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Autoimmune Diseases and Immune Tolerance

Lagarteja, Regrine
MICRO 202

Autoimmune Diseases
Criteria, Pathogenesis, Types

Autoimmune Disease
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Lack of recognition of self from non-self Diseases that arise from an inapppropriate response of the body against substances and tissues normally present in the body

Witebsky postulates
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Source: nfs.unipv.it

Pathogenesis
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Sex MHC Haplotype Self reactive T-cell clones not destroyed Polyclonal B-cell activation Molecular mimicry Others:
Hormones Environment Defect in NK cells Secretion of Cytokines

Immunological Tolerance
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Definition:

specific unresponsiveness to an antigen that is induced by exposure of lymphocytes to that antigen (implies antigen specificity, in contrast to nonspecific immunosuppression)
All individuals are tolerant of their own antigens (selftolerance); breakdown of self-tolerance results in autoimmunity Therapeutic potential: Inducing tolerance may be exploited to prevent graft rejection, treat autoimmune and allergic diseases, and prevent immune responses in gene therapy, perhaps stem cell transplantation

Significance:

The immunological equilibrium: balancing lymphocyte activation and control


Activation Effector and memory T cells Tolerance Regulatory T cells

Normal: reactions against pathogens Pathologic: inflammatory disease, e.g. caused by reactions against self

No response to self Controlled response to pathogens

Source: Lecture slide from Abbas

Source: Lecture slide from Abbas

Central Tolerance
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Source: Lecture slide from Abbas

Peripheral Tolerance
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Source: Lecture slide from Abbas

T-cell Anergy
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Source: Lecture slide from Abbas

Tregs
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Source: Lecture slide from Abbas

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Source: Lecture slide from Abbas

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Source: Scientific American Sept. 1993 issue

Genetic Basis of Autoimmunity


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Genome wide association studies are revealing genetic polymorphisms associated with autoimmune diseases

Crohns disease:

NOD-2: microbial sensor in intestinal epithelial and other cells IL-23 receptor: involved in TH17 responses PTPN-22 (tyrosine phosphatase): may control kinasedependent lymphocyte activation CD25 (IL-2 receptor): role in T cell activation and maintenance of regulatory T cells

Rheumatoid arthritis, others:

Multiple sclerosis, others:

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Source: Lecture slide from Abbas

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Source: Abbas Basic Immunology 2nd Edition

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AUTOIMMUNE DISORDERS
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SYSTEMIC ORGAN-SPECIFIC

Systemic Lupus Erythematosus


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Chronic systemic inflammatory disease marked by alternating exacerbations and remissions 10:1 More common among African Americans

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About 90% of SLE sufferers are women while about 10% are men and children. About 90% of women with SLE are in their childbearing years, within the range of 15 to 50 years old. Ratio of SLE sufferers : In the West, among Afro-Carribeans 1 in 250500 people USA - 1 in 2,000 people China - 1 in 1,000 people

Associated Risk Factors


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HLA DR and DQ Inherited deficiencies of complement components C1q, C2, and C4 Abnormalities of Fcy receptor UV light Hormones Estrogen-containing contraceptives

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Source: doctortripster.com

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Symptoms
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SYMPTOMS Achy joints / arthralgia Fever of more than 100 degrees F / 38 degrees C Arthritis / swollen joints Prolonged or extreme fatigue Skin Rashes Anemia Kidney Involvement Pain in the chest on deep breathing / pleurisy Butterfly-shaped rash across the cheeks and nose Sun or light sensitivity / photosensitivity Hair loss Abnormal blood clotting problems Fingers turning white and/or blue in the cold Mouth or nose ulcers

PERCENTAGE (%) 95 90 90 81 74 71 50 45 42 30 27 20 17 12

Diagnosis
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Clinical
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of 11 criteria must be present


Discoid rash Oral ulcer Serositis Neurological disorders Immunologic disorders

Malar rash Photosensitivity Arthritis Renal Disorder Hematologic Disorder Presence of ANA

