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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.

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Presentation on theme: "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."— Presentation transcript:

1 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 UMDNJ – Robert Wood Johnson Medical School New 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 life Auto-immunity- breakdown in tolerance- genetic predisposition plus environmental exposure as trigger

4 AUTO-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

5 AUTO-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.

6 AUTO-IMMUNITY Organ-specific: single or a few Systemic Auto-immunity of a single organ often means there is another organ affected Family history is often positive

7 Self-recognition- salubrious examples Self-recognition- salubrious examples Idiotype network- regulation of antibody production Antigen presentation: MHC and cell-surface antigen receptors interact Ligand-receptor interactions Antigen-specific suppressor cells & factors

8 Why 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

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

11 FOXp3 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).

12 T-regs: CD4+ CD25+ GITR, CD62L, CTLA4 or E/ 7 integrin might be better markers than CD25

13 non 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).

14 Antigen Presenting Cell MHC class I MHC class II Adaptive/Acquired Immunity: Activation of Effector T cells Viral antigen Self antigen CD4+ Helper CD8+ Cytotoxic Cytotoxic cell activity Antibodies Cytokines Effector T cells Foreign antigen Processing & Loading CD4+ Th17 Possible autoimmune activity CD4+ CD25+ Treg Foxp3 Regulatory functions TGF + IL6 TGF TGF IL10 IL17 IL22

15 CD4 cell populations of note Th1 Th2 Th17 Intracellular Extracellular pathogens Extracellular pathogens like parasites bacteria* IFNIL4 IL17A LT IL5 IL17F TNF IL6 IL6 IL2IL9 IL10 IL13 * Bacterial species implicated include : Klebsiella pneumoniae, Bordetella pertusis, Citrobacter rodentium, and Borrelia burgdorferi

16 T Cells Orchestrate the Adaptive and Innate Responses CD4+ T-helper cell B-cell Stem cell Macrophage T cell T cell T cell T cell IL-2 IFN-, TNF- B-cell proliferation B-cell differentiation cytokine production APC activity antibody production IL-4, IL-10 IL-3, IL-7, GM-CSF TNF-, IL-1, IL-6, IL-12 IFN- IL-4 IL-5 TNF- TGF- Osteoclast RANK-L Proliferate and differentiate to effectors

17 2. Abnormal Immune Response C1q,C2,C4 HLA-D2,3,8 MBL FcR 2A,3A,2B IL-10 MCP-1 PTPN22 Rash Nephritis Arthritis Leukopenia CNS dz Carditis Clotting Etc Renal Failure Atherosclerosis Pulm fibrosis Stroke Damage from Rx Etc Chr. inflam Chr. oxid. UV light Gender EBV Other Infe Others 3. Autoantibodies Immune Complexes C3 C3a Ag DC Bcell Tcell Suppressive networks Environment 1. Genes 5.Damage 4. Inflammation Ag DC Bcell Tcell Suppressive networks Courtesy Bevra Hahn, MD

18 Auto-antibodies- receptor targets: Receptor StimulateBlock TSH R. GravesHashimotos Insulin R. Hypo-Hyperglycemia ACTH R.Addisons Intrinsic FactorPernicious anemia ACh R.Myasthenia gravis

19 Auto-antibodies- other targets: Basement membraneGoodpastures syndrome Uveal tractSympathetic ophthalmia Cardiac tissueDresslers syndrome Exocrine glandsSjogrens syndrome Epidermal Bullous pemphigus hemidesmosomes Blood cells Hemolytic anemia, AITP

20 TREATMENT OF AUTO- IMMUNITY If hormonal deficiency- REPLACE If organ inflammation- SUPPRESS Pulse corticosteroids Oral corticosteroids Cytotoxic agents Immunomodulatory agents Plasmapheresis

21 TREATMENT OF AUTO- IMMUNITY Neutralize inflammatory cytokines: Solubilized receptor TNF Monoclonal antibody TNF, BLyS Antibody to receptor IL-6 Receptor antagonist IL-1 Suppress antigen-specific response Co-stimulation blockade CTLA4Ig Counterbalancing cytokines

22 MP/DC DR TCR Peptide Inosinic acid Inosinic acid purines IMPDH purines IMPDH CD28 B CellT Cell CD20 CD22 BCMA APRIL Y BCR Anti-CD20 Edratide LJP394 CTLA4-Ig Mycophenolate Anti-BLyS TACI-Ig BLyS Anti-CD22 IFNa Anti-IFNa Clinical Trials Treg X Courtesy Bevra Hahn, MD CD28 B7

