Adaptive Immunity and Antibody Isotypes

• Adaptive immunity and MHC are the focus.

Adaptive Immunity Types

• Humoral immunity is mediated by secreted antibodies.
• Cell-mediated immunity eradicates infections by intracellular microbes.
• Humoral immunity defends against extracellular microbes and microbial toxins.

Functions of Antibody Isotypes

• Neutralization of microbes and microbial toxins involves antibodies blocking microbe binding to cells to prevent infection.
• Antibodies inhibit microbe spread from infected to adjacent cells.
• Antibodies block toxin binding to cellular receptors to inhibit toxin's effects.
• Antibodies of IgG isotype opsonize microbes and promote phagocytosis by binding to Fc receptors on phagocytic cells like neutrophils and macrophages.
• IgG binds to infected cells by the Fab regions, and bind by Fc to Fc receptors on NK cells. The NK cells are activated and kill the cells in antibody-dependent cell-mediated cytotoxicity (ADCC).
• IgE binds to helminthic parasites by the Fab regions, and bind by Fc to Fc receptors on eosinophils which results in eosinophil activation and release of granule contents to kill parasites in antibody-dependent cell-mediated cytotoxicity (ADCC).
• IgG and IgM activate the complement system.
• IgA provides mucosal immunity by neutralizing microbes and toxins in the gut and respiratory tract lumens.
• Neonates are protected through maternal IgG antibodies transferred across the placenta and IgA antibodies from breast milk.

Primary vs. Secondary Immune Response

• The primary response occurs upon first exposure to an antigen.
• A lag phase of approximately 10 days occurs before the specific antibody is detectable during the primary response.
• The primary response predominately involves IgM antibodies.
• Antibody levels decline after a short time, during a primary response.
• Secondary response occurs upon subsequent exposure to the same antigen.
• The secondary response results in a more rapid antibody appearance, greater amount, and IgG class.
• The secondary response remains detectable for months or years.
• The secondary response requires class switching from IgM to IgG.
• Immunologic memory enables the secondary response and is possible, because the immune system has memory.
• Memory cells are long-lived B lymphocytes that form during the primary response after B lymphocytes become memory cells.
• The primary response is slow in onset, low in magnitude, forms IgM type antibodies, and is short lived.
• The secondary response is rapid in onset, IgG ( or IgA, or IgE) type, and is long lived.

Cell-Mediated Immunity

• T cells activation is key where naive T cells proliferate and differentiate into effector cells, including CD4+ T helper cells and CD8+ cytolytic cells (CTLs).
• CD4+ T cells differentiate into 2 effector cells:
  • IL-12 leads to T helper 1 (Th1)
  • IL-4 leads to T helper 2 (Th2)
• Th1 cells secrete IFN-γ activates phagocytes to kill microbes.
• Th2 cells secrete IL-4 and IL-5 which stimulate eosinophil and mast cell degranulation in allergy and helminthic infection.
• CD8+ T cells kill cells containing intracellular microbes or microbial proteins through direct cell cytotoxicity, eliminating infection reservoirs
• T cell activation needs two signals
  • The 1st signal is a peptide + MHC on the surface of APCs recognized by TCR-CD3.
  • The 2nd signal is the co-stimulatory, involving the interaction of B7 molecule on APCs with CD28 on T cells.
  • T cells doesn't work when exposed to antigen in absence of 2nd signal, and that leads to anergy (unresponsiveness).

Steps for CD8+ CTLs to kill infected cells

• CTLs must recognize class I MHC and peptides on the surface of the infected target cell
• Tight adhesions "conjugates" with these cells formation occurs
• CTLs are activated by IL-2 and IFN-γ to release granule contents toward the target cell, i.e., granule exocytosis.
• Granule contents include:
  • Perforin, which forms pores in the target cell membrane.
  • Granzymes enter the target cells through these pores, inducing apoptosis.
• CTL detaches from the target cell to kill other target cells.
• The target cell dies.

Major Histocompatibility Complex (MHC)

• MHC is a group of genes on the short arm of chromosome 6 that produces MHC molecules found on cell surfaces responsible for protein Ag display to T cells.
• MHC is also called human leucocytic Ag = HLA.
• Class I MHC genes: HLA-A, HLA-B, and HLA-C, which present Ag to Tc.
• Class II MHC genes: HLA-D region (HLA-DR, HLA-DP, and HLA-DQ), which present Ag to Th.
• Class III MHC genes: located between class I & II, which does not produce MHC but produce some complement components & TNF-α.
• MHC molecules are membrane proteins expressed on cells; each class I & II molecule consists of an extracellular, transmembrane, and cytoplasmic part
• Class I molecules:
  • Made of two polypeptide chains with α chain with 3 domains (α1, α2, α3) along side a polypeptide chain called β2 microglobulin encoded by a gene outside MHC.
  • α1 and α2 domains form the cleft or groove that binds peptides.
  • The cells present antigen to CD8+ cells using Class I molecules and also are expressed on all nucleated cells.
• Class II molecules:
  • Made of two polypeptide chains α and β . The α chain (α1 & α2) and the β chain (β1 & β2)
  • α1 and β1 domains form the peptide-binding cleft.
  • The cells present antigen to CD4+ cells using Class II molecules and also are expressed on APCs only.
• Class I MHC presents antigens to Tc (CD8).