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MBBS II HIS > L25 - Autoimmune diseases > Flashcards

L25 - Autoimmune diseases Flashcards

1
Q

Describe the selection process in central tolerance?

A

Immature clones of autoreactive lymphocytes = highly specific to self-antigens

> > bind to self-antigen in primary lymphoid organs

> > negative selection and clonal deletion

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2
Q

Describe the mechanism of self-antigen expression in thymic epithelial cells?

A

AIRE (autoimmune regulator):

regulates gene transcription

> > stimulates medullary thymic epithelial cell to express tissue-restricted antigens TRAs

> > Auto-immune T cells react strongly with TRA

> > apoptosis

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3
Q

List 3 distinct processes of peripheral tolerance?

A

Mature autoreactive lymphocytes bind to self-antigen in peripheral lymphoid organs:

  1. Clonal anergy
  2. Regulatory T (Treg) cells suppression
  3. Deleted: activation-induced self death (negative feedback)
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4
Q

Mechanism of clonal anergy in peripheral tolerance?

A

Autoreactive lym. mature and leave to peripheral lymphoid organs

> > Functionally unresponsive/ tolerized to self- antigen

> > No co-stimulation signal for activation

> > death

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5
Q

Mechanism of Treg in peripheral tolerance?

A

Treg makes suppressive cytokines = TGFβ, IL-10***

> > actively suppress autoreactive T cells

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6
Q

Pathology arising from breakdown of central tolerance/ disruption of AIRE? List symptoms?

A

Disruption of AIRE = no negative selection = APECED
(Autoimmune Polyendocrinopathy-Candidiasis Ectodermal Dystrophy)

Diseases:
 Hypoparathyroidism
 Primary adrenocortical failure
 Chronic mucocutaneous candidiasis

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7
Q

Pathology arising from breakdown of Treg in peripheral regulation?

A

IPEX = immune dysfunctions:

Lymphoproliferative, autoimmune, allergic disorders

(polyendocrinopathy, enteropathy)

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8
Q

Genetic cause of Treg dysfunction?

A

deletion in the transcriptional regulator Foxp3 results in loss of function = lack of Treg cells

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9
Q

Explain how areas of the body can be immunologically previledged?

A

Sequestrated antigens: anatomically isolated from contact with circulating lymphocytes

> > Lack of antigen presentation

i.e. eyes, testis

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10
Q

Pathogenesis of sympathetic opthalmia?

A

trauma breaks barrier that keep eye antigens from circulating lymphocytes

> > Eye antigens go to circulation

> > Inflammation

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11
Q

Name 2 conditions that cause immune attack to immunologically privileged sites?

A

sympathetic opthalmia

Complication of vasectomy

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12
Q

Enhanced Ag presentation or co-stimulatory signal increases the threshold for autoimmune disease. T or F?

A

False

Enhanced Ag presentation or co-stimulatory signal DECREASE THRESHOLD

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13
Q

List all 5 types of T helper cells?

A

Th0,1,2,17

Treg

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14
Q

Distinguish the type of immunity induced by Th1, Th2, Th17?

A

Th1 = Cell-mediated

Th2 = Antibody-mediated

Th17 = Cell-mediated

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15
Q

Distinguish the types of pathogens targeted by TH1, TH2, Th17?

A

Th1 = Intracellular viruses, bacteria)

Th2 = Extracellular parasites

Th17= extracellular bacteria, Fungal

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16
Q

List the CD markers for Treg cells? Function?

A

CD4+ CD25+ foxp3+

Thymus derived

Mediate self tolerance and prevent autoimmune disease

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17
Q

Cytokine secretions and functions of Th0?

A

undifferentiated naïve precursor of TH1 and TH2 cells

produce cytokines of both TH1 and TH2 types

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18
Q

Specific cytokines secretion and function of Th1?

A

IL-2, IFNγ, TNF, lymphotoxin (LT)

Supports macrophage activation, Delayed-Type Hypersensitivity response (e.g. tuberculosis, intracellular pathogens)

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19
Q

What cytokine from APC stimulates Th1 dominant response?

A

IL-12 (produced by APC)

> > induces differentiation of TH1 cells
Induce IFNγ secretion

IFNγ inhibits differentiation and effector functions of TH2 = dominant Th1 response

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20
Q

Describe the interactive regulation between Th1 and Th2?

A

Reciprocal regulation:

cytokines inhibit development of counterpart but stimulate their own type

> > positive feedback

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21
Q

Cytokines secreted by Th2? Function of Th2?

A

IL-4, IL-5, IL-6, IL-10 and IL-13

Help B cell activation, antibody production, switch to IgG1 and IgE isotypes

vs extracellular pathogens

22
Q

What cytokine from APC simulates Th2 dominant response?

A

IL-6 (produced by APC) induces IL-4

> > directs development of TH2 cells

> > IL-4, IL-10, IL-13 inhibit TH1 proliferation
oppose the effects of IFNγ on macrophages

23
Q

Name the cytokine that drives Th1 dominant response?

A

IL-12 from APC = drives differentiation of TH1 cells

IFNγ = inhibits differentiation and effector functions of TH2

24
Q

Name the cytokine that drives Th2 dominant response?

