not yet approved
44 DERMATOMYOSITIS Multi-system inflammatory disease Adults and children Acute and chronic inflammation of striated muscle and skin
45 SERONEGATIVE SPONDYLOARTHROPATHIES Ankylosing spondylitisPsoriatic arthritisPsoriatic spondyloarthropathyInflammatory joint disease associated with inflammatory bowel diseaseReactive arthritis (no longer called Reiter syndrome)
46 SERONEGATIVE SPONDYLOARTHROPATHIES No serum rheumatoid factorInflammation of spine and sacroiliac jointsPrimary focus of inflammation is the enthesisHLA-B27: independent linkage with aortic disease (and anterior uveitis)
50 COMBINATIONS OF FEATURES GREATLY ENHANCE PROBABILITY OF VASCULITIS FeverGlomerulonephritisPalpable purpuraPeripheral neuropathyEstablished auto-immune diseaseIschemia, e.g. gut, heart, brain especially in young patients
51 DIAGNOSING VASCULITIDES Based on collection of current findingsConsider historical featuresMay be overlap in syndromesAlways try to substantiate diagnosis by biopsy of affected tissue(s)
53 VASCULITIDES OF OLDER PEOPLE Giant cell arteritisPolyarteritis nodosa (PAN)Wegener granulomatosisCryoglobulinemiaLeukocytoclastic vasculitis
54 SIGNS AND SYMPTOMS OF GCA > 50 years of age %ESR: > %Headache %Tenderness of arteries %Jaw claudication %Bruits %Visual symptoms: %Diplopia Vision loss Ultimate blindnessWeight Loss %Fever %
55 POLYMYALGIA RHEUMATICA Shoulder and hip girdle painPerceived weakness, but normal strengthMorning stiffness, but not obvious synovitisOver age 50Dramatic 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
58 Classical Polyarteritis Nodosa : Medium-sized vessel involvement. Absence of vasculitis of arterioles, venules and capillaries. Renal disease may occur, but notglomerulonephritis.Microscopic Polyangiitis:Involvement of "microscopic" vessels (arterioles, venules, and capillaries), with or without medium-size vessel involvement.Glomerulonephritis is common and pulmonary capillaritis may occur.Few or no "immune deposits," no granulomas - distinct from HSP, cryoglobulinemic vasculitis, lupus, serum sickness.
59 Polyarteritis NodosaSkin: Small (purpura) and medium (gangrene) vessels, subcutaneous nodules, livedo reticularis, ischemic atrophyRenal: Rapid renal failure as a consequence of multiple infarctsGastrointestinal: abdominal pain, bleeding, bowel perforation, and malabsorption.Cardiac and pulmonary: Cardiomegaly, pericarditis, coronary artery involvement leading to ischemia and infarction,Reproductive: Orchitis in males.
60 WEGENER'S GRANULOMATOSIS Idiopathic systemic inflammatory diseasewith an unusual propensity to affect therespiratory tract and kidneys.Small and medium-sized vessels.Tissue damage often associated with necrosis and granuloma formation.Active disease is often associated withantibody formation to proteinase 3 (Pr3).
63 ANCA: anti-neutrophil cytoplasmic antibodies WGMPACGUCMyeloperoxidase, Lactoferrin, Proteinase-3elastase, cathepsin C
64 CryoglobulinemiaImmunoglobulin 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 complexesCan be associated malignancy or underlying inflammatory disease, e.g. Sjogren syndromeBUT, “idiopathic” is common and no clear explanation until… a few years ago discovery of association with Hepatitis C infectionNow known that essentially all of these “idiopathic” cases are due to Hepatitis C infection
66 BEHÇET SYNDROME Adamantiades-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 awarenessTurkey 300/100,000; US/EU 10-17/100,000
73 VASCULITIDES OF YOUNGER PEOPLE Takayasu aortitisHenoch-Schonlein purpura (HSP)Leukocytoclastic vasculitis (LCV)Kawasaki syndromeSerum sickness-immune complex-mediatedGoodpasture syndrome
74 TAKAYASU ARTERITIS Young women Disease of aorta and its first branches Loss 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 silentlyEven when thought to be quiescent ~40% of patients still have active inflammation at surgery
76 HENOCH-SCHONLEIN PURPURA Palpable purpuraGlomerulonephritisArthritisAbdominal painMales~females; mean age 5 yrs.Preceding URI in 2/3 (1-3 weeks).
77 HENOCH-SCHONLEIN PURPURA Small vessels, esp. Post-capillary venules.All lesions about same stage in evolution.Bx with i.F. TYPICALLY IgA deposits in skin and kidneyUsually single episodes < 4 weeks duration.40% recurrence rate after period of wellness.May be permanent renal damage
82 Goodpasture SyndromeTypically young men presenting with pulmonary-renal syndrome: hemoptysis AND renal failureCaused by auto-antibodies that uniquely bind to basement membranes of lung and kidney, causing alveolitis and glomerulonephritisSerum from patients can cause a similar syndrome to develop in serum-recipient monkeys
84 Goodpasture Syndromeanti-GBM antibodies directed against noncollagenous (NC1) globular domain of the 3 chain of type IV GBM collagen
85 VASCULITIS- Treatment Which organ system?How severe?Rate of damage?Potential reversibility?
86 VASCULITIS- Treatment Corticosteroids Daily or PulseCytotoxic agents, e.g. Methotrexate Azathioprine CyclophosphamideImmunomodulatories Mycophenolate mofetil Cyclosporine
87 Immunomodulation General Principles If we accept the premise that many systemic inflammatory diseases are auto-immune, manipulation of the immune response may help control the diseaseIdentification of which immune mechanism is causative/contributory is crucial
88 Immunomodulation- Immediate control of disease Pulse IV corticosteroids can be very useful in getting some diseases under control immediatelyPlasmapheresis has limited usefulness auto-antibody- (Goodpasture) or immune-complex-mediated (systemic JRA?) diseasesIVIG- ITP, dermatomyositis
89 Immunomodulation: Present IVIG: Regulatory idiotypes vs. Saturating Fc receptors? vs. Induction of IL-10Steroids: LympholysisCytotoxics: Kill inflammatory cellsPheresis: Removal of effector cells and “evil humors”
90 MOLECULAR BIOLOGIC AGENTS Interfere with TNF Soluble receptor- EtanerceptInterfere with TNF Monoclonal antibody- Infliximab AdalimumabInterfere with IL Receptor antagonist- AnakinraInterfere with T cell costimulation Abatacept
91 Immunomodulation: 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
92 Immunomodulation: Future Enzyme blockade- e.g. TACE, ICE*Kinase blockade, e.g. p38 MAP kinase- intracellular messengers to nucleusInduce 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
93 Molecular biology has given us a new therapeutic world Repair immunodeficiencies- IVIG, ADARepair genetic defects- on hold for nowStem cell transplantsCytokines, receptors, antibodies- antagonist and agonistSupport patients until defect identified andtoxicity of therapy can be overcome
94 Confused? firstname.lastname@example.org JCR: Journal of Clinical Rheumatology Basic Science for the ClinicianImmunology TodayNature Immunology ReviewsScience- introductory piecesAnnual Review of ImmunologyCurrent Opinions in Immunology
95 Auto-immune diseases Leonard H Sigal MD, FACP, FACR P.R.I.- CD& E- ImmunologyBristol-Myers SquibbPrinceton, NJClinical Professor of Medicine and PediatricsUMDNJ – Robert Wood Johnson Medical SchoolNew Brunswick, NJ