2-29 Immune Regulation Flashcards Preview

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Flashcards in 2-29 Immune Regulation Deck (17):
1

Why is regulation of the immune system important?

To prevent:

  • over-responsiveness (autoimmunity)
  • under-responsiveness (immunodeficiency)

2

What is immunological tolerance, and what are the general mechanisms by which it is accomplished?

Unresponsiveness to a specific antigen.

  1. Elimination of reactive cells
  2. Neutralization of reactive cells
  3. Generation of suppressive cells

3

What are the mechanisms of T-cell tolerance?

  • Negative selection
  • Regulatory T cells
  • Clonal anergy
  • Activation inhibition

4

What is negative selection in T cells?

In thymus, TF AIRE triggers the expression of tissue-specific antigens → deletion of autoreactive T cells before they can reach the periphery and cause autoimmunity

5

What is AIRE?

Thymic transcription factor that triggers the expression of tissue-specific antigens (e.g., insulin), allowing deletion of reactive T cells before they can reach the periphery and cause autoimmunity.

Defective AIRE expression leads to a severe autoimmune disease known as autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, or APECED.

6

What are Tregs?

Regulatory T cells (Tregs) are CD4+/CD25+ T cells reactive to self antigen because of TF FoxP3.

Canonical Tregs are generated during thymic selection, possibly because their TCRs possess a strong affinity for self- peptide presented in class II MHC.

To prevent autoimmunity, individual Tregs patrol the body’s tissues, scanning antigen presenting cells (APCs) for expression of their specific self-Ag. If Tregs locate their cognate self-Ag, they will remain with the APC and prevent the activation of potentially autoreactive effector T cells.

7

How do Tregs perform immune suppression?

  • Production of suppressive cytokines (IL-10 and TGFβ)
  • Deprivation of T cell proliferative cytokines (IL-2 “sponging”)
  • APC killing
  • (granzymeA/B → dendritic cell → death)
  • Stripping of co-stimulatory molecules from APCs (removal of CD28)

8

What is clonal anergy?

self-Ag not expressed in the thymus → autoreactive T cell not eliminated by negative selection → solution: clonal anergy

APCs must express the co-stimulatory molecule B7 (ligand for CD28) for T-cell activation to occur. T cells bearing TCRs that recognize Ag (including self-Ag) but do not receive B7 become anergic and cannot be activated by later encounters with the antigen.

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9

What is inhibition of T-cell activation?

Given the importance of B7-CD28 co-stimulation in T cell activation, T-cell responses can be regulated by interfering with co-stimulatory signaling.

Activation → CTLA4 expressed on the T cell surface → CTLA4 binds to APC B7 w/ affinity > CD28 → T-cell activation and proliferation limited

CTLA4-related drugs are used clinically to modulate T cell responses.

10

What are the mechanisms of B-cell tolerance?

  1. Clonal deletion
  2. B-cell anergy
  3. Functional deletion
  4. Suppression of activation

11

What is clonal deletion?

Clonal deletion occurs in the bone marrow to immature B lymphocytes.

Cells express BCRs (essentially, surface IgM) that bind to self-Ag expressed in the marrow → inhibitory signals → cells retained in marrow

A self-reactive immature B cell may edit its receptor via rearrangements to generate a new, non-autoreactive BCR. If successful, maturation continues; if not, apoptosis.

12

What is B-cell anergy?

A method of B-cell tolerance.

Immature B cells encounter soluble, monovalent (non-crosslinking) self-Ag → autoreactive cells become anergic → cells express IgD at the surface but NOT a functional IgM BCR → cells enter circulation, but brief lifespan

13

What is functional deletion of B cells?

A method of B-cell tolerance caused by loss of T-cell help for a T-dependent antigen.

CD4+ Helper T cells are essential to B cells: activation, proliferation, affinity maturation, Ig isotype switching, and the determination of whether to become an antibody-secreting plasma cell or memory B cell.

14

What is suppression by existing antibodies?

Naïve B cells express the inhibitory receptor FcγRIIB1, which delivers a signal to prevent B-cell activation when a secondary response is already underway.

ex) hemolytic disease of the newborn

15

What is hemolytic disease in the newborn?

Pregnant, Rh- women w/ Rh+ fetuses may generate anti-Rh Abs during subsequent pregnancies, destroying fetal erythrocytes.

Prevented by RhoGAM.

16

How does antigen immunogenicity influence immunity?

  • Strong immunogen → immunity
  • Weak immunogen → tolerance
  • Relative immunogenicity: protein antigens >> polysaccharides > lipids and nucleic acids

Protein Ags can induce both a humoral (antibody) and cell mediated (T cell) response. Other biomolecules can be recognized by B cells but cannot be presented to T cells.

17

What are some immunogenic factors that influence immunity?

  • Dose: optimum dose range, not too high/low
  • Form: clumpy aggregates stimulate APCs
  • Route: subcutaneous/intradermal → immunogenic, IV/oral → tolerogenic
  • Age: tolerance more likely if Ag encountered early in life
  • Genetic background: certain MHC alleles
  • Immunosuppressive drugs
  • Adjuvants enhance immunogenicity