23 Molecular biology has given us a new therapeutic world Replace deficiencies- IVIG, ADA Repair genetic defects- ADA Stem cell transplants Cytokines, receptors, antibodies- antagonist and agonist Support patients until defect identified and toxicity 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) -nakinraIL1 receptor antagonist -tinib Inhibitor of a tyrosine kinase

25 SYSTEMIC INFLAMMATORY SYNDROMES Systemic lupus erythematosus (SLE) Rheumatoid arthritis (RA) Juvenile rheumatoid arthritis (JRA)- aka Juvenile idiopathic arthritis (JIA) Juvenile dermatomyositis Kawasaki disease Seronegative spondylarthropathies (SNSA)

26 SYSTEMIC LUPUS ERYTHEMATOSUS 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; externalized locus of control

27 SYSTEMIC LUPUS ERYTHEMATOSUS-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

28 SYSTEMIC LUPUS ERYTHEMATOSUS 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

29 Crow MK, A&R, 2003 IFN IL-10 TGF Ts

30 Miyara et al, J Immunology, 2005 Treg (Foxp3 CD4+ T) are Depleted in Patients with Active SLE


32 TGF in Normals NK IL-2 NK CD8 B TGF T AB Treg CD4

33 Patients with SLE Make Abnormally Low Levels of TGF Patients with SLE Make Abnormally Low Levels of TGF TGF pg/m l Human cells stimulated with anti- CD2 Ohtsuka et al, JI 1998 * *

34 SYSTEMIC LUPUS ERYTHEMATOSUS Therapy tailored to the organ system(s) affected, severity/type of damage NSAIDs Hydroxychloroquine Corticosteroids Cyclophosphamide Azathioprine Biologics in trials- BLyS, CTLA4Ig

35 Rheumatoid 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 factor Anti-CCP (cyclic citrullinated peptide) prior to disease

36 Rheumatoid arthritis- focus? T cell Macrophage Synoviocyte (fibroblastoid) B cell Genetics Anti-CCP2

37 Rheumatoid arthritis- therapies NSAIDs, COX2s Corticosteroids Methotrexate, leflunomide Cyclosporine (T cell target) Anti-CD3; total nodal irradiation Anti-TNFs Co-stimulation modulation B cell assassination; B cell activation blockade

38 JUVENILE IDIOPATHIC ARTHRITIS (JIA)-ILAR 1995 Seven categories: Systemic Oligoarthritis Polyarthritis (RF-) Polyarthritis (RF+) Psoriatic arthritis Enthesitis-related arthritis- related to SNSAs Other arthritis

39 JUVENILE RHEUMATOID ARTHRITIS (JRA)/ 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

40 Macrophage Activation Syndrome- complication 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

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 Methotrexate Etanercept Infliximab Adalimumab Leflunomide Abatacept (CTLA4-Ig) Anakinra not very effective Anti-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 spondylitis Psoriatic arthritis Psoriatic spondyloarthropathy Inflammatory joint disease associated with inflammatory bowel disease Reactive arthritis (no longer called Reiter syndrome)

46 SERONEGATIVE SPONDYLOARTHROPATHIES No serum rheumatoid factor Inflammation of spine and sacroiliac joints Primary focus of inflammation is the enthesis HLA-B27: independent linkage with aortic disease (and anterior uveitis)

47 SNSA- therapy NSAIDs, COX2 Sulfasalazine TNF blockade

48 SYSTEMIC INFLAMMATORY SYNDROMES-Vasculitis Classified by size of vessel affected Large: Takayasu Medium: PAN; Churg-Strauss Medium: Wegener; Goodpasture Small: Henoch-Schonlein Purpura Pathogenesis is unclear: immune complex; auto-antibody; cellular reactivity


50 COMBINATIONS OF FEATURES GREATLY ENHANCE PROBABILITY OF VASCULITIS Fever Glomerulonephritis Palpable purpura Peripheral neuropathy Established auto-immune disease Ischemia, e.g. gut, heart, brain especially in young patients

51 DIAGNOSING VASCULITIDES 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)


53 OF OLDER PEOPLE VASCULITIDES OF OLDER PEOPLE Giant cell arteritis Polyarteritis nodosa (PAN) Wegener granulomatosis Cryoglobulinemia Leukocytoclastic vasculitis

