Autoimmune Diseases 202

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Autoimmune Diseases and Immune

Tolerance

Lagarteja, Regrine

MICRO 202


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Criteria, Pathogenesis, Types

Autoimmune Diseases2


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Autoimmune Disease

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

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Witebsky postulates

Source: nfs.unipv.it

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Pathogenesis

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

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Immunological Tolerance

Definition:

specific unresponsiveness to an antigen that isinduced by exposure of lymphocytes to that antigen(implies antigen specificity, in contrast to non-

specific immunosuppression) Significance:

All individuals are tolerant of their own antigens (self-tolerance); breakdown of self-tolerance results in

autoimmunity Therapeutic potential: Inducing tolerance may be

exploited to prevent graft rejection, treat autoimmuneand allergic diseases, and prevent immuneresponses in gene therapy, perhaps stem cell

transplantation

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Normal: reactions against pathogensPathologic: inflammatorydisease, e.g. caused by reactionsagainst self

ToleranceRegulatory T cells

No response to selfControlled response to pathogens

The immunological equilibrium: balancinglymphocyte activation and control

ActivationEffector and memory Tcells

Source: Lecture slide from Abbas8


9/62Source: Lecture slide from Abbas

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Central Tolerance

Source: Lecture slide from Abbas

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T-cell Anergy12



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Tregs


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Source: Scientific American Sept. 1993 issue15


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Genetic Basis of Autoimmunity16

Genome wide association studies are revealinggenetic polymorphisms associated withautoimmune diseases

Crohnsdisease: NOD-2: microbial sensor in intestinal epithelial and other

cells

IL-23 receptor: involved in TH17 responses

Rheumatoid arthritis, others:

PTPN-22 (tyrosine phosphatase): may control kinase-dependent lymphocyte activation

Multiple sclerosis, others: CD25 (IL-2 receptor): role in T cell activation and

maintenance of regulatory T cells


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Source: Abbas Basic Immunology 2ndEdition19


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AUTOIMMUNE DISORDERS

- SYSTEMIC

- ORGAN-SPECIFIC

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Systemic Lupus Erythematosus

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 whileabout 10% are men and children.

About 90% of women with SLE are in their

childbearing years, within the range of 15 to 50years old.Ratio of SLE sufferers :In the West, among Afro-Carribeans 1 in 250-

500 peopleUSA - 1 in 2,000 peopleChina - 1 in 1,000 people

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Associated Risk Factors

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.com24


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Symptoms

SYMPTOMS PERCENTAGE (%)

Achy joints / arthralgia 95

Fever of more than 100 degrees F / 38 degrees C 90

Arthritis / swollen joints 90

Prolonged or extreme fatigue 81

Skin Rashes 74

Anemia 71

Kidney Involvement 50

Pain in the chest on deep breathing / pleurisy 45

Butterfly-shaped rash across the cheeks and nose 42

Sun or light sensitivity / photosensitivity 30

Hair loss 27

Abnormal blood clotting problems 20

Fingers turning white and/or blue in the cold 17

Mouth or nose ulcers 12

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Diagnosis

Clinical

4 of 11 criteria must be present

Malar rash Discoid rash

Photosensitivity Oral ulcer

Arthritis Serositis

Renal Disorder Neurological disorders

Hematologic Disorder Immunologic disorders

Presence of ANA

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Immunologic Findings

LE cell

Source: American Society of Rheumatology

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Antinuclear Antibodies (ANA)

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Rheumatoid Arthritis

Chronic, symmetric, erosive arthritis of the

peripheral joints

Associated with MHC Class II genes

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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 ifhe or she has satisfied 4 of7 criteria, with criteria 1-4present for at least 6 weeks

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Immunologic Findings34


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Destruction

of CT,cartilage,

bone

TNF-

Interleukin 1,6, 8

Transport ofWBC to the

affected area

Collagenaseand other

tissuedegrading

enzymes

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Source: nutritionremarks.com

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Rheumatoid Factor

Source: American College of Rheumatology

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Other a toantibodies fo nd in


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Other autoantibodies found in

RA

Anti-CCP (Cyclic Citrullinated Peptides)

Antiperinuclear antibody

Antifilaggrin

Anti-Sa antibody

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Type 1 Diabetes Mellitus

Other names:

Autoimmune Diabetes Mellitus

Insulin-Dependent Diabetes Mellitus

Juvenile Onset Diabetes

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Definition40

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 Factors43

Genetic Predisposition

HLA Class II Association

HLA-DR4 and/or DR-3positive association

DR-15- negatively associated

Presence of other autoimmune disease

Pernicious Anemia, Addisons Disease,

Autoimmune Thyroid Disease Lymphocytic Infiltration of the Islets of

Langerhans


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Diagnostic Criteria44

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 glucoseload 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


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Multiple Sclerosis45

Source: Wikipedia


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46 Dr.AgawalsPPT slides


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47 Source: Wikipedia


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48 Source: Wikipedia


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Myasthenia Gravis50


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Myasthenia Gravis51

Autoimmune disease affecting the

neuromuscular junction

Not a brain disorderbrain functions normally

Characterized by fluctuating muscle weaknessand 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 Dis


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54 From Dr.AgawalsSlides on Autoimmunity


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Diagnosis55

Edrophonium test (Tensilon)

Blood analysis

Repetitive nerve stimulation

Single-fiber electromyography (EMG)

Imaging scans


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Signs and Symptoms56

Affects any of the muscles that you controlvoluntarily, certain muscle groups are morecommonly 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 orbackward.


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Other Autoimmune Diseases57


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Source: Scientific American Sept. 1993 issue58


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Pernicious Anemia59


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60 Turgeon, ML., Clinical Hematology


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Graves Disease

Symptoms of

Hyperthyroidism

Heat intolerance

Increasedmetabolism and

weight loss

Palpitations

Fatigue

Nervousness

Ophthalmia

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Autoimmune Diseases 202

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