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Auto-immune diseases Leonard H Sigal MD, FACP, FACR

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

15 CD4 cell populations of note
Th Th Th17 Intracellular Extracellular pathogens Extracellular pathogens like parasites bacteria* IFN IL IL17A LT IL IL17F TNF IL IL6 IL2 IL9 IL10 IL13 * 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 effectors Osteoclast CD4+ T-helper cell RANK-L T cell T cell IL-2 IL-4, IL-10 T cell T cell B-cell IFN-g, TNF-a IL-3, IL-7, GM-CSF IFN-g IL-4 IL-5 TNF-a TGF-b Macrophage Stem cell B-cell proliferation B-cell differentiation cytokine production APC activity antibody production TNF-a, IL-1, IL-6, IL-12

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

18 Auto-antibodies- receptor targets: Receptor Stimulate Block
TSH R. Graves Hashimoto’s Insulin R. Hypo- Hyperglycemia ACTH R. Addison’s Intrinsic Factor Pernicious anemia ACh R. Myasthenia gravis

19 Auto-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

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

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) -nakinra IL1 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 IL-10 Ts TGF TGF IFN Crow MK, A&R, 2003

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

31

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

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

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

49

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)

52 RESULTS OF VASCULAR INFLAMMATION
STENOSIS & OCCLUSION ISCHEMIA / INFARCTION DILATATION & RUPTURE TURBULENT FLOW / BLEED

53 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 % ESR:       > % Headache % Tenderness of arteries % Jaw claudication % Bruits % Visual symptoms:   % Diplopia            Vision loss            Ultimate blindness Weight Loss % Fever %

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 involvement.
Absence of vasculitis of arterioles, venules and capillaries. Renal disease may occur, but not glomerulonephritis. 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 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. Small and medium-sized vessels. Tissue damage often associated with necrosis and granuloma formation. Active disease is often associated with antibody formation to proteinase 3 (Pr3).

61 Wegener Granulomatosis

62 Wegener Granulomatosis

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

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 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

67 BEHÇET SYNDROME The Silk Road HLA-B51

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

69 BEHÇET SYNDROME

70 BEHÇET SYNDROME Hypopyon

71 BEHÇET SYNDROME

72 BEHÇET SYNDROME Pathergy sign

73 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 % 5 days or more, remittent Conjunctivitis Bilateral Lymphadenopathy Cervical >1.5 cm Lips/oral mucosa Strawberry tongue Dry, red vertical fissures Red oropharynx Extremities 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

81

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 Goodpasture Syndrome 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
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 Receptor antagonist- Anakinra Interfere with T cell costimulation Abatacept

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 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

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? 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

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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