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Immunology > Immunologic tolerance and tolerance > Flashcards

Immunologic tolerance and tolerance Flashcards

1
Q

Immunologic tolerance

A

unresponsiveness to an Antigen anduced by the exposure of specific lymphocytes to that Antigen

–> tolerance to self Antigen is a dunfamental protpery of the normal immune System

Antigens that induce tolerance= tolerogens
Antigens that generate immunity = immunogens

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2
Q

Immunogens and tolerogens

A
  • foreign Antigens in the ansence of costimulatory Signals may inhibit immune Responses by inducing tolerance in specific lymphocytes
  • induction of immunologic tolerance may be exploited as a therapeutic Approach for preventing harmdul immune responses
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3
Q

Features that favor Simulation of immune responses

A
  • short lived persistance
  • subcutaneous, intradermal Portal of entry
  • Antigens with adjuvants (stimulate helper T cells)
  • High Levels of co stimulants
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4
Q

Features that favor tolerance

A
  • prologed persistance
  • intravenous, mucosal Portal of entry
  • Antigens without adjuvants
  • low Levels of costimulators and cytokines
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5
Q

Central tolerance

A
  • in central lymphoid organ
  • when immature lymphocytes Encounter self Antigens present in the organ
  • These are eliminated or develop into T regs (in case of CD4+)
  • might just Change their receptors
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6
Q

Peripheral tolerance

A
  • mature lmyphocytes recognize self Antigens in peripheral tissues
  • important for maintaining unresponsiveness to self Antigens
  • imp. for tolerance to self Antigens that are expressed only in adult life
  • may serve as back up for central mechanism
  • eliminated by apoptosis
  • become incapable of responding to Antigen (anergy)
  • actively suppressed by Tregs
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7
Q

Anergy - functional unresponsiveness

A
  • exposure of matuer CD4+ cells to the Antigen in the Absence of costimulation
  • functional inactivation via B7 interaction with inhibitory receptors: CTLA-4, PD-1
  • T cells do not die but become unresponsive to the antigen
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8
Q

Autoimmunity

A

FAILURE OF SELF TOLERANCE

Reactions may be triggered:

  • by environmental Stimuli, such as infections
  • in genetically susceptible humans
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9
Q

Mechnisms of autoimmune reactions

A
  • Defects in deletion of T or B cells Primary lymphoid Organs
  • Defective number and functions of Tregs
  • Defective apoptosis of mature self-reactive lymphocytes
  • Inadequate function of inhibitory receptors
  • Activation of APCs which overcomes regulatory mechnisms and results in excessive T cell activation
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10
Q

Autoimmune diseases

A

Systemic disease: systemic lupus erythematosus
–> Formation of circulating immune complexes

Myasthenia Gravis, type 1 Diabetes, multiple sclerosis
–> autoantibodies or T cell respones against self Antigens with restricted tissue distribution

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11
Q

Effector mechanisms responsible for tissue injury

A
  • immune complexes
  • circulating autoantibodies
  • autoreactive T lymphocytes
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12
Q

Mechanism of chronicity if autoimmune diseases

A
  • once an autoimmune infection develops, amplification mechanisms (such as cytokines) promote activation of autoreactive lymphocytes
  • release of self Antigens from damages cells and tissues leads to Epitope spreading
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13
Q

Genetic Basis of autoimmunity

A
  • most autoimme diseases are complex polygenic traits
  • affected People inherit multiple genetic polymorphisms that contribute to disease susceptibility
  • genes act with environmental factors to cause the diseases
  • greatest contribution is from MHC genes
  • other genes may influence the selection or Regulation os self-reactive lymphocytes
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14
Q

Single gene mutations that cuase autoimmunity

A

are examples of mendelian disorders
- Mutation is rare but has high penetrance

importance of various molecular pathways in the maintenance of self-tolerance

  • mechanisms of central tolerance (AIRE)
  • Generation of Tregs
  • functions of Tregs
  • peripheral deletion of T and B lymphocytes
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15
Q

Examples of single genes mutations that cause autoimmune disorders

A

AIRE

  • destruction of endocrine Organs by antibodies, lmyphocytes
  • failure of central tolerance
  • autoimmune polyendocrine Syndrome

C4

  • SLE
  • defective clearance of immune complexes

Fas/FasL

  • immune complex Nephritis, arthiritis, …
  • defective deletion of anergic self reactive B cells

IL2

  • Inflammatory bowel disease
  • defective development, sirvival or function of Tregs
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16
Q

Bystander activation

A
  • infections induce local innate immune Responses that recruit leukocytes and result in activation of APCs
  • APCs begin to express co Stimulators and secrete T cell activating cytokines
  • microbes may engange Toll like receptors on DCs
  • infection results in the activation of T cells that are not specific for the infectious pathogen
17
Q

Molecular mimicry

A
  • some microbial Antigens may cross-react with self-antigens

- immune Responses initiated by the microbes may activate T cells specific fot self-antigens

18
Q

Immune privileged tissues

A
  • Inflammation in certain tissues carry a high Risk of organ dysfunction or reproductive failure
  • -> These tissues are protected from immune Responses

EYE: anterior chamber -associated immnune Deviation; systemic tolerance to Antigen induced by Tregs
BRAIN: BBB; micriglia
TESTIS: blood-tissue-barrier, anti-inflammatory cytokines
FETUS: Expresses paternal MHC genes allogenic to mother but is not rejects; local Suppression at the placental maternal-fetal interface

19
Q

Trauma-induced autoimmune responses

A
  • ocular Antigens are released after Trauma in one eye
  • are carried to peripheral lymphoid Organs
  • T cells become activated
  • activated T cells attack both eyes
20
Q

Markers of autoimmune diseases

A

ANA - antinuclear antibodies

ANCA - anti neutrophil cytoplasmic antibodoes

21
Q

ANA

A
  • General marker of the autoimmune process
  • positive in different autoimmune diseases –> not specific
  • if test is positive, often followed up with other tests
22
Q

ANCA

A
  • detects IgG antibodies specific to the cytoplasma-located Antigens of neutrophils and granulocytes
  • many autoimmune disorders, particulary systemic vasculitis
23
Q

New approaches in Treatment of autoimmune diseases

A
  • Inhibition of T cell Responses and proinflammatory cytokines: anti- TNF therapy in rhematoid arthitis
  • Activation of regulatory T cells specific to self antigens

Immunology (7 decks)

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