A

IL-4 directs development of TH2 cells

IL-4, IL-10 and IL-13 inhibit TH1 proliferation

25
3 aetiologies of autoimmune diseases?
Genetic factors Hormonal factors Environmental factors= Mainly infective
26
Describe the penetrance, number of genes affected and inheritance of inherited autoimmune diseases?
Low penetrance Multiple genes involved/ Polygenic No clear Mendelian inheritance: Multifactorial
27
Type of genes closely asso. with autoimmune diseases?
1) HLA allotypes (especially HLA class II antigens) e. g.: HLA-DR4 vs. rheumatoid arthritis HLADR3/4 vs. insulin-dependent (type 1 / juvenile) diabetes mellitus (IDDM) 2) Non-MHC genes
28
Describe the family clustering effect of autoimmune diseases?
Higher risk of autoimmune disease within family of affected individual compared to general population
29
Describe the prevalence of autoimmune diseases in twins?
Higher risk in identical twins than non-identical twins
30
First relatives of patients with organ-specific autoimmunity have high autoantibody titre and symptomatic. T or F?
False Firsst relatives have LOW autoAb titre Usually asymptomatic
31
Describe the effects of hormones on autoimmune disease epidemiology?
Many autoimmune diseases have sex preponderance: FEMALE predom. e.g. SLE 9x risk than male
32
2 mechanisms for infection to cause autoimmunity?
1. Cytokines activate APC to express costimulatory molecules (lower threshold): i.e. APC present self antigen to self-reactive T cell 2. Molecular mimicry: cross-reacting microbial antigen has common sequence with autoantigen >> activates specific self-reactive T cells
33
Give 2 examples of infections causing autoimmunity?
rubella (congenital) and enteroviruses >> IDDM Streptococcus >> rheumatic fever >> rheumatic heart disease (molecular mimicry)
34
List examples of drug induced autoimmunity?
hydrallazine, penicillamine: drug-induced lupus methyldopa*: haemolytic anaemia Dietary iodine*: autoimmune thyroiditis
35
Classify Autoimmune disease by extent of involvement in body.
Organ specific = Target Ag on specific organs: Usually endocrine organs: Non-organ specific = Multi-system disorders: Immune complex deposition
36
List the common organs targeted in Organ-specific autoimmunity? Give examples of each organ affected?
Usually endocrine organs,  Thyroid: Hashimoto’s thyroiditis, Graves’ disease, primary myxoedema, thyrotoxicosis  Adrenal: Addison’s disease  Pancreas: insulin-dependent (type I) diabetes mellitus
37
List non-endocrine organs targeted in Organ-specific autoimmunity?
- Renal: anti-glomerular basement membrane (GBM) disease / Goodpasture Syndrome - Haematological: autoimmune haemolytic anaemia - Muscular: myasthenia gravis - Stomach: pernicious anaemia - Liver, bile: primary biliary cirrhosis
38
2 mechanisms that induce organ-specific autoimmunity?
Interaction of antibodies with cell surface components: e.g. Ab bind to AchR causing MG sensitisation of T cells causing tissue damage: e.g. CD4 recruit macrophages >> Hashimotos
39
List examples of multisystem autoimmune diseases?
Rheumatic diseases - systemic lupus erythematosus (SLE) - rheumatoid arthritis (RA) Vasculitis - Wegener’s granulomatosus - polyarteritis nodosa
40
3 mechanisms to induce non-organ specific autoimmune diseases
1) cytokines produced by T cells and macrophage, e.g. rheumatoid arthritis, 2) Immune complex formation and deposition e.g. SLE, anti-dsDNA bind dsDNA and deposit in kidneys 3) AutoAb against common self antigens e.g. anti-mitochondria Ab
41
List some AutoAb used to Dx and monitor SLE?
Dx = ANA (highly sensitive), Anti-dsDNA (highly specific), C3, C4 Monitor = anti-dsDNA; C3 and C4 correlate with the clinical parameter closely
42
Compare the changes in thyroid gland size and function between Hashimoto, Graves and Primary myxoedema?
Hashimoto = Larger, Hypothyroidism Grave's = Larger, Hyperthyroidism Primary Myxoedema = Smaller, Hypothyroidism
43
List 3 types of autoimmune cytopenia?
haemolytic anemia (e.g. transfusion, HDN. Autoimmune) autoimmune thrombocytopenia autoimmune neutropenia
44
Name the AutoAb and 3 symptoms of Goodpasture's syndrome?
anti-GBM antibodies nephritis ± renal failure, pulmonary haemorrhage
45
List symptoms of SLE?
skin rash, arthritis, nephritis, cytopenia, serositis, cerebritis
46
Autoimmune diseases can be prevented by routine screening and lab tests. T or F?
Futile screening | No lab test gives absolute answer
47
CRP is increased in systemic SLE flare. T or F?
False Increased in infective episode of SLE
48
List 2 tests to determine the prognosis of IDDM?
anti- glutamic acid decarboxylase Ab positive HLADR3/4 haplotype
49
Principle of treating autoimmune endocrine** diseases?
Treat endocrine dysfunction i.e. hormone therapy Usually non-reversible damage done already by clinical presentation
50
4 Principle of treating wide-spread autoimmune diseases e.g. Lupus, RA ?
- Corticosteroid >> dampen the excessive inflammatory response - Immunosupressant >>dampen immune response - Plasmapheresis >> Remove autoAb, immunosuppression - Intravenous immunoglobulin >> Anti-idiotypic antibodies against pathogenic autoantibody (block Fc receptors)

MBBS II HIS (30 decks)

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