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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