Transcript Who Gets Lupus?

“SLE: Fighting Self Sabotage”
Feb. 2005
Immunology in health and Disease
Susan Manzi, MD, MPH
Associate Professor of Medicine and
Epidemiology
Co-Director Lupus Center of Excellence
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
Who Gets Lupus?
Females > Males
– Childbearing
– Children, elderly
7:1
12:1
2:1
African-American (3-4x) > Caucasian
Asian
Hispanic
Female Preponderance of
Autoimmune Disease
Disease
Female/
Male Ratio
Thyroid diseases
Diffuse lymphocytic thyroiditis
Goitrous, struma lymphomatosa (Hashimoto),
Hypercellular variant, adult onset
25-50:1
Hypercellular variant, juvenile onset
4-7:1
Fibrous variant
4:1
Non goitrous
Severe atrophic (myxedema)
6:1
Mild atrophic (asymptomatic)
8:1
Primary hyperthyroidism (Graves Basedow disease)
With benign or no exophthalmos
4-8:1
With progressive ophthalmopathy
2:1
Female Preponderance of
Autoimmune Disease
Disease
Female/Male
Ratio
Systemic lupus erythematosus
Rheumatoid arthritis
Sjogren’s syndrome
Idiopathic adrenal insufficiency
(autoimmune adrenal disease)
Scleroderma
Myasthenia gravis
Multiple sclerosis
9:1
2-4:1
9:1
2-3:1
3-4:1
2:1
1-5:1
Prevalence of SLE
•
•
•
•
African-American women:
Caucasian women:
African-American men:
Caucasian men:
56-283
17-71
3-53
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
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
Pathogenesis of SLE
Pathogenesis of SLE
Environmental
Genetic
Ag
T
HELPER
Autoantibodies
B
Hormonal
B and T Cell
Hyperactivity
Defective Immune
Regulation
Immune
Complexes
Tissue Damage
Mode of Inheritance
Polygenic (>95%)
VS
Monogenic (<5%)
Homozygous deficiency of:
C1q
38/41 (93%)
C4
14/16 (88%)
C2
38/66 (58%)
Paradox
Complement activation plays a critical
role in the inflammatory process and
tissue damage in SLE, but early
complement deficiencies cause SLE.
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.
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
Sources of Autoantigens
1. Apoptotic cells
2. Activated cells (antigens move to cell
membrane)
3. Modification of proteins during
apoptosis
4. Infectious agents
Sources of Autoantigens
4. Infectious agents
- molecular mimicry
- epitope spreading
- nonspecific activation of B/T cells
- infection induced apoptosis
Environmental Triggers
Ultraviolet light (photosensitivity)
Drug-induced lupus
milder, male =female, older ages
Infectious agents (EBV, CMV)
Ultraviolet Irradiation Induces
Keratinocyte Apoptosis
Ultraviolet Irradiation Induces
Pro-Inflammatory Cytokines
TNF
IL1
GMCSF
IL8
PGE2
LTB4
Complement Mediates
Clearance of Apoptotic Blebs
TNF
IL1
GMCSF
IL8
PGE2
LTB4
C4
C3
C3
C4
Tolerance
C4
C3
C4
C4
C4
C3
C4
C4
C3
C3
C4
C3
C4
C3
C4
C3
Impaired Clearance of
Apoptotic Blebs in SLE
TNF
IL1
GMCSF
IL8
PGE2
LTB4
C4
C3
C3
Lymph Nodes
Spleen
Auto-Antibody
C4
C4
C3
C4
C4
C4
C3
C4
C4
C3
C3
C4
C3
C4
C3
C4
C3
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
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)
CD40L-CD40 Interactions
TCR
B
Cell
T-cell
CD3
CD40
CD40L (gp39)
CD40: B-cells, endothelial cells,
macrophages, Ag-presenting cells,
renal parenchymal, tubular, etc cells
CD40L: T-cells,
platelets