OPT 201 - Lecture 8 (Autoimmunity)

Tissue-specific antibody-mediated autoimmune diseases (Type II):

1. Acute rheumatic fever (Step infection induces cross-reactive auto-ab) 2. Pernicious anemia (auto ab block transport of GI molecule) 3. Myasthenia gravis (auto ab blocks muscle function) 4. Graves disease (auto ab stimulates thyroid gland)

From Left to Right, describe the Pathogenesis of SLE

1. DNA and histones released from cells 2. Phagocytized by APCs 3. Activate T-cells 4. Activate B-cells 5. Produce Ab's against Nuclear Antigens

Antigens in Autoimmunity:

1. Sequestered antigens 2. Infectious Disease (Molecular mimicry & Original Insult)

What are the 3 characteristics of Systemic Autoimmune Diseases?

1. Wide range of antigens 2. Widespread damage 3. General defect in immune regulation

When are most people affected by Sjogren's, and what is the female to male ratio?

40-60 yr old; 9:1

Autoimmune Disease Epidemiology (stats)

80+ known illnesses caused by Autoimmunity 50 million affected 8% risk for women 5% risk for men

If a person has HLA-B27, what is their increased risk rate for recurrent Uveitis?

90x

Organ-Specific Autoimmune Diseases are directed against...

A unique antigen in a given organ

Autoimmunity manifests as...

Acute/Chronic Inflammation and Cell Injury

What kinds of damage does Type II Hypersensitivity cause?

Affect normal function of that target organ Induce tissue damage

What diseases is HLA-B27 allele mutation associated with?

Ankylosing Spondylitis -inflammatory fusion of the spine/joints Reactive Arthritis - inflammation of joints, urethria Acute Anterior Uveitis - idiopathic

There are 5 "Anti" associations with Type II Hypersensitivity. What are the auto-antibodies directed at?

Anti-DNA Anti-IgG (Rheumatoid factor) Anti-Phospholipids (Cardiolipin) Anti-Erythrocyte Anti-Lymphocyte

How does Autoimmunity play a role in Myasthenia gravis?

Auto-antibodies block and destroys receptors - typically bind to Acetylcholine receptors in muscle cells

If Faulty Clonal Deletion develops, what happens?

Auto-reactive Lymphocytes aren't eliminated, and allowed to mature Central Tolerance

How does Autoimmunity play a role in Graves disease?

Autoantibodies activate TSH receptors - causes unregulated overproduction of thyroid hormones Breaks feedback loop

Central tolerance and Clonal Deletion both work together to prevent what?

Autoimmunity

SLE targets which organs?

Blood, joints, skin, kidneys, heart, lungs, brain

What Organs and Tissues are mostly affected?

Bone marrow Lining of Joints Blood Vessels CT Endodrine glands Kidneys Muscles Skin

Cells and Flare, what is it?

Cells are leukocytes within the anterior chamber and have an appearance similar to dust in a beam of light, and flare is protein in the same region, it appears finer, like smoke.

Describe SLE (lupus):

Chronic, multi-system inflammatory disease Type III hypersensitivity

What do Non-HLA alleles release to cause Autoimmunity?

Co-stimulatory molecules Cytokines

What are some Type IV Organ-Specific hypersensitivities?

Crohn's Disease Type I Diabetes

What are the Ocular Manifestations of Type IV Hypersensitivities? (4)

Crohn's Disease: Uveitis, Episcleritis, Scleritis Multiple Sclerosis: Optic neuritis Sjogren's Syndrome: Keratoconjunctivitis sicca Giant-Cell Arteritis: Amaurosis fugax

What determines Allergic vs. Autoimmune Hypersensitivity?

Depends on antigen and duration of response

What are the Ocular Manifestations of Myasthenia gravis?

Diplopia Ptosis Blurred vision

What are the characteristics of Allergy?

Environmental Antigen and Limited

What are the characteristics of Autoimmunity?

Environmental Trigger and Chronic

Autoimmunity can be cured for most (T/F)

F

There is only one gene that causes Autoimmune diseases (T/F)

F; hence why its Multigenic

SLE has a bunch of freakin' manifestations in the body! Need 4 to be officially diagnosed. What are the 11 main symptoms?

Facial rash, discoid rash, photosensitivity, oral or nasopharyngeal ulcers, non-erosive arthritis, serositis, renal disorders, neurological disorders, hematologic disorders, immunologic disorders, and presence of anti-nuclear Ab (ANA)

What occurs with the breakdown of Central and Peripheral Tolerance?

Faulty clonal deletion Loss of Treg-cells Aberrant expression of HLA-class II molecules (Peripheral Tolerance)

What is the breakdown of tolerance that leads to Autoimmunity? (Left to right)

Genes ->Hormonal ->Enviro. Triggers

What is an example of Organ-Specific Autoimmune Disease?

Graves Disease causing TSH receptor saturation via Auto-Ab's in the Thyroid

Mutation in HLA-DR allele is associated with what diseases?

