Lectures 1 & 2 The immune system Overview

Grading: Exam I 25% Exam II 25% State Exam 35% Lecture highlight 5% Final oral report 10%

Textbook LCME 514 Lectures Core

Oral reports: A student each lecture will take turn to summarize the last lecture’s highlights for 5 minutes, and take questions from other students

Experts in Clinical Immunology On 4/19/05, each student should present for 5 minutes as if he or she is an expert immunologist on the disease. This presentation accounts for 10% of the final grade. The students should include following components in their presentation: 1. What is the immunological mechanism of the disease? Describe the major immune components (cells, cytokines or molecules) and their functions in each disease. 2. What are the diagnosis criteria? 3. What are the therapy options?

Before lecture Read the textbook and try to understand all the terminologies in bold. These are building blocks so that we can build a “nice house of Immunology” in the class.

Lecture objectives What components make up the immune system? Cells, organs, cytokines and molecules involved in the immune system What is the goal of the immune system? To clear pathogens and cancer cells in our body Innate and adaptive immune responses Humoral Immunuty and Cell-Mediated Immunity What are the side effects of the immune system? Autoimmune diseases, Allergies, Transplantation Rejection

goal of the immune system The goal of the immune system Figure 1-2 Plus tumor cells

Figure 1-3 part 1 of 4

Figure 1-3 part 2 of 4

Figure 1-3 part 3 of 4

Figure 1-3 part 4 of 4

The territory to defend by the immune system: the physical barriers Figure 1-4 The immune system =The defense system of the body

Innate (immediate) and adaptive (late but antigen-specific) immune responses Figure 1-7

Innate and adaptive responses work together Antigen-dependent Slower (days) T cells B cells Innate Antigen independent Immediate (hours) Neutrophils NK cells Macrophages Dendritic cells *Innate immune responses help form adaptive immune responses, and Adaptive immune responses utilize the machinery of innate immunity for effector function

Cells of Innate Immunity Neutrophils NK cells Macrophages Mast cells Eosinophils Basophils

Cells of Adaptive Immunity Dendritic cells B cells T cells (CD4 or CD8)

Immune cell recognition of pathogens followed by destruction Figure 1-5

Infection induces inflammation to recruit more immune cells Figure 1-6

Hematopoiesis generates immune cells Stem cells: 1. Self renewal 2. Totipotency They are in bone marrow after fetal development. They make all myeloid and Lymphoid blood/immune cells T cell progenitors migrate to thymus and generate T cells B cell progenitors reside in bone marrow to make naïve B cells Immune cells = Soldiers

Hematopoiesis occurs in the adult bone marrow Figure 1-10

Myeloid vs. Lymphoid cells Stem cells Myeloid cells Lymphoid cells T cells: T cell antigen receptor B cells: B cell antigen receptor NK cells: no antigen-specific receptor

Monocytes: Macrophage precursors Origin : bone marrow Antigen receptors: No Function: to become macrophages Present in blood circulation

Neutrophils: Phagocytes Origin and maturation: Bone marrow Antigen receptors: No Function: Phagocytosis and killing of microorganisms Where: in blood circulation Sites of function: infection sites Short life span

NK cells: natural killers Origin : many (bone marrow and thymus) Antigen receptors: No Function: Kill tumor and virus-infected cells Effector machinery (=weapons): perforins and granzymes

Macrophages: Phagocytosis and antigen presentation Origin : bone marrow Antigen receptors: No Function: phagocytosis of microorganisms and antigen presentation to T cells Present in various tissues in various forms (Kupffer cells, intraglomerular, alveolar, serosal, microglia, spleen sinus and lymph node sinus macrophages)

Dendritic cells (DC): transport antigens and activate T cells Origin : bone marrow Antigen receptors: No Function: antigen presentation to T cells Mechanisms: phagocytosis, cytokines (IL-4, IