MIC 505 Dr. John Tew IMMUNOLOGICAL MEMORY AND IMMUNOREGULATION

2. MIC 505 Dr. John Tew IMMUNOLOGICAL MEMORY AND IMMUNOREGULATION • Discuss immunological memory and explain how it has been demonstrated in the following: Ab responses, responses to infections, transplant rejections, tumor rejections, allergy, and specific immunological unresponsiveness. • Explain why memory so important in vaccine development. • 3. Describe the differences between primary and secondary antibody responses and explain how the differences relate to immunological memory. • 4. Describe the various T cell responses and explain how immunological memory can be demonstrated in these various T cell responses. • 5. Describe how serum antibody levels can be established and regulated after immunization. Explain how persisting antigen might relate to maintenance of serum antibody levels with high affinity (Hypermutation & Affinity maturation).

3. I. The concept of immunological memory. The ability to learn requires “memory” and the remarkable ability of humans to learn distinguishes them from lower species. Similarly, immunological memory is most apparent in man and in the higher species. • Historically first apparent in infectious diseases (e.g. Victims of previous epidemics remembered [both mentally & immunologically] and were immune to the current epidemic. Adults are generally resistant to infectious diseases they remember from childhood).Moreover, immunological memory serves as the basis for vaccine development. • Apparent in both limbs of the immune response --- Humoral immunity and cell mediated immunity (See Fig. 1 illustration of memory in the immune system overview). • II. Humoral immunity and immunological memory • The primary and secondary antibody responses (secondary = anamnestic, recall, or booster response - See Fig. 2). • Differences include: Lag, rate of increase, IgG vs IgM, maintained plateau level, amounts of Ag, affinity of Ab. • Both memory B & T cells (helper) are needed for T cell dependent Ags.

5. I. The concept of immunological memory. The ability to learn requires “memory” and the remarkable ability of humans to learn distinguishes them from lower species. Similarly, immunological memory is most apparent in man and in the higher species. • Historically first apparent in infectious diseases (e.g. Victims of previous epidemics remembered [both mentally & immunologically] and were immune to the current epidemic. Adults are generally resistant to infectious diseases they remember from childhood).Moreover, immunological memory serves as the basis for vaccine development. • Apparent in both limbs of the immune response --- Humoral immunity and cell mediated immunity (See Fig. 1 illustration of memory in the immune system overview). • II. Humoral immunity and immunological memory • The primary and secondary antibody responses (secondary = anamnestic, recall, or booster response - See Fig. 2). • Differences include: Lag, rate of increase, IgG vs IgM, maintained plateau level, amounts of Ag, affinity of Ab. • Both memory B & T cells (helper) are needed for T cell dependent Ags.

6. -mostly IgG, IgA, or IgE -high affinity -rapid -long duration -high titer -initially IgM -low affinity -short duration

9. III. Cell mediated immunity and memory T cells (i.e. helper, suppressor/regulatory and cytotoxic T cells) A. Cell mediated immunity — evidence for memory. 1. Graft rejection (first set vs. second set reaction), allergic reactions i.e. delayed type hypersensitivity, and infectious diseases (e.g. virus diseases) 2. General mechanisms for acquired cell mediated immunity: The 3 pathways are illustrated in figure Fig. 3). a. Activation of Macrophages: T cells produce factors, monocytes are attracted; monocytes localized at the site and monocytes are activated to become "angry" killer macrophages. b. Cytotoxic T cells (CTL): CTL attach to target cells via TCR binding Class I molecules on target bearing appropriate Ag & CTL release compounds that create holes in the cell membranes of the target cells or signal Fas. c. Lymphotoxin/Tumor Necrosis Factor: Cells instruct the target cells to suicide (apoptosis) or upregulate Class I which improves CTL killing

10. Acquired Cell Mediated Immunity Presented by DCs Th-1 response (T cell) Soluble factors leading target cell death: Lymphotoxin b, TNF-b (and TNF-a from macrophages). Binding to death receptor TNFR1 leading to apoptosis. Death Receptors FAS & TNFR1

13. IV. Regulation of antibody responses A. Plasma cells are an end line cell type -- produce antibody for a few days and then most die. B. Antibody feedback regulation, excess antigen is eliminated. 1. Passive antibody aborts the immune response, basis for rhogam anti-D (72 hrs) C. Suppressor T cells or regulatory T cells (Tregs )(Fig. 5. Infectious tolerance also represents an expression of memory)

14. Antibody Response Suppressor T cell & Infectious Tolerance Immunogenic Dose of Ag Transfer to Naïve Recipient Isolate T cells Immunogenic Dose of Ag Immunogenic Dose of Ag Suppressive Dose of Ag Transfer to Naïve Recipient Isolate T cells Suppressive Dose of Ag Immunogenic Dose of Ag

15. V. FDC, B cell, T cell interactions in the induction of secondary or recall antibody responses. A. FDCs trap and retain Ag-Ab complexes (ICs) Fig 8. B. Trapping involves IC formation, ICs to ATC, ATC to FDC, FDC to iccosomes, iccosomes to B cells for endocytosis (Fig. 9). B. B cells then process and present the iccosomal-Ag to T cells, T cells provide growth and differentiation factors necessary for B cells to differentiate into plasma cells and memory B cells.

17. Reminder - Follicular Dendritic Cells (FDCs) • Cardinal features of FDCs • Located in the follicles of secondary lymphoid tissue. • Dendritic morphology -- Note the numerous processes wrapped “spaghetti-like ” and the beads (Iccosomes) on scanning electron micrograph ofthe FDC. • Binds and retains immune complexes (ICs).

20. V. FDC, B cell, T cell interactions in the induction of secondary or recall antibody responses (Fig. 6) A. Antigen to immune complex, immune complex to ATC, ATC to FDC, FDC to iccosomes, iccosomes to B cell for endocytosis. B. B cells then process and present the iccosomal-Ag to T cells, T cells provide growth and differentiation factors necessary for B cells to differentiate into plasma cells and memory B cells.

21. IV. The maintenance of antibody levels. (Ab T1/2 ~3 wks) A. The persisting antigen model along with plasma cells persisting in the bone marrow B. Bleeding experiments & cycles of antibody formation C. Persisting antigen to iccosome release, antibody production and restoration of memory B cell numbers (see Fig. 5 and Janeway et. al. Fig. 9.14 & 9.15 for FDC & Ag in germinal centers). Memory B cells are distinct because of somatically mutated high affinity mIgG. D. FDC involved in selection of high affinity B cell clones (Somatic mutants whose product is high affinity Ab -- leads to affinity maturation).

22. Somatic Hypermutation and FDC Mediate Selection of B cells with High Affinity BCRs Plasmablasts/Memory Cells Survival Interaction with FDC-Ag High Affinity BCRs SomaticHypermutation Low Affinity BCRs Apoptosis

23. MIC 505 Dr. John Tew IMMUNOLOGICAL MEMORY AND IMMUNOREGULATION • Discuss immunological memory and explain how it has been demonstrated in the following: Ab responses, responses to infections, transplant rejections, tumor rejections, allergy, and specific immunological unresponsiveness. • Explain why memory so important in vaccine development. • 3. Describe the differences between primary and secondary antibody responses and explain how the differences relate to immunological memory. • 4. Describe the various T cell responses and explain how immunological memory can be demonstrated in these various T cell responses. • 5. Describe how serum antibody levels can be established and regulated after immunization. Explain how persisting antigen might relate to maintenance of serum antibody levels with high affinity (Hypermutation & Affinity maturation).