Immunology In Rheumatic Diseases

Immunology in RheumaticDiseaseszKnowledge of immunology forms thebasis of understanding many of theRheumatologicg diseases and hasbecome the focus of many excitingnew treatment strategies .Topics coveredAIMS OF THIS LECTUREzzIntroduce the important components ofthe immune systemShow how they interact & protect the body(IMMUNITY)zWithout attacking itself (TOLERANCE)zDemonstrate what happens when things gowrong & the body turns against itself(AUTOIMMUNITY)zProvide examples of immunology in clinicalRheumatology1.2.3.4.Immune mechanismsToleranceAutoimmunityRheumatologic diseases––––––Rheumatoid arthritisSystemic Lupus ErythematosisSpondarthropathiesInflammatory myopathiesSystemic sclerosisOsteoarthritisImmune Mechanisms1. IMMUNE MECHANISMSzOverviewzSpecific components–––––2. Tolerance3 A3.Autoimmunityii4. Rheumatologic diseases––––––Rheumatoid arthritisSystemic Lupus ErythematosisSpondarthropathiesInflammatory myopathiesSystemic sclerosisOsteoarthritiszPhysical barrierComplementCellsMHCCytokinesActivation of adaptive immune system bythe innate system1

Immunity Can Be Divided Into 2Main Components:1.InnateInnate immunity Rapid acting, nonspecificIMMUNITY2 Specific or adaptive immunity2. Slower onset of action Targets pathogens that escape the innateimmune system Activated by the innate immune systemSpecificBarriers against infectionzzz– Skin– Bactericidal fluids eg tearsz– Secretion of mucous– Gastric acid– Microbial antagonismzNK( Natural killer) cells–Large granularlymphocyteympy–Lyses viralinfected cells &tumor cells–Note the smaller NKcell destroying itstarget cell by poreforming perforinsHumoral ( B cells)CMI ( T cells)ComplementMicroorganisms are kept out of thebody by:Cells in the Innate System(1)Physical barrierComplementNK cellsPhagocytic cells- neutrophils- macrophagesEosinophilsMast CellsA group of serumproteinswhich act in anenzymatic cascadeProduce moleculesinvolved in– Cell lysis– phagocytosis– inflammationCells in the Innate System (2)zPhagocytic cells1. Neutrophils-70% of circulating WCC- Major circulating phagocyticcell2. Macrophages-Large phagocytic cellderived from bloodmonocyte- Also acts as an antigenpresenting cell ( APC)Neutrophil2

Cells in the Innate System (3)zCells in the adaptive system(1)Eosinophilsz– Granulocytes important inthe killing of parasiteszB & T lymphocytes– are the major cells of the adaptive systemEosinophilszMast cellsCD4 T cells– helph l to stimulatelB cellll antibodyb d productiond– Contain abundant granules– activate macrophages– complement componentsztrigger degranulationCD8 T cells ( cytotoxic cells)– kill target cells expressing foreign antigen– results in release ofinflamatory mediatorsincluding histamine &leukotrienesLYMPHOCYTECells in the adaptive system (2)zAntigen Presenting CellsB cells– May mature to become plasma cellsUnlike the other cells, TH cells onlyrecognise antigen that is properlypresented with MCH bypy other cellsz These specialised cells are calledantigen presenting cellsz They include macrophages, B cells,fibroblasts & dendritic cellszproducing antibodies. The function ofantibodies are to :zzzdirectly stimulate or neutralise its targetActivate complementform a bridge between the target & cytotoxic cell egmacrophages & NK cells) Antibody dependantcellular cytotoxicity ( ADCC)– Act as antigen presenting cellsz(More about these cells later .)PLASMA CELLSMajor HistocompatibilityComplex (MHC)zAntigen is ingested by the antigenpresenting cell then presented on itssurface in molecules called majorjHistocompatibility complexMajor HistocompatibilityComplexzzzzMHC are also the molecules responsible forrejection in transplant organszzzMHC proteins HLA (Human LeucocyteAntigen) in humansMolecules on cells fsurfacess whichhi h candisplay antigenProducts of a region ofhighly polymorphogenicgenes on chromosome 62 types :Class I &Class II3

