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YEAR 2 S2 IMMUNO > Theme 5 - 5a (Tolerance) > Flashcards

Theme 5 - 5a (Tolerance) Flashcards

1
Q

tolerance is important in which kind of immunity

A

adaptive

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2
Q

how are self reactive immune cells made

A
  • random gene arrangements that generate TCR and BCR can produce self reactive immune cells
  • self reactive immune cells have potential to trigger ‘horror autotoxicus’ or AUTOIMMUNITY
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3
Q

what is immunological tolerance

A

the body maintains immunological tolerance - a state of unresponsiveness to particular antigens

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4
Q

what is central tolerance

A
  • when T cells are ‘EDUCATED’ in the thymus
  • when B cells are ‘EDCATED’ in the BONE MARROW
  • to not respond to self antigens
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5
Q

what is peripheral tolerance

A

there are many mechanisms used by B and T cells to maintain peripheral tolerance

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6
Q

describe central tolerance of the T cells in thymus
what are the two parts
where do they occur
what are the limitations?

A
  • thymocytes develop in bone marrow BEFORE migrating to thymus
  • POSITIVE SELECTION: in thymic cortex, the T cells are tested for MHC BINDING. T cells that dont bind undergo APOPTOSIS
  • NEGATIVE SELECTION: in thymic MEDULLA, specialised epithelial cells (tmec - thymic medullary epi cells) and some DCs present SELF ANTIGEN AND MHC complexes. The T cells that bind with HIGH AFFINITY for self antigen or MHC undergo APOPTOSIS

LIMITATIONS: - not all self antigens/MHC can be expressed in the thymus

  • deleting ALL self reactive cells would limit the REPERTOIRE (we do not know what we may encounter in the future)
  • this method cannot account for INNOCUOUS ENVIRONMENTAL ANTIGENS
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7
Q

recap: what % of thymocytes surive and do not undergo apoptosis and can become T cells

A

~5%

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8
Q

describe central tolerance of the B cells in bone marrow

A
  • B cells that bind self antigen can undergo 3 POSSIBLE FATES
    1) if they have HIGH AFFINITY BCRs then they undergo RECEPTOR EDITING: the LIGHT chain of B cell is edited and genes reordered to express a new receptor that does NOT bind self antigen
    2) if this fails and the new receptor binds self antigen then it DELETED and undergoes APOPTOSIS
    3) if there is WEAK recognition of self antigen, then the B cell can be released in an ANERGIC (unresponsive) state
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9
Q

why are some self reactive /binding immine cells req

A

for: mediating tumour surveillance, regulating inflammatory immune responses

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10
Q

if an autoreactive immune cell escapes central tolerance and enters the periphery, how are they regulated?

A

via 4 mechanisms for T cells and 3 mechanisms for B cells

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11
Q

achieving diversity in the host immune response is done at the risk of what

A

the risk of generating specificity for self antigens

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12
Q

what are the names of the 4 mechanisms used for peripheral tolerance

A

1) IGNORANCE
2) LACK OF CO-STIMULATION (ANERGY)
3) ACTIVATION-INDUCED CELL DEATH (DELETION VIA APOPTOSIS)
4) EFFECT OF REGULATORY T CELLS

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13
Q

describe ignorance as a mechanism of peripheral tolerance used by T cells

A
  • some self antigens are ONLY EXPRESSED at certain times (eg hormones in puberty, inflammatory responses) so they are NOT PRESENT during positive or negative selection in the thymus
  • some self antigens are SEQUESTERED/HIDDEN in immunologically privileged sites (amterior chambe rof eye, behind BBB) which are not accessible to T cells
  • some self antigens are not present in SUFFICIENT QUANTITIES (low dose) to reach threshold of activation for TCR

O if self antigen remains hidde/not expressed, tolerance is maintained

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14
Q

describe lack of co-stimulation: anergy as a mechanism of peripheral tolerance used by T cells

A
  • if TCR os stimulated in the ABSENCE of co stimulation (via CD28/CD80/86) it can lead to ANERGY
    can be induced via:
  • costimulator deficient APCs (including tolerogenic or immature DCs) (eg lack of CD80 on APC)
  • the action of distinct co-stimulatory pathways eg. CTLA-4 that INHIBITS CD28 binding to CD80/86 (B7 . 1/7.2)
  • CTLA-4 expression is induced upon TCR stimulation and has high affinity for CD80/86 (B7.1/7.2) on APCs
  • CTLA-4 engagement sends an inhibitory signal to block further TCR signalling – so works as a regulatory function to dampen down T cell responses – binding to CD80/86 also supresses APC(Mutations in CTLA-4 gene are associated with some autoimmune diseases)
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15
Q

what is the role of CTLA-4

A

it is a reglatory ‘checkpoint molecule’

