Lecture 7: Challenge to the System - Autoimmune Diseases part 2

Breaking Tolerance: Environmental Factors

• Infections:

1. Damaging barriers → release sequestered antigens

2. Superantigens → released by microbes→ don’t require costimulation

3. Significant Inflammation → increased cytokine production

4. Inflammatory cytokines can activate autoreactive lymphocytes

•Drugs- procainamide- can induce lupus

•Foods- gluten

•Appropriate immune response to microbial infection that mimic host antigens (antibody cross-reactivity). Guillain Barre--> human gangliosides that look like Camplobacter jejuni lipopolysaccharides→ microbial antigens evolve to resemble host antigens to evade host immune response

Molecular Mimicry

Breaking Tolerance: Susceptibility Genes

Multiple genes involved

• HLA Alleles (MHC):

1. Don't display self-antigens properly to maturing T-cells in thymus

2. Unusually high affinity for binding self-antigens

3. Cross-reactive antigen presentation (molecular mimicry)

• Non-HLA Genes:

1. Rheumatoid Arthritis/Graves/Systemic Lupus Erythrematous: PTPN22 gene polymorphisms

2. Encodes Lyp: Lymphoid tyrosine phosphatase

3. Normal function: Brake on T-cell and B-cell receptor signaling to prevent overactivation

4. Mutation leading to autoimmunity: Gain-of-function- suppresses the immune receptor signaling too strongly; disrupts negative selection' process in thymus- autoreactive T-cells in circulation

Systemic Lupus Erythematosus (SLE)

• Hallmark Characteristic:

1. Development of autoantibodies that bind dsDNA

2. Often preceded by viral illness

3. Range of symptoms and disease severity vary greatly among individuals

4. MHC genes & deficiencies in complement strongly associated (clearing apoptotic cells)

5. Major propensity for females (9:1 vs. males); role for hormones

Type 1 Diabetes Mellitus

• Genetic Susceptibility:

1. HLA-DR3 & DQ8 genes

2. Polymorphisms in CTLA-4

3. * < 10% progress to clinical disease

• Exogenous Triggers:

1. Viral infections: congenital rubella

2. Foods-early exposure cow milk proteins (bovine insulin)

• Environmental triggers in an individual with genetic predisposition leads to infiltration of the pancreatic islets with CD4+ and CD8+ T-cells, B-cells, and macrophages, and the production of autoantibodies

• CD4+/CD8+ cells induce apoptosis of beta cells in pancreas

• Clinical expression of disease only after 90% of B-cells in pancreas are destroyed.

Multiple Sclerosis

• Demyelinating disease

• Neurologic deficits: relapsing course followed by progressive phase

• More common in females (2:1 vs. males)

• More in temperate climates

• Relapses after viral respiratory tract infections

• Characterized by myelin-reactive T-Cells

• Genetic predisposition. HLA-DR2 and DQ6

Celiac Disease

• Genetically predisposed individuals

• Environmental cause is known: Gluten

• Gliadin-primary antigen leading to inflammation

• HLA phenotype: HLA-DQ2 or DQ8-–necessary for development; not sufficient for developing disease

Population Based Surveillance

• NHANES serum data to assess prevalence of autoimmunity in the US

• Thyroid autoantibodies present in 18% of US adults, 10 % of younger adults and 25% of older adults

• 32% of adults >60 years old had at least one of the 4 autoantibodies studied:

1. Rheumatoid factor

2. Anti-thyroidoglobulin or anti-thryroperoxidase,

3. Anti-tissue transglutaminase autoantibodies

Estimated Prevalence of Antinuclear Antibodies

• *Frequent screening assay for autoimmune diseases

• Period 1: 1988-1991

• Period 2: 1999-2004

• Period 3: 2011-2012

Autoimmune Disease: Diagnostics

• Considerations:

1. Non-specific symptoms differ from individual to individual

2. Medical history, Physical examinations, Laboratory tests, Diagnostic Imaging, Biopsies

• Historical starting point: Detection of autoantibodies:

1. Not sufficient to diagnose; define presence of autoimmunity

2. Oftentimes are excellent predictors of disease because of their persistence

3. Traditionally detection of antibodies using ELISA & Western Blotting

4. Can be expensive, time consuming, tests require expertise and not very sensitive

Autoimmune Disease: Therapeutics

• Complement Dependent Cytotoxicity (CDC): Monoclonal antibodies engineered to bind specific antigens on surface of target T and B cells—activates the complement cascade→ destroy target cell

• Antibody-dependent cellular cytotoxicity (ADCC): Monoclonal antibodies engage natural killer cells recognize and target T and B cells in antigen specific manner

Further Considerations of Autoimmune Disease

• Understanding risk factors:

1. Changes in exposures to foods, air pollution, infections, stress, climate change

2. Difficult task to determine doses, duration and effects of environmental factors

• Improve preventative approaches:

1. How?

2. Is this feasible based on the molecular basis of these types of diseases?