Comparison of MHC Class I & IIMoleculesClass IClass IIGenesHLA A/B/CHLA DExpressed onAll nucleated cellsAPCs – B cells,macrophages &dendritic cellsSize9 to 10 amino acids(smaller)12 to 28 amino acids(larger)Intracellular eg viralinfectionsExtracellular egbacterial infectionsActivation of the AdaptiveImmune SystemAntigens that escape the innateimmune system encounter theadaptivepsystemyz Adaptive immune system – powerful must be activatedzSource of antigendisplayedAntigen presented to CD8 T cellsCD4 cells( APC Antigen presenting cell)Activation of the Adaptive ImmuneSystemThis diagramshows the immunesystem in action.In this diagram, the macrophage represents the innate system& the TH cell, the adaptive system1.Take a closerlook .3. T cell recognisesgAggits cognate2. Ag presentedon cell surfacewith MHC4. 2nd signal required protein on APC a TH cell receptorAPC egMacrophageingests Ag5. ACTIVATION&6. Cytokine productionDo these steps look familiar?1.CytokinesAg (virus) ingestedz2. Ag presentedon cell surfacewithith MHC5.ACTIVATION&6. CytokineproductionCells of the immune systemcommunicate with each other usingcytokinesy3. T cell recognisesits cognate Ag4. 2nd signal required protein on APC a T cell receptor4

Cytokine typesCytokineszzzzz– produced by leucocytes & have effects mainlyProtein hormonesMediate the effect of the innate &specific immunityAutocrine/ paracrine/endocrineEffects include cell activation, division,apoptosis, movementon WBCzChemokines –zColony stimulating factors –zInterferons –– chemoattractants– differentiation & proliferation of stem cells– interfere with viral replicationzCells & cytokine productionCells produce different subgroups of cytokines whichwill instruct the innate & adaptive systems to producecells & antibodies against specific antigens.Here is an exampleCellsTH 0TH 1(CD4)CytokinesIl 2IFN γTNFTH 2(CD8)Il 4Il 5Il 10Interleukins –AntigenVirusesBacteriaEg.Il-2 a growth factor that stimulates CTLs & NKcells to proliferateTNF activates primed macrophages & NK cells1.Immune Mechanisms2. TOLERANCE3. Autoimmunity4. Rheumatologic diseases––––––Rheumatoid arthritisSystemic Lupus ErythematosisSpondarthropathiesInflammatory myopathiesSystemic sclerosisOsteoarthritisParasitesTolerance Is .the immunologic unresponsivenessto self antigensCentral T CellTolerancezzzzzzIt allows the immune system to protect the bodywithout turning against itselfThe focus is on the adaptive immune systemT & B cells must be able to discriminate self fromnon selfThis occurs centrally & peripherallyzzNEJM 2001;344(9): 655 – 664.T cells areproduced in thebone marrow &migrate to thethymus.Here they goththroughh a rigorousiselections process.Only T cells thatreact to antigen butnot self exit.The rest die byapoptosis.5

B Cell TolerancePeripheral T Cell TolerancezzCENTRAL– Clonal deletion of autoreactive Bcells in the bone marrow, spleen& lymph nodes.nodesPERIPHERAL– Lack of help from T cells is thepredominant factor.If autoreactive T cells enter the circulation,there are several mechanisms that can preventan autoimmune reaction.NEJM 2001;344(9): 655 – 664.Immune MechanismsTolerance1.2.3. AUTOIMMUNITY4. Rheumatologic diseases––––––Rheumatoid arthritisSystemic Lupus ErythematosisSpondarthropathiesInflammatory myopathiesSystemic sclerosisOsteoarthritisAutoimmune diseaseszOrgan specific e.g.– Insulin dependant diabetes– Myasthenia graviszAutoimmunityzBreakdown in mechanisms preservingtolerance to selfzSevere enough to cause a pathologicalconditionMechanismsGENETIC FACTORSzAberant MHC/HLA present self peptidezAutoreactive T & B cellsENVIRONMENTALFACTORSzInfectious/noninfectious triggerszHypothesisyp: MolecularmimicryMultisystem e.g.– Rheumatoid arthritis– SLEAUTOIMMUNE DISEASEMolecular mimicry :The antigen looks similar to a self-peptide. As a result, the bodyproduces an immune response to the trigger factor as well as to self.6

