Pathophysiology of Lupus - Stebulis Flashcards
What are the 11 criteria considered in the diagnosis of lupus
A RAIN SHOP MD
Arthritis
Renal disorder
Antinuclear antibodies
Immunologic disorder
Neurologic disorder
Serositis
Hematologic disorder
Oral ulcers
Photosensitivity
Malar rash
Discoid rash
If four of these criteria are present within the course of disease, a dx of SLE can be made with 98% specificity and 97% sensitivity
SLE epidemiology
Onset?
F/M ration
Ethinicity
Majority of onset between 16 and 55
mostly in females (of child bearing years)
US Blacks and hispanics > Caucasians
What causes lupus?
Environmental factors
- UV light (increased IL-1 release and decreases in T cell DNA methylation)
- Infection (through molcular mimicry)
- Drugs (hypomethylation and histone deacetylation)
- Stress
- Dilica dust
- Diet (maybe)
Hormonal factors
- Estrogen containing OCP, early marnachy and postmenopausal HRT increase risk of SLE. But OCPs in stable SLE do not increase flares
- Pregnancy exacerbates SLE, but breast feeding reduces risk
- The X chromosome itself may increase risk of SLE
Genetics
- Genetics play a role but they are not the whole story. 25% concordance in identical twins. 8 fold increased risk in first degree relative (2-5% risk)
- Genes important in SLE
- FCGRs - cleareance of immunu complexes
- HLA-DRs - antigen presentation
- MBLs - Antigen presentatin and immune complex clearence
What are the genetic abnormalities in SLE?
- Presentation and clearence of antigens
- MHC - HLA DR3, HLA DR2
- Complement deficiencies - C1q, C2, C4 (important for clearence of antigens)
- Phagocytic function
- B and T cell activation and survival
- Altered cytokine expression
- Increased levels of pro-inflammatory cytokines (IFN-alpha, IL-10)
- Reduction in IL-2 necessary to suppress activation-induced cell death
- Increased BLyS (B lymphocyte stimulator) - -promotes B cell survival and differentiation
Loss of tolerance
What are the three factors involved in SLE immunopathogenesis?
- Autoantibody production
- Widespread immune system dysregulation
- Unrestrained humoral immunity
- Impaired cell-mediated immunity
- Tissue injury
- Autoantibodies
- Immune complexes
- Inflammation
- Cell mediated cytotoxicity
In what way do SLE anitbodies differ from natural antibodies?
- They isotype switch to IgG (natural are IgM)
- Poorly controlled (longer life span and not very much regulated)
- Fix complement
- Cause tissue injury instead of being protective
What are the B cell abnormalities in SLE
- Resistance to apoptosis
- Failure to eliminate autoreactive B cells during development
- Prolonged life span
- Increased numbers of antibody-producing cells
- Hypergammaglobulinemia
- Lower activation threshold
- Augmented calcium responses
- Enhanced production and response to cytokines
What is the central role of B cells in autoimmunity?
- Autoantibody production
- Present self antigen to autoreactive T cells
- Activate T cells via TC
- Maintain T cells in activated state
- Induce T cell proliferation
- Promote entry of T cells into memory compartment
- Cytokine production
- IL-10, IL-6, IFN-α
Explain how T cells are dyregulated in SLE?
- Increased numbers of autoreactive T cells
- Failure of thymic deletion
- Failure of peripheral tolerance (anergy) – lower activation threshold
- Increased expression of adhesion molecules facilitates migration into tissues
-
Exaggerated T helper cell (CD4+) response
- Promote class switching to high affinity IgG antibodies
- Promote B cell differentiation to memory B cells and plasma cells
- Diminished T cell regulatory function
reduced or defective CD8+ and/or NK cell function
Describe the production of pathogenic autoantibodies?
- Nuclear and cytosolic antigens are exposed on blebs of cells undergoing apoptosis
- Reduced clearance of cellular debris
- Deficiency of early complement components reduces opsonization impairs phagocytosis
- Abberent FC receptors on phagocytes
- Lower activation threshold of B and T cells
- Resistance of B cells to apoptosis
- Reduction in numbers and function of regulatory T cells
- Class switching from low affinity IgM autoantibodies to high affinity IgG autoantibodies
What is the role of Anti-nuclear antibodies in Lupus?
They are involved in lupu but pathogenic role is not proven
They are checked in people with suspicion of lupus
But they are also positive wih 5-15% of people without lupus
What are the antibodies involved in lupus?
- DS-DNA antibody ≈60%
- Correlate with disease activity
- Associated with renal disease
- Sm antibody
- Highly specific but low sensitivity
- 30% Afro-Americans, 3-10% caucasions
- Ro (SSA), LA (SSB) antibodies
- SCLE
- Neonatal lupus
- Congential heart block
- Antiphospholipid antibodies
- Arterial and vevnous thrombosis
- Fetal loss
- Antibody to cell surface antigens
- Hemolytic anemia
- Thrombocytopenia
Describe the pathogenesis of tissue injury in in SLE
- Immune complex deposition in tissue (Type III)
- Complement activation and inflammation
- Lupus nephritis rash
- Antibody mediated cytotoxicity (Type II)
- Complement mediated cytotoxicity and phagocytosis
- Anti-erythrocyte, -platelet, -lymphocyte ab’s
- Autoreactive cytotoxic T/NK cells (Type IV)
- Direct pathogenic effect of most autoantibodies is not proven
What is the mechanism of heart block in a fetus of a mother that SLE
- 18-24 wks heart muscle is developing and there is remodelling going on
- during this stage Ro and La are expresed on the surface of ectopic cardiocytes
- IgG antibodies from the mother can pass to the fetus through the placenta and attack the heart causing fibrosis of the fetus heart
- This is what causes the heart block
- This baby does not have lupus
- Cardiac heart block is not reversible
What is the mechanism of thromboembolic events in lupus?
- Antiphospholipid Antibodies (aPL’s) bind plasma proteins, endothelial cells, and platelets resulting in thrombosis
- β-2 glycoprotein I, the most common aPL target, has important anticoagulant activity
- aPL interfere with activated Protein C
- Binding to endothilial cells upregulates cytokines and tissue factor
