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SLE Fighting Self SabotageFeb.
2005Immunology in health and Disease

• Susan Manzi, MD, MPH
• Associate Professor of Medicine and Epidemiology
• Co-Director Lupus Center of Excellence

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Objectives

• I. Epidemiology
• II. Pathogenesis
• Genetic
• Sources of autoantibodies
• Environmental triggers
• Defective immune regulation
• Gender/hormonal factors
• III. Clinical and laboratory features
• Diagnosis/natural history
• Autoantibodies
• Treatment

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Who Gets Lupus?

• Females gt Males 71
• Childbearing 121
• Children, elderly 21
• African-American (3-4x) gt Caucasian
• Asian
• Hispanic

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Female Preponderance of Autoimmune Disease
Disease
Female/ Male Ratio
Thyroid diseases Diffuse lymphocytic
thyroiditis Goitrous, struma lymphomatosa
(Hashimoto), Hypercellular variant, adult
onset Hypercellular variant, juvenile
onset Fibrous variant Non goitrous
Severe atrophic (myxedema) Mild atrophic
(asymptomatic) Primary hyperthyroidism (Graves
Basedow disease) With benign or no
exophthalmos With progressive
ophthalmopathy
25-501
4-71 41
61 81
4-81 21
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Female Preponderance of Autoimmune Disease
Disease Female/Male Ratio
Systemic lupus erythematosus Rheumatoid arthritis Sjogrens syndrome Idiopathic adrenal insufficiency (autoimmune adrenal disease) Scleroderma Myasthenia gravis Multiple sclerosis 91 2-41 91 2-31 3-41 21 1-51
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Prevalence of SLE

• African-American women 56-283
• Caucasian women 17-71
• African-American men 3-53
• Caucasian men 3-19
• Range of prevalence figures per 100,000 persons
• Systemic lupus erythematosus in Women and
  Health
• (Goldman and Hatch, eds.), pp 704-723, 2000

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Observations to Support Genetic Factors in Lupus

• 1. Clustering in families
• 2. Concordance
• - monozygotic (identical twins)
• 25-30
• - dizygotic 5
• 3. Other autoimmune conditions in family members

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Pathogenesis of SLE
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Pathogenesis of SLE
Ag
Autoantibodies Immune Complexes Tissue Damage
Environmental
T HELPER
B
Genetic
Hormonal
B and T Cell Hyperactivity Defective Immune
Regulation
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Mode of Inheritance
Polygenic (gt95)
Monogenic (lt5)
VS
Homozygous deficiency of C1q 38/41
(93) C4 14/16 (88) C2 38/66 (58)
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Paradox
Complement activation plays a critical role in
the inflammatory process and tissue damage in
SLE, but early complement deficiencies cause SLE.
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Possible Explanations

• 1. C1q clears immune complexes
• 2. C1q binds to and clears apoptotic
• blebs (sources of autoantigens)
• 3. Absence of C1q permits sustained infections
  that could trigger autoimmune response.

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Genes increase susceptibility to SLE
In the major histocompatibility complex
(MHC) C2,C4 deficiency DR2,DR3 TNF-?
polymorphisms In non-MHC C1q deficiency (rare,
but greatest risk!!) Chromosome 1 region 1q41-43
(PARP) region 1q23 (Fc?RIIA,
RIIIA) Polymorphisms in IL-10, IL-6
and mannose-binding protein
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Sources of Autoantigens

• 1. Apoptotic cells
• 2. Activated cells (antigens move to cell
  membrane)
• 3. Modification of proteins during apoptosis
• 4. Infectious agents

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Sources of Autoantigens

• 4. Infectious agents
• - molecular mimicry
• - epitope spreading
• - nonspecific activation of B/T cells
• - infection induced apoptosis

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Environmental Triggers

• Ultraviolet light (photosensitivity)
• Drug-induced lupus
• milder, male female, older ages
• Infectious agents (EBV, CMV)

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Ultraviolet Irradiation Induces Keratinocyte
Apoptosis
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Ultraviolet Irradiation Induces Pro-Inflammatory
Cytokines
TNF? IL1 GMCSF IL8 PGE2 LTB4
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Complement Mediates Clearance of Apoptotic Blebs
TNF? IL1 GMCSF IL8 PGE2 LTB4
Tolerance
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Impaired Clearance of Apoptotic Blebs in SLE
TNF? IL1 GMCSF IL8 PGE2 LTB4
Lymph Nodes Spleen
Auto-Antibody
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Defective Immune Regulation

• B and T-cell hyperactivity
• Sustained autoantigens/impaired clearance of
  apoptotic cells
• Epitope spreading due to lack of turn off
• Exaggerated intracellular response to
  activation

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Defective Immune Regulation

• B and T-cell hyperactivity
• Increased production of pro-inflammatory
  cytokines
• Decreased clearance of immune complexes
• Increased expression of surface molecules
  that increase B/T- cell activation (CD40L)

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CD40L-CD40 Interactions
TCR
T-cell
B Cell
CD3
CD40
CD40L (gp39)
CD40 B-cells, endothelial cells, macrophages,
Ag-presenting cells, renal parenchymal, tubular,
etc cells
CD40L T-cells, platelets