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Immunologic Findings
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LE cell

Source: American Society of Rheumatology

Immunologic Findings
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Antinuclear Antibodies (ANA)

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Rheumatoid Arthritis
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Chronic, symmetric, erosive arthritis of the peripheral joints Associated with MHC Class II genes

Rheumatoid Arthritis

Description

Morning stiffness Arthritis of 3 or more joints Arthritis of hand joints Symmetric arthritis Rheumatoid nodules Serum rheumatoid factor Radiographic changes

A person shall be said to have rheumatoid arthritis if he or she has satisfied 4 of 7 criteria, with criteria 1-4 present for at least 6 weeks

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Immunologic Findings
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Immunologic Findings
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Interleukin 1, 6, 8

Transport of WBC to the affected area

TNF-

Destruction of CT, cartilage, bone

Collagenase and other tissue degrading enzymes

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Source: nutritionremarks.com

Rheumatoid Factor
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Source: American College of Rheumatology

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Other autoantibodies found in RA

Anti-CCP (Cyclic Citrullinated Peptides)


Antiperinuclear
Antifilaggrin Anti-Sa

antibody

antibody

Type 1 Diabetes Mellitus


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Other names:
Autoimmune

Diabetes Mellitus Insulin-Dependent Diabetes Mellitus Juvenile Onset Diabetes

Definition
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Type of Diabetes Mellitus that results from autoimmune destruction of beta cells of Islets of Langerhans, causing insufficient insulin production Differentiated from Diabetes Mellitus by:
GADA-

Glutamic Acid Decarboxylase Antibodies ICA- Islet Cell Autoantibodies IA-2- Insulinoma Associated Autoantibodies ZnT8- Zinc Transporter Autoantibodies

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Risk Factors
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Genetic Predisposition HLA Class II Association


and/or DR-3 positive association DR-15- negatively associated
HLA-DR4

Presence of other autoimmune disease


Pernicious

Anemia, Addisons Disease, Autoimmune Thyroid Disease

Lymphocytic Infiltration of the Islets of Langerhans

Diagnostic Criteria
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Fasting glucose level at or above 7.0 mmol/L (125 mg/dL) Plasma glucose at or above 11.1 mmol/L (200 mg/dL) two hours after a 75 g oral glucose load in a glucose tolerance test Symptoms of hyperglycemia and causal plasma glucose at or above 11.1 mmol/L Glycated Hemoglobin (HbA1c) at or above 6.5

Multiple Sclerosis
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Source: Wikipedia

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Dr. Agawals PPT slides

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Source: Wikipedia

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Source: Wikipedia

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Myasthenia Gravis
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Myasthenia Gravis
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Autoimmune disease affecting the neuromuscular junction Not a brain disorder brain functions normally Characterized by fluctuating muscle weakness and fatigability Disease may be generalized or ocular specific

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Src: Dr. Charles PPT on Autoimmune Disorders

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Src: Dr. Charles PPT on Autoimmune Diso

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From Dr. Agawals Slides on Autoimmunity

Diagnosis
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Edrophonium test (Tensilon) Blood analysis Repetitive nerve stimulation Single-fiber electromyography (EMG) Imaging scans

Signs and Symptoms


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Affects any of the muscles that you control voluntarily, certain muscle groups are more commonly affected than others

Eye, face, throat, neck, limb muscles

Difficulty speaking (dysarthria) Difficulty swallowing (dysphagia), Drooping eyelids (ptosis) Double vision (diplopia) Nasal-sounding speech and weak neck muscles that give the head a tendency to fall forward or backward.

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Other Autoimmune Diseases

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Source: Scientific American Sept. 1993 issue

Pernicious Anemia
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Turgeon, ML., Clinical Hematology

Graves Disease

Symptoms of Hyperthyroidism
Heat

intolerance Increased metabolism and weight loss Palpitations Fatigue Nervousness Ophthalmia
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