Post on 04-Jun-2018
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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
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Central Tolerance
Source: Lecture slide from Abbas
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T-cell Anergy12
Source: Lecture slide from Abbas
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Tregs
Source: Lecture slide from Abbas
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Source: Lecture slide from Abbas14
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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: Lecture slide from Abbas17
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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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Immunologic Findings
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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Immunologic Findings
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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