Adaptive Immunity and MHC

• Module: Foundations of Immunology BMS172.
• Lecture Title: Adaptive immunity and MHC.
• Instructor: Professor Doctor Mohammed Mahmoud El-Naggar, Medical Microbiology and Immunology.
• Email:[email protected]
• Mobile: 01126625177
• Academic hours: Sunday 10:00-12:00 AM

Learning Outcomes

• Describe types of adaptive immunity.
• Identify functions of antibody isotypes.
• Compare primary and secondary humoral immune responses.
• Identify types of cell mediated immunity.
• Define MHC and describe MHC classes, structure, distribution, and functions.

Lecture Outline

• Types of adaptive immunity (humoral and cellular).
• Primary and secondary humoral immune response.
• Types of cell mediated immunity.
• Major histocompatibility complex.

Case Scenario

• A 65-year-old man with chronic renal failure received a kidney transplant from a blood group-matched friend.
• Two weeks post-transplant, continuous rises in creatinine levels occurred, and the patient may need renal dialysis again.
• Diagnosis and further tests are required.

Types of Adaptive Immunity

• Humoral (Antibody-Mediated) Immunity.
• Cell-Mediated Immunity.

Humoral Immunity

• Mediated by secreted antibodies.
• Defends against extracellular microbes and microbial toxins.

Functions of Antibody Isotypes

• Neutralization of microbes & toxins:
  • Antibodies block microbe binding to cells, preventing infection.
  • Antibodies inhibit microbe spread from infected to adjacent cells.
  • Antibodies block toxin binding to cellular receptors, inhibiting pathologic effects.
• Opsonization and phagocytosis:
  • IgG antibodies opsonize microbes, promoting phagocytosis by binding to Fc receptors on phagocytic cells like neutrophils and macrophages.
• Antibody-dependent cell-mediated cytotoxicity (ADCC):
  • IgG binds infected cells via Fab regions and NK cells via Fc regions, activating NK cells to kill.
  • IgE binds helminthic parasites via Fab and eosinophils via Fc, activating eosinophils to release granule contents and kill parasites.
• Activation of the complement by IgG and IgM.
• Functions of antibodies at special sites:
  • Mucosal immunity: IgA, produced in mucosa-associated lymphoid tissues (MALT) in the GIT and RT, neutralizes microbes and toxins in organ lumens.
  • Neonatal immunity: IgG from maternal antibodies crosses the placenta, and antibodies from breast milk protect newborns.

Primary Immune Response

• Occurs upon first exposure to an antigen.
• Lag phase of about 10 days before specific antibody detection.
• The main antibody is IgM.
• Antibody levels decline after a short period.

Secondary Immune Response

• Occurs upon re-exposure to the same antigen.
• Rapid antibody appearance.
• Greater antibody amount.
• IgG class antibodies.
• Detectable for months or years.
• Properties of the specific response to a different antigen for the first time are those of the primary response.

Comparison of Primary and Secondary Immune Response

• Primary response: slow onset, low magnitude, short-lived, IgM.
• Secondary response: rapid onset, high magnitude, long-lived, IgG (or IgA, or IgE).

Immunologic Memory

• The immune system possesses specific immunologic memory for antigens.
• During the primary response, some B lymphocytes become long-lived memory cells.
• The secondary response requires class switching (IgM to IgG).

Cell-Mediated Immunity

• Eradicates infections by intracellular microbes.
• Involves activation of naïve T cells, which proliferate and differentiate into effector cells such as CD4+ T helper cells and CD8+ cytolytic cells (CTLs).

Types of Cell-Mediated Immunity

• CD4+ T cells differentiate into 2 effector cells based on cytokine production:
  • IL-12 leads to Th1.
    • Th1 secretes IFN-γ: Activates phagocytes to kill microbes.
  • IL-4 leads to Th2.
    • Th2 secrets IL-4 and IL-5: Stimulates eosinophil and mast cell degranulation in allergy and helminthic infection.
• CD8+ T cells kill any cells containing microbes or microbial proteins in the cytoplasm (intracellularly) through direct cell cytotoxicity, eliminating the reservoir of infection.

Activation of T Cells

• Activated by two signals:
  • Signal 1: peptide + MHC on the surface of APCs recognized by TCR-CD3.
  • Signal 2 (co-stimulatory): interaction of B7 molecule on APCs with CD28 on T cells.
• Absence of the 2nd signal leads to T cell anergy (unresponsiveness).

Steps of Killing of Infected Cells by CD8+ CTLs

• CTLs recognize class I MHC + peptides on infected "target" cells.
• Formation of tight adhesions “conjugates” with these cells.
• CTLs are activated by IL-2 & IFN-γ to release their granule contents toward the target cell (granule exocytosis).
• The granules include:
  • Perforin: Forms pores in the target cell membrane.
  • Granzymes: Enter and induce apoptosis through caspase activation.
• Detachment of CTL from target cells to kill other target cells.
• Death of the target cell.

Major Histocompatibility Complex (MHC)

• Group of genes on the short arm of chromosome 6 which produce MHC molecules.
• Present on cell surfaces and are responsible for the display of protein Ag to T cells.
• Also known as human leucocytic Ag = HLA.

Classification of MHC Genes

• Class I MHC genes → HLA-A, HLA-B, HLA-C, involved in Ag presentation to Tc cells.
• Class II MHC genes → HLA-D region (HLA-DR, HLA-DP, HLA-DQ), involved in Ag presentation to Th cells.
• Class III MHC genes lie between class I & II, do not produce MHC, but produce complement components & TNF-α.

Structure and Distribution of MHC Molecules

• Membrane proteins expressed on cells, each class I & II molecule has an extracellular, transmembrane, and cytoplasmic part.
  • Class I MHC molecules:
  • 2 polypeptide chains: α chain formed of 3 domains (α1, α2, α3), attached to β2 microglobulin (encoded outside MHC).
  • α1 and α2 domains form the cleft or groove which bind peptide.
  • Present antigen to CD8+ cells, are expressed on all nucleated cells.
  • Class II MHC molecules:
  • 2 polypeptide chains: α chain (α1 & α2) and β chain (β1 & β2).
  • α1 and β1 domains form the peptide-binding cleft.
  • Present antigens to CD4+ cells and are expressed on APCs only.

Clinical case points

• Class I MHC presents antigen to: Tc(CD8).

Important notes on activation of T cells

• During activation of T cells, the 2nd co-stimulatory signal is the interaction of B7 molecule on APCs with CD28 on T cells.

Incorrect information

The secondary immune response in antibody formation is characterised with the following incorrect ideas:

• First exposure to antigen
• Usually formed of IgM
• It is slow in onset
• Antibody levels decrease rapidly
• Amount of antibody is great