  • when there are ENOUGH T cells for the immune response, the activation of T cells needs to be SLOWED
  • after several mitotic divisions T cells start expressing FEWER CD28 and instead express MORE CTLA-4
  • CTLA-4 can then bind to CD80/86 which sends an INHIBITORY SIGNAL to the T cell, making it UNRESPONSIVE - anergic
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16
Q

mutations in CTLA-4 genes are associated with what

A

autoimmune diseases

  • T cells are not regulated and their effects are not dampened down
  • even if you have T cell that recognises self antigen with low affinity, it won’t be stopped
17
Q

what happens when CTLA-4 and CD80 bind

A

sends negative signal to T CELL AND APC

  • this causes supression of CD80/86
  • O less CD80/86 can bind to T cells
18
Q

describe activation induced cell death:deletion via apoptosis as a mechanism of peripheral tolerance used by T cells

A
  • self reactive T cells can BE DELETED in the periphery by ACTIVATION INDUCED CELL DEATH (AICD)
  • REPEATED ACTIVATION of TCR induces expression of DEATH RECEPTORS such as Fas and FasLigand, and pro-apoptotic proteins such as Bax, Bad and Bim (Bcl-2 proteins)
19
Q

describe effects of regulatory T cells as a mechanism of peripheral tolerance used by T cells

A

there are 2 groups:

1) natural (as they leave thymus they are already T reg)
2) inducible (infection/inflammation can trigger T cell to be induced to become a T reg)
- all T reg cells express either CD4 (more common) or CD8
- majority express internal marker FoxP3

ACTION:

1) CELL CELL CONTACT DEPENDENT:
- T regs have fully functional TCR and also express high levels of CTLA-4 so when in contact with APCs CTLA-4 binds to CD80/86 (B7.1/7.2) making the APCs tolerogenic
- Can directly kill APCs and other T cells via perforin and granzyme secretion (lysis)

2) SOLUBLE (cell contact independent):
- Secretion of cytokines such as IL-10 and TGF-b
- Mopping up of IL-2 – they possess low affinity IL-2R so act as sponge depriving other T cells of IL-2

20
Q

describe peripheral tolerance in B cells

A
  • A high proportion of short-lived, low-avidity, auto-reactive B cells are present in peripheral lymphoid organs
  • B cell activation depends on adequate co-stimulation (CD40L, TLR etc)

mechanisms:
1) ) Chronic, LOW LEVEL , BCR cross-linkage and lack of sufficient co-stimulation results in B cell anergy – seen in chronic infections and sometimes referred to as B cell ‘exhaustion’
2) Acute, HIGH LEVEL, BCR cross-linkage and lack of co-stimulation results in B cell deletion via apoptosis
3) Partially activated B cells do not express the right chemokine receptors and are EXCULDED from the lymphoid follicles – cannot develop into mature plasma B cells

Other factors to consider: - - - FcgammaR2b receptor (ITIM in cytoplasmic tail) when crosslinked
by Ab/Ag complexes leads to –ve signal into B cell
- availability of BAFF (survival factor)

21
Q

how can uncontrolled immune responses cause disease

A
  • inflammatory responses towrads self-antigens triggers AUTOIMMUNE DISORDERS (which are mediated by HYPERSENSITIVITY mechanisms II, III, IV)
  • inappropriate or uncontrolled responses towards environmental antigens causes ALRRERGY (ATOPY) and HYPERSENSITIVITY DISEASES
  • unwanted immunity can also arise in response to transplanation
22
Q

give example of autoimmune disorders

A
  • Grave’s disease (organ specific)
  • Hashimoto’s thyroiditis
  • Addison’s
  • Type I diabetes
  • myasthenia gravis
  • systemic lupus (systemic)
23
Q

what triggers autoimmune diseases

A
  • genetic component (eg HLA-DQ, DR and other genes)
  • environmental trigger (gluten, grains, deficiencies, virus, bacteria etc)
  • also immune regulation (caused by Vit D deficiency and disrupted by leaky gut)
24
Q

which autoimmune diseases affect the brain

A
  • MS
  • autism
  • Guillain-Barre syndrome
25
Q

what autoimmune diseases affect bones

A
  • rheumatoid arthiritis
  • ankylosing spondylitis
  • polymyalgia rheumatics
26
Q

what autoimmune diseases affect muscles

A
  • fibromyalgia

- muscular dystrophy

27
Q

what autoimmune disease affect skin

A
  • eczema
  • psoriasis
  • vitiligo
  • scleroderma
28
Q

how many autoimmune diseases/syndromes are there

A

> 50

29
Q

autoimmune diseases affect who more

A

women

30
Q

give examples of environmental triggers for autoimmune diseases

A
  • stress
  • hormones
  • metals
  • food antigens
  • pesticides/poisons

YEAR 2 S2 IMMUNO (14 decks)

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