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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
Q

3 aetiologies of autoimmune diseases?

A

Genetic factors
Hormonal factors
Environmental factors= Mainly infective

26
Q

Describe the penetrance, number of genes affected and inheritance of inherited autoimmune diseases?

A

Low penetrance
Multiple genes involved/ Polygenic
No clear Mendelian inheritance: Multifactorial

27
Q

Type of genes closely asso. with autoimmune diseases?

A

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
Q

Describe the family clustering effect of autoimmune diseases?

A

Higher risk of autoimmune disease within family of affected individual compared to general population

29
Q

Describe the prevalence of autoimmune diseases in twins?

A

Higher risk in identical twins than non-identical twins

30
Q

First relatives of patients with organ-specific autoimmunity have high autoantibody titre and symptomatic. T or F?

A

False

Firsst relatives have LOW autoAb titre

Usually asymptomatic

31
Q

Describe the effects of hormones on autoimmune disease epidemiology?

A

Many autoimmune diseases have sex preponderance: FEMALE predom.

e.g. SLE 9x risk than male

32
Q

2 mechanisms for infection to cause autoimmunity?

A
  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&raquo_space; activates specific self-reactive T cells
33
Q

Give 2 examples of infections causing autoimmunity?

A

rubella (congenital) and enteroviruses&raquo_space; IDDM

Streptococcus&raquo_space; rheumatic fever&raquo_space; rheumatic heart disease (molecular mimicry)

34
Q

List examples of drug induced autoimmunity?

A

hydrallazine, penicillamine: drug-induced lupus

methyldopa*: haemolytic anaemia

Dietary iodine*: autoimmune thyroiditis

35
Q

Classify Autoimmune disease by extent of involvement in body.

A

Organ specific = Target Ag on specific organs: Usually endocrine organs:

Non-organ specific = Multi-system disorders: Immune complex deposition

36
Q

List the common organs targeted in Organ-specific autoimmunity? Give examples of each organ affected?

A

Usually endocrine organs,

 Thyroid: Hashimoto’s thyroiditis, Graves’ disease, primary myxoedema, thyrotoxicosis

 Adrenal: Addison’s disease

 Pancreas: insulin-dependent (type I) diabetes mellitus

37
Q

List non-endocrine organs targeted in Organ-specific autoimmunity?

A
  • 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
Q

2 mechanisms that induce organ-specific autoimmunity?

A

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&raquo_space; Hashimotos

39
Q

List examples of multisystem autoimmune diseases?

A

Rheumatic diseases

  • systemic lupus erythematosus (SLE)
  • rheumatoid arthritis (RA)

Vasculitis

  • Wegener’s granulomatosus
  • polyarteritis nodosa
40
Q

3 mechanisms to induce non-organ specific autoimmune diseases

A

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
Q

List some AutoAb used to Dx and monitor SLE?

A

Dx = ANA (highly sensitive), Anti-dsDNA (highly specific), C3, C4

Monitor = anti-dsDNA; C3 and C4 correlate with the clinical parameter closely

42
Q

Compare the changes in thyroid gland size and function between Hashimoto, Graves and Primary myxoedema?

A

Hashimoto = Larger, Hypothyroidism

Grave’s = Larger, Hyperthyroidism

Primary Myxoedema = Smaller, Hypothyroidism

43
Q

List 3 types of autoimmune cytopenia?

A

haemolytic anemia (e.g. transfusion, HDN. Autoimmune)

autoimmune thrombocytopenia

autoimmune neutropenia

44
Q

Name the AutoAb and 3 symptoms of Goodpasture’s syndrome?

A

anti-GBM antibodies

nephritis ± renal failure, pulmonary haemorrhage

45
Q

List symptoms of SLE?

A

skin rash, arthritis, nephritis, cytopenia, serositis, cerebritis

46
Q

Autoimmune diseases can be prevented by routine screening and lab tests. T or F?

A

Futile screening

No lab test gives absolute answer

47
Q

CRP is increased in systemic SLE flare. T or F?

A

False

Increased in infective episode of SLE

48
Q

List 2 tests to determine the prognosis of IDDM?

A

anti- glutamic acid decarboxylase Ab positive

HLADR3/4 haplotype

49
Q

Principle of treating autoimmune endocrine** diseases?

A

Treat endocrine dysfunction i.e. hormone therapy

Usually non-reversible damage done already by clinical presentation

50
Q

4 Principle of treating wide-spread autoimmune diseases e.g. Lupus, RA ?

A
  • Corticosteroid&raquo_space; dampen the excessive inflammatory response
  • Immunosupressant&raquo_space;dampen immune response
  • Plasmapheresis&raquo_space; Remove autoAb, immunosuppression
  • Intravenous immunoglobulin&raquo_space; Anti-idiotypic antibodies against pathogenic autoantibody (block Fc receptors)

MBBS II HIS (30 decks)

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