Autoimmune diseases

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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
• UMDNJ Robert Wood Johnson Medical School
• New Brunswick, NJ

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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

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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

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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

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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.

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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

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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

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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

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What Induces Autoimmunity?
CENTRAL (prenatal) and PERIPHERAL (later)
MECHANISMS
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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

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FOXp3

• Mouse strain scurfy develops an X-linked
  recessive auto-immune disorder with multiple
  organ-specific inflammation, hypergammaglobulinemi
  a, 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).

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T-regs CD4 CD25

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

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non T-reg T regulators

• CD4 TH1 cells (secreting gamma interferon)
• CD4 TH2 cells (secrete IL-4)
• CD4CD25 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).

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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
IL17 IL22
Effector T cells
Possible autoimmune activity
Antibodies Cytokines
Cytotoxic cell activity
TGF? IL10
Regulatory functions
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CD4 cell populations of note
Th1
Th2 Th17
Intracellular Extracellular pathogens
Extracellular pathogens like
parasites bacteria
?IFN IL4 IL17A LT? IL5
IL17F TNF? IL6 IL6 IL2 IL9 IL1
0 IL13
Bacterial species implicated include 
Klebsiella pneumoniae, Bordetella pertusis,
Citrobacter rodentium, and Borrelia burgdorferi
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T Cells Orchestrate the Adaptive and Innate
Responses
Proliferate and differentiate to effectors
CD4 T-helper cell
Osteoclast
RANK-L
T cell
T cell
IL-2
IL-4, IL-10
T cell
T cell
B-cell
IFN-g, TNF-a
IFN-g IL-4 IL-5 TNF-a TGF-b
IL-3, IL-7, GM-CSF
Stem cell
B-cell proliferation B-cell differentiation cytok
ine production APC activity antibody production
TNF-a, IL-1, IL-6, IL-12
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1. Genes
2. Abnormal Immune Response
4. Inflammation
5.Damage
C1q,C2,C4 HLA-D2,3,8 MBL
FcR 2A,3A,2B IL-10 MCP-1 PTPN22
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
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Auto-antibodies- receptor targets Receptor
Stimulate Block

• TSH R. Graves Hashimotos
• Insulin R. Hypo- Hyperglycemia
• ACTH R. Addisons
• Intrinsic Factor Pernicious anemia
• ACh R. Myasthenia gravis

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Auto-antibodies- other targets

• Basement membrane Goodpastures syndrome
• Uveal tract Sympathetic ophthalmia
• Cardiac tissue Dresslers syndrome
• Exocrine glands Sjogrens syndrome
• Epidermal Bullous pemphigus hemidesmosomes
• Blood cells Hemolytic anemia, AITP

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TREATMENT OF AUTO-IMMUNITY

• If hormonal deficiency- REPLACE
• If organ inflammation- SUPPRESS Pulse
  corticosteroids Oral corticosteroids Cytotox
  ic agents Immunomodulatory agents Plasmaphere
  sis

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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

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

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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

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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)

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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

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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
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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

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IL-10
Ts
TGF?
TGF?
IFN?
Crow MK, AR, 2003
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Treg (Foxp3 CD4 T) are Depleted in Patients with
Active SLE
Miyara et al, J Immunology, 2005
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TGF? in Normals

T
CD8
B
TGF?
IL-2
AB
NK
NK
Treg
CD4
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Patients with SLE Make Abnormally Low Levels of
TGF?
TGF? pg/ml


Ohtsuka et al, JI 1998
Human cells stimulated with anti-CD2
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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

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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

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Rheumatoid arthritis- focus?

• T cell
• Macrophage
• Synoviocyte (fibroblastoid)
• B cell
• Genetics
• Anti-CCP2

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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

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JUVENILE IDIOPATHIC ARTHRITIS (JIA)-ILAR 1995

• Seven categories
• Systemic
• Oligoarthritis
• Polyarthritis (RF-)
• Polyarthritis (RF)
• Psoriatic arthritis
• Enthesitis-related arthritis- related to SNSAs
• Other arthritis

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JUVENILE RHEUMATOID ARTHRITIS (JRA)/ IDIOPATHIC
ARTHRITIS (JIA)

• Unknown etiology
• Unknown immune focus in joints, eyes, etc.
• Age
• Genetic pre-disposition
• Multiple cytokines involved, e.g. TNF, IL-1,
  IL-6

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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

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Macrophage activation syndrome

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

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Macrophage activation syndrome

• Neutrophilic bands and metamyelocyte within an
  activated macrophage.

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JUVENILE IDIOPATHIC ARTHRITIS- New management

• Methotrexate
• Etanercept
• Infliximab
• Adalimumab
• Leflunomide
• Abatacept (CTLA4-Ig)
• Anakinra not very effective
• Anti-IL-6 effective not yet approved

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DERMATOMYOSITIS

• Multi-system inflammatory disease
• Adults and children
• Acute and chronic inflammation of striated
  muscle and skin

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SERONEGATIVE SPONDYLOARTHROPATHIES

• Ankylosing spondylitis
• Psoriatic arthritis
• Psoriatic spondyloarthropathy
• Inflammatory joint disease associated with
  inflammatory bowel disease
• Reactive arthritis (no longer called Reiter
  syndrome)

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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)

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SNSA- therapy

• NSAIDs, COX2
• Sulfasalazine
• TNF blockade

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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

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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

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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)

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RESULTS OF VASCULAR INFLAMMATION

• STENOSIS OCCLUSION
• ISCHEMIA / INFARCTION
• DILATATION RUPTURE
• TURBULENT FLOW / BLEED

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VASCULITIDES OF OLDER PEOPLE

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

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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           Ultim
  ate blindness
• Weight Loss 40
• Fever 20

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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

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GIANT CELL ARTERITIS
Disrupted internal elastic lamella
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Not merely temporal arteritis
ANEURYSMS
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• 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.

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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.

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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).

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Wegener Granulomatosis
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Wegener Granulomatosis
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ANCA anti-neutrophil cytoplasmic antibodies
WG
MPA CG UC
Myeloperoxidase, Lactoferrin, Proteinase-3 elasta
se, cathepsin C
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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

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Cryoglobulinemia
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BEHÇET SYNDROMEAdamantiades-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".
• Malesfemales 11 more female in US, Japan,
  Korea, the West
• Increasing prevalence with increased awareness
• Turkey 300/100,000 US/EU 10-17/100,000

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BEHÇET SYNDROME
The Silk Road

• HLA-B51

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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

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BEHÇET SYNDROME
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BEHÇET SYNDROME
Hypopyon
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BEHÇET SYNDROME
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BEHÇET SYNDROME

• Pathergy sign

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VASCULITIDES OF YOUNGER PEOPLE

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

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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

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Takayasu arteritis
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HENOCH-SCHONLEIN PURPURA

• Palpable purpura
• Glomerulonephritis
• Arthritis
• Abdominal pain
• Malesfemales mean age 5 yrs.
• Preceding URI in 2/3 (1-3 weeks).

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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
• 40 recurrence rate after period of
  wellness.
• May be permanent renal damage

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Henoch-Schonlein purpura
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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

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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

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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

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Goodpasture Syndrome
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Goodpasture Syndrome
anti-GBM antibodies directed against
noncollagenous (NC1) globular domain of the ?3
chain of type IV GBM collagen
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VASCULITIS- Treatment

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

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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

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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

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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

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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 costimulation Abatacept

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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_at_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

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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
• UMDNJ Robert Wood Johnson Medical School
• New Brunswick, NJ