Gender Differences in Immune Response

Females resist a variety of infections better than males ???

Females may reject transplanted organs more rapidly

Females have a higher frequency of autoimmune diseases

Evidence to Support Hormone Rolein Human Lupus

Female predominance

Disease during pregnancy, menses

Levels of androgen in women with lupus

Frequency of lupus in Klinefelter (XXY) men

Disease with estrogen administration ?

Evidence to Support Hormone Rolein Murine Lupus

Mouse model lupus (NZB x NZW) disease identical to human F > M

Female mice die earlier than males

Male castration and estrogen accelerates disease

Male sex hormones delay onset of lupus in female mice

Role of Hormones on Immune Function

Male hormones (androgen) suppress

Female hormones (estrogen) enhance

CRITERIA FOR THE DIAGNOSIS OF SLE(As revised in 1997 by the American College of Rheumatology)

A person is said to have SLE if four of these criteria are present at any time:Skin criteria• Butterfly rash (lupus rash over the cheeks and nose)• Discoid rash (thick rash that scars, usually on sun-exposed areas• Sun sensitivity• Oral ulcerationsSystemic criteria• Arthritis• Serositis• Proteinuria or cellular urinary casts• Seizures or psychosis with no other explanation

Diagnostic ChallengesCon

1. Interpretation of criteria

2. Manifestations not in criteria

3. Other diseases may mimick lupus

4. Evolving symptoms over time

5. Patients may present very differently

Disease Mimickers

• Sjogren’s syndrome

• Fibromyalgia (+ ANA)

• Early rheumatoid arthritis

• ITP

• Primary antiphospholipid syndrome

• Drug-induced lupus

Natural History of SLE

• Disease flares/activity (reversible)

• Organ damage (irreversible) disease

treatment

Time (years)1 2 3 4 5 6 7 8

SLEActivity

SLEDamage

SLE Activity vs Damage

Activity

Nephritis

Inflammation and

medications

Damage

Renal failure/scar

Osteoporosis/Fx

Ovarian failure

Myocardial infarction

Autoantibody Determined Clinical Subsets of SLE

RNP

SSA (Ro)SSB (La)

dsDNA

ANA (+)>95% patientsANA + > 90%, nonspecific

Ribosomal-P

phospholipids

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

Autoantibody Determined Clinical Subsets of SLE

SSA/SSB (rash and neonatal lupus, dry eyes and mouth)

dsDNA (kidney disease)Ribosomal-P(CNS, psychosis)

Phospholipid(clotting and

miscarriage)

RNP(Raynauds)

Pathogenesis of SLE

Current Standard Therapy

Mild to Moderate Disease Therapy

arthritis photoprotectionfever NSAIDpleurisy corticosteroidspericarditis methotrexatecutaneous antimalarials

topical agentsphysical therapy

Current Standard Therapy

Moderate to Severe Disease Therapy

nephritis corticosteroidsvasculitiscyclophosphamidepneumonitis azathioprineCNS cyclosporinehematologic IVIg

plasmapheresis ??? mycophenylate mofetil

Novel Therapies Immunosuppressants

T cells

B cells

Complement

Cytokine

Hormonal

Immunoablation

Lupus Center of Excellence 2004

Lupus Center of Excellence 2003