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• 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
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 cellundergoes apoptosis.
Mechanisms of T Cell Tolerance
• Antigen Sequestration Immunological Privileged Site
• Deletion
• Suppression
• Anergy
• Immunological Ignorance
• Receptor Editing NOT important
Fetus is anallograft, butno immuneresponse occurs.
Immune Privileged Sites
• Lack of immune responses • Examples: fetus, brain, anterior
chamber of eye• Lymphocytes have access and self
antigens exit• Lack of conventional lymphatics• Rich in inhibitory molecules
DELETION
• Cells killed • Activation-induced cell death
Peripheral tolerance mechanismCells die during an immune responseMediated by Fas pathway
• Main mechanism of central tolerance:Negative selection in thymus
Activation-Induced CellDeath
Apoptosis is mediatedby Fas pathway.
Defect causes fatalmulti-organ autoimmunedisease
Medulla
Implications for bone marrow transplantation patients
No SignalNo Positive Selection Cell DeathWeak or Partial SignalPositive SelectionStrong or Full SignalNegative Selection Cell DeathStromal CellMHC + AntigenTCRDP T Cell
Avidity Model vs.Differential Signaling Model
SUPPRESSION
• Hallmark Feature: Adoptively transferred with T cells
• Regulatory CD4+ T cells secrete inhibitory cytokines especially TGF-
• Release of soluble cytokine receptors
• Immune Deviation - Change TH1 to TH2 response or reverse
FoxP3
IL-4, IL-10,TGF-
Mutations in FoxP3 cause fatal multi-organ autoimmune disease in humans
Soluble cytokine receptors neutralize cytokines
Immune Deviation =Cytokine Deviation
Subverts main pathological mechanismcausing theautoimmunedisease
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 costimulatory signal
Peptide analog acts as partial agonist delivering negative signal
Not suppression
Primarysignal
Secondsignal =co-stimulatory
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.
Lack of signal via CD28 renders T cells unable to produce IL-2
B-7’s
CD28
Particular CTLA-4 allele increases risk for certain autoimmune diseases in humans
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 costimulatory signal from non-
professional antigen-presenting cellsNo CD28 signal renders T cells unable to
produce IL-2• CTLA-4 generates negative signal
Blocks IL-2 production
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
Example ofImmunologicalIgnorance
IMMUNOLOGICAL IGNORANCE
• One Mechanism involves 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,
and nothing happens.2. Administer peptide of mouse cytochrome c,
and autoimmune disease develops.
Promising Immunotherapies
• Peptide agonists to treat allergies
• Anti-B7 antibodies to prevent graft rejection
• Soluble CTLA-4 to treat autoimmune diseases and prevent graft rejection
• Anti-CD4 antibody to prevent graft rejection and treat multiple sclerosis
• Th1 cytokines to treat IgE-mediated allergies
• Soluble TNF receptor (Enbrel) to treat rheumatoid arthritis, ankylosing spondylitis and severe psoriasis - FDA approved
Promising Immunotherapies - Continued
• Anti-CTLA-4 antibody to boost T cell responses to melanoma and prostate cancer
• Tumors transfected with B7 genes to induce T cell responses to tumorsOne published clinical trial with melanoma and glioblastoma patients
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