Autoantibodies associatedwith diseaseAutoantibodies in ConnectiveTissue DiseaseszzzzDISEASEProduced by B cellsMay pathogenic eg.– Form immune complexes in lupus nephritisMarkers of certain diseasesNot diagnosticfound in normal population & with other conditions– Therefore only test when clinically indicated.Cellular Targets for autoantibodiesAb to intracellular proteins-proteinase 3 cANCAAb to cell membraneProteins ACLAAb to IgG Rheumatoid factorAntinuclear antibodies (ANA) dsDNA ENA – Smith, Ro , La, RNP Centromere, topoisomeraseRibosomal &lysosomal components-t RNA synthetase AntiJo 1This diagram depicts the autoantibodies & theirrespective target antigensRheumatoid ArthritisRheumatoid ArthritisRheumatoid factorSLEANA,dsDNA, omeraseAnticardiolipin (ACLA)AntiphospholipidSyndrome– Apart from rheumatic disorders, they may beAUTOANTIBODYSjogren’s syndromeRo, LaPolymyositisJo-1DermatomyositisMi-2Wegener’s granulomatosis C-ANCA1.2.3.Immune MechanismsToleranceAutoimmunity4. Rheumatologic conditions––––––Rheumatoid arthritisSystemic Lupus ErythematosisSpondarthropathiesInflammatory myopathiesSystemic sclerosisOsteoarthritisThe above disease will be used to highlight some ofthe concepts of Immunology in Rheumatology.Note that the details of each pathway does NOT haveto be memorised.The immune mechanisms in RAz1.A symmetricalperipheralpolyarthritis ofunknown aetiologythat leads to jointdeformity &destruction due toerosion ofcartilage & bone2.NEJM 2001; 344 (12): 907 – 916Note:The interactionbetween thecells of theinnate &adaptiveimmune systemsThe cytokinesproduced aretargets fornewer therapyin RA7

Rheumatoid FactorRAzzTheinflammatoryprocessresults indamage tocartilage &bonezNEJM 2001; 344 (12):907 – 916.Systemic Lupus ErythematosisA generalisedconnective tissuedisorderaffectingff ti manyorgans andcharacterised bythe productionof manyautoantibodiesLupus NephritiszThe kidney biopsy on the right is from a patientwith diffuse proliferative lupus nephritis showsmassive deposits of IgG on immunofluorescenceRheumatoidFactor is anautoantibodyproduced in RAIt is howeverproduced inseveral otherconditions theclinical featuresare important inmaking thediagnosisARA Criteria for the diagnosis of SLENote:1. Manyorgans canbeaffectedz2. Severalautoantibodiesareassociatedwith SLEAnkylosingSpondylitisAS is a chronic inflammatory disease of theaxial skeleton manifested by back pain &progressive stiffness of the spine8

AnkylosingSpondylitiszTheprevalence ofthe MHC,HLA B27 ishigh inCaucasiansbut rare inBlackpopulationswithAnkylosingSpondylitisNote: the inflammatory infiltrate in the musclebiopsy of this patient with DermatomyositisThe inflammatory process in Scleroderma results amarked fibrotic precess responsible for many of theclinical featuresDermatomyositisAn idiopathic inflammatory myopathy associatedwith certain characteristic cutaneous manifestationsSclerodermaThe term encompasses a heterogeneous group ofconditions linked by the presence of thickenedsclerotic skin lesionsScleroderma Lung Disease2 important lung diseases which occur due tothe inflammatory process in Scleroderma9

OsteoarthritisImmune pathways in OsteoarthritisImmunemechanismshave evenbbeenshownhto play a rolein OA .References (cont)References1.2.3.4.5.Sompayrac L. How the Immune System works.Blackwell Science, Inc. 1999Roitt IM. Roitt’s Essential Immunology 10th ed.Blackwell Science 2001Hochburg et al. Rheumatology 3rd ed. Mosby 2003UpToDate 12.3Kalla AA. Rheumatology Handbook. RheumaticDiseases Unit Univrersity of Cape Town. 2003Parkin J, Cohen B. An overview of the immunesystem. Lancet 2001;357: 1777-1789.7.Mackay IR, Rosen FS. Tolerance andAutoimmunity. NEJM 2001;344(9): 655 – 664.8.Mackay IR, Rosen FS. Autoimmune diseases.NEJM 2001; 345(5): 340-350.9.Epstein FH. Cytokine pathway and JointInflammation in Rheumatoid Arthritis. NEJM2001; 344 (12): 907 – 916.10. Yuan G et al. Immunologic Intervention in thePathogenesis of Osteoarthritis. Arthritis &Rheumatism 2003; 48(3) 602- 611.6.The End .10

Roitt IM. Roitt’s Essential Immunology 10th ed. Blackwell Science 2001 3. Hochburg et al. Rheumatology 3rd ed. Mosby 2003 4. UpToDate 12.3 5. Kalla AA. Rheumatology Handbook. Rheumatic Diseases Unit Univrersity of Cape Town. 2003 References (cont) 6. Parkin J, Cohen B. An overview of the immune system. Lancet 2001;357: 1777-1789. 7. Mackay IR .