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GENERAL CONCEPTS. Immune system distinguishes between self (auto) and non-self (foreign) antigens V genes encode TCR’s and BCR’s with anti-self reactivity Autoreactive T and B cells are produced If mature autoreactive T and B cells are activated, autoimmune disease may develop

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general concepts
GENERAL CONCEPTS
  • Immune system distinguishes between self (auto) and non-self (foreign) antigens
  • V genes encode TCR’s and BCR’s with anti-self reactivity
  • Autoreactive T and B cells are produced
  • If mature autoreactive T and B cells are activated, autoimmune disease may develop
  • Self-tolerance mechanisms eliminate or prevent autoreactive cells from responding
tolerance
TOLERANCE
  • Antigen-specific unresponsiveness
  • Acquired characteristic - Somatic process
  • Central tolerance occurs in primary lymphoid organs during lymphocyte maturation
  • Peripheral tolerance occurs in secondary lymphoid organs involving mature cells
  • Time dependent
  • Antigen concentration dependent Low vs. High Zone Tolerance
slide3

T cells are easier to tolerize than B cells.

If helper T cell is tolerant,

B cell will not respond.

Without T cell help, B cell

undergoes apoptosis.

mechanisms of t cell tolerance
Mechanisms of T Cell Tolerance
  • Immunologically Privileged Site Antigen Sequestration
  • Deletion
  • Suppression
  • Anergy
  • Immunological Ignorance
  • Receptor Editing NOT important
slide5

Fetus is an

allograft, but

no immune

response occurs.

immune privileged sites
Immune Privileged Sites
  • Lack of immune responses to allografts
  • Examples: fetus, brain, anterior chamber of eye
  • Lymphocytes have access and self antigens exit
  • Lack of conventional lymphatics
  • Rich in inhibitory molecules
deletion
DELETION
  • Autoreactive cells killed
  • Negative selection in thymus Main mechanism of central tolerance
  • Activation-induced cell death

Peripheral tolerance mechanism

T cells die during an immune response

thymic selection
Thymic Selection
  • Final outcome depends on both thymic & peripheral environments
  • Males usually do not have T cells specific for male self antigens, but females do
  • For bone marrow transplant patients, donor must share some MHC molecules with recipient for donor precursor T cells to become mature cells
  • Donor T cells will fail to be positively selected on mismatched recipient MHC molecules
slide10

Possible Outcomes of Selection

Positive Selection

If autoreactive,

Negative Selection

Failure of

Positive Selection

slide11

What is different?

Avidity Model vs.

Differential Signaling Model

slide12

Not 100%

effective

slide13

Activation-

Induced Cell

Death

Apoptosis is mediated

by Fas pathway.

Defect causes fatal

multi-organ autoimmune

disease

suppression
SUPPRESSION
  • Hallmark Feature: Adoptively transferred with T cells
  • Infectious Tolerance
  • Regulatory CD4+ T cells secrete inhibitory cytokines especially TGF-b, and impair presenting cell function
  • Release of soluble cytokine receptors
  • Immune Deviation - Change TH1 to TH2 response or reverse
regulatory t cells
Regulatory T cells
  • Viewed as most important suppressive mechanism
  • TH3 in mucosal immune system - defect linked to autoimmune diseases in gut
  • TR1 generated in culture
  • TH3 & TR1 are adaptive regulatory T cells
  • Treg is natural regulatory T cell
  • Linked suppression
slide16

Treg

IL-4, IL-10,

TGF-b

FoxP3

Impair

CTLA-4 required for function of Treg cells

Mutations in FoxP3 cause fatal multi-organ autoimmune disease in humans

slide18

Immune Deviation =

Cytokine Deviation

Subverts main

pathological

mechanism

causing tissue

damage and

destruction

anergy
ANERGY
  • Peripheral tolerance mechanism
  • Cells functionally inactivated and not capable of responding to antigen
  • Low or no interleukin-2 secretion is one main effect
  • Cells remain alive
  • Long-term effect
  • Caused by improper primary signal or lack of co-stimulatory signal
slide21

Peptide analog acts

as partial agonist

Generates negative

signal

slide23

Not suppression

Impairs primary signal through TCR

slide24

Second

signal =

co-stimulatory

Primary

signal

slide26

Naive T cells interact with professional antigen-presenting cells for a primary response.

Other cell types lack MHC class II and co-stimulatory molecules and cause anergy.

slide29

CTLA-4 allele increases

risk for certain autoimmune

diseases in humans

summary of anergy
SUMMARY OF ANERGY
  • Analog peptides act as partial agonist and generate negative signal
  • Disruption of CD4 or CD8 co-receptors impairs primary signal
  • Lack of co-stimulatory signal from non-professional antigen-presenting cells No CD28 signal renders T cells unable to produce IL-2
  • CTLA-4 generates negative signal Blocks IL-2 production
two roles of ctla 4 in tolerance
Two Roles of CTLA-4 in Tolerance
  • Delivers negative signal to CD8+ cytotoxic T cells and classical CD4+ helper T cells
  • Overrides positive signals through T cell receptor and co-stimulatory molecules
  • Critical for function of regulatory T cells that suppress autoimmune responses
  • CTLA-4 defects cause massive proliferation of classical helper T cells and systemic autoimmune disease
immunological ignorance
IMMUNOLOGICAL IGNORANCE
  • Peripheral tolerance mechanism
  • Cells are alive and capable of responding
  • Cells “ignorant” of antigen and do not respond
  • Occurs if TCR has low affinity and/or antigen concentration is low
  • Increase in antigen concentration may lead to a response
slide33

Example of

Immunological

Ignorance

immunological ignorance1
IMMUNOLOGICAL IGNORANCE
  • Involvement of Antigen Processing
  • Peptide of intact self protein antigen is not made by antigen-presenting cells during antigen processing
  • T cells are not tolerant to that self peptide
  • Example:

1. Administer intact mouse cytochrome c to mouse and nothing happens.

2. Administer peptide of mouse cytochrome c, and autoimmune disease develops.

promising immunotherapies to induce suppression
Promising Immunotherapies -To Induce Suppression
  • Soluble TNF receptor to treat rheumatoid arthritis, ankylosing spondylitis and severe psoriasis

Enbrel is FDA-approved

  • Th1 cytokines to treat IgE-mediated allergies
promising immunotherapies to induce anergy
Promising Immunotherapies - To Induce Anergy
  • Anti-B7 antibodies to prevent graft rejection
  • Soluble CTLA-4 to treat autoimmune diseases and prevent graft rejection

Orencia is FDA-approved for rheumatoid arthritis

  • Peptide agonists to treat allergies
  • Anti-CD4 antibody to prevent graft rejection and treat multiple sclerosis
promising immunotherapies for cancer
Promising Immunotherapies for Cancer
  • Anti-CTLA-4 antibody to boost T cell responses

Clinical trials with non-Hodgkin’s lymphoma, and colon & ovarian cancer patients

Ipilimumab to treat melanoma, prostate & lung cancer - FDA application pending

  • Killed tumor cells expressing B7 genes to induce T cell responses

Clinical trials with melanoma, renal cell carcinoma, and glioblastoma patients