54 SIGNS 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%

55 POLYMYALGIA RHEUMATICA Shoulder and hip girdle pain Perceived weakness, but normal strength Morning stiffness, but not obvious synovitis Over age 50 Dramatic and rapid response to steroids Overlap with GCA; up to 40% of PMR have GCA (may be delayed) and up to 65% of GCA have PMR Recent studies suggest the shoulder and hip pain is due to a mild synovitis of those joints

56 GIANT CELL ARTERITIS Disrupted internal elastic lamella

57 Not merely temporal arteritis ANEURYSMS

58 Classical Polyarteritis Nodosa : Medium-sized vessel Medium-sized vessel involvement. Renal diseasenot Absence of vasculitis of arterioles, venules and capillaries. Renal disease may occur, but notglomerulonephritis. Microscopic Polyangiitis: "microscopic" vessels with or without medium-size vessel Involvement of "microscopic" vessels (arterioles, venules, and capillaries), with or without medium-size vessel involvement. Glomerulonephritis is common Glomerulonephritis is common and pulmonary capillaritis may occur. Few or no "immune deposits," no granulomas Few or no "immune deposits," no granulomas - distinct from HSP, cryoglobulinemic vasculitis, lupus, serum sickness.

59 Polyarteritis Nodosa Skin: 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.

60 WEGENER'S GRANULOMATOSIS Idiopathic systemic inflammatory disease with an unusual propensity to affect the respiratory tract and kidneys. vessels.Small and medium-sized vessels. necrosis and granuloma formation.Tissue damage often associated with necrosis and granuloma formation. Active disease is often associated with antibody formation to proteinase 3 (Pr3) antibody formation to proteinase 3 (Pr3).

61 Wegener Granulomatosis


63 ANCA: anti-neutrophil cytoplasmic antibodies Myeloperoxidase, Lactoferrin, Proteinase-3 elastase, cathepsin C WG MPA CG UC

64 Cryoglobulinemia Immunoglobulin 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

65 Cryoglobulinemia

66 BEHÇET SYNDROME Adamantiades-Behcet May have been described first by Hippocrates in the 5 th 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


68 BEHÇET 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


70 Hypopyon


72 Pathergy sign

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

74 TAKAYASU ARTERITIS Young women Disease of aorta and its first branches Loss of pulse (Pulseless disease), stroke, hypertension Can affect pulmonary circulation, as well Progression 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

75 Takayasu arteritis

76 HENOCH-SCHONLEIN PURPURA Palpable purpura Glomerulonephritis Arthritis Abdominal pain Males 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 kidney Usually single episodes < 4 weeks duration. 40% recurrence rate after period of wellness. May be permanent renal damage

78 Henoch-Schonlein purpura

79 KAWASAKI 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

80 KAWASAKI DISEASE- other features Cardiac- most serious complication Pericarditis, arrhythmias, infarction Myocarditis- Heart failure, aneurysms CNS- irritability is almost universal consider aseptic meningitis, focal lesions, seizures- CNS vasculitis


82 Goodpasture 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

83 Goodpasture Syndrome

84 anti-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 Pulse Cytotoxic agents, e.g. Methotrexate Azathioprine Cyclophosphamide Immunomodulatories 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 disease Identification of which immune mechanism is causative/contributory is crucial

88 Immunomodulation- Immediate control of disease Immunomodulation- Immediate 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

89 Immunomodulation: 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

90 MOLECULAR BIOLOGIC AGENTS Interfere with TNF Soluble receptor- Etanercept Interfere with TNF Monoclonal antibody-Infliximab Adalimumab Interfere with IL-1 Receptor antagonist- Anakinra Interfere with T cell costimulationAbatacept

91 Immunomodulation: Future Interfere with antigen-specific responses- costimulation blockade* Regulatory anti-inflammatory cytokine Monoclonal antibody and soluble receptors for effector molecules Receptor 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 messengersto 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

93 Molecular biology has given us a new therapeutic world Repair immunodeficiencies- IVIG, ADA Repair genetic defects- on hold for now Stem cell transplants Cytokines, receptors, antibodies- antagonist and agonist Support patients until defect identified and toxicity of therapy can be overcome

94 Confused? 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

95 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 UMDNJ – Robert Wood Johnson Medical School New Brunswick, NJ

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