HLA DR2 & MS HLA DR3 & Myasthenia Gravis HLA DR4 & Rheumatoid arthritis

19%-88% of people with recurrent Uveitis have...

HLA-B27

Genetic Factors of Autoimmunity (2)

HLA-B27: Class I MHC Non-HLA alleles

Post Streptococcal Autoimmunity can lead to what bodily issues?

Heart damage, Joint problems, CNS problems

Where is the MHC Class I gene found in the human genome?

Human Chromosome 6

Loss of Treg cells occurs, what happens?

Hyper-responsive T and B lympocytes Prolonged Immune Reaction Peripheral Tolerance

What is Autoimmunity?

Hypersensitivity reactions directed at self-antigens

What are the 4 disease etiologies associated with Uveitis?

Idiopathic Infection Injury Autoimmune disorders*

What are manifestations of recurrent Uveitis?

Infection, Hypopyon, Cells and Flare (inflamm. in anterior chamber)

What is Uveitis?

Inflammation of the Uvea

90% of Lupus patients have...

Joint problems

What 3 things can cause Autoimmunity?

Multigenic Hormonal Environmental Triggers

Name the diseases classified as Autoimmune Diseases (8)

Multiple Sclerosis Lupus Type I Diabetes Type 2 Diabetes Graves Rheumatoid Arthritis IBD Celiac

Myasthenia gravis causes...

Muscle dysfunction

What are some Type II Organ-Specific hypersensitivites?

Myasthenia Gravis Hasimoto's Thyroiditis Pernicious Anemia

Where are Sequestered Antigens located?

Not typically exposed to IS, Found in Immunoprivleged organs like the Eye, Testes, CNS

SLE produces Ab's against...

Nucleic acids, Erythrocytes, Lymphocytes, Platelets, Coagulation proteins, Phospholipids

What is Molecular Mimicry?

Pathogenic antigen is very similar to Self-antigens -> Immune system creates IR to pathogen -> Ab's created to battle pathogen now go on to start attacking the very similar Self-antigens

Molecular mimicry leads to...

Post streptococcal autoimmunity - via Fimbrial Antigen M Protein & Peptidoglycan (cell wall) Fancy word for Strep Throat

Where are MHC II molecules found?

Professional APCs only

What are the Ocular Manifestations of Graves disease?

Proptosis Periorbital edema Abnormal EOMs Exposure keratopathy Optic nerve compression

Infectious initiation of Type III causes what diseases?

Reactive arthritis Poststreptococcal glomerulonephritis

Most common Ocular Manifstation of SLE patients?

Retinal Vasculopathy, typically observed as Cottonwool spots

Which autoimmune disease is considered a Type III and IV Hypersensitivity?

Rheumatoid Arthritis

Cell-mediated Autoimmune Diseases ( Type 4):

Rheumatoid Arthritis Crohn's Disease Multiple Sclerosis Type I Diabetes

Undetermined initiation of Type III causes what diseases?

SLE Rheumatoid Arthritis

What does Sjogren's Syndrome target in the body?

Salivary and Lacrimal glands

What are the Ocular Manifestations of SLE?

Secondary Sjogren Syndrome Uveitis (rare) Episcleritis/Scleritis Neuro-Ophthalmic lesions Retinal vasculopathy Bull-eye maculopathy

What are some examples of Systemic Autoimmune Diseases?

Systemic Lupus Erythematosus (SLE) Multiple Sclerosis Scleroderma

What is Sjogren's Syndrome Pathogenesis?

Systemic autoimmune dieases Lymphocytic infiltrations Auto-Abs play a role Clinically: Look for Dry Eye damage (Keratoconjunctivitis Sicca) superficially and Increased tooth decay from Dry Mouth (Xerostomia)

Autoimmune complex-mediated diseases (Type 3)

Systemic lupus erythematosus (SLE) Rheumatoid arthritis Reactive arthritis Poststreptococcal glomerulonephritis

Autoimmunity is a type of Hypersensitivity (T/F)

T

Estrogen is a strong Autoimmunity promoter (T/F)

T

Sjogren's Syndrome has two forms (T/F)

T

TSH comes from what structure?

Thyroid Stimulating Hormone comes from the Pituitary gland

Name 4 types of Autoimmune Hypersensitivity

Type I: Allergic Hypersensitivity Type II: Auto-Ab against Self-Antigens Type III: Auto-Ab:Ag immune complexes Type IV: Auto-reactive T-cells These can all combine

What are the Ocular Manifestations of Type III Hypersensitivites?

Uveitis (SLE & Reactive arthritis) Peripheral Ulcerative Keratitis (Rheumatoid arthritis & Polyarteritis nodosa) Keratoconjunctivitis sicca (Sjogren's Syndrome)

75% of Autoimmune patients are...

Women; one of the top 10 killers of women under 65

How many cases of SLE are reported each year, and what is the male vs. female susceptibility?

~160k per year 90% women 20-40 yrs old Female:Male = 10:1

How many are affected by Sjogren's Syndrome?

~4 million