“SLE: Fighting Self Sabotage”

Feb. 2005Immunology in health and Disease

Susan Manzi, MD, MPH

Associate Professor of Medicine and Epidemiology

Co-Director Lupus Center of Excellence

ObjectivesI. 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 7:1– Childbearing 12:1– Children, elderly 2:1

African-American (3-4x) > CaucasianAsianHispanic

Female Preponderance of

Autoimmune Disease

25-50:1

4-7:1

4:1

6:1

8:1

4-8:1

2:1

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

Female/ Male Ratio

Disease

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: 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

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

Genetic

Environmental

Hormonal

THELPER

Ag Autoantibodies

Immune Complexes

Tissue Damage

B

B and T Cell Hyperactivity

Defective Immune Regulation

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 deficiencyDR2,DR3TNF- polymorphisms

In non-MHCC1q deficiency (rare, but greatest risk!!)Chromosome 1 region 1q41-43 (PARP)

region 1q23 (FcRIIA,

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

TNFIL1GMCSFIL8PGE2LTB4

Complement Mediates Clearance of Apoptotic Blebs

TNFIL1GMCSFIL8PGE2LTB4

Tolerance

C3C3

C3

C3

C3

C4

C4

C4

C4

C4 C4

C4

C4

C4

C3

C3C3

C3C4

C4

Impaired Clearance of Apoptotic Blebs in SLE

Lymph NodesSpleenAuto-Antibody

TNFIL1GMCSFIL8PGE2LTB4

C3C3

C3

C3

C3

C4

C4

C4

C4

C4 C4

C4

C4

C4

C3

C3C3

C3C4

C4

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

T-cellB

Cell

CD40 CD40L (gp39)

TCR

CD3

CD40: B-cells, endothelial cells, macrophages, Ag-presenting cells, renal parenchymal, tubular, etc cells

CD40L: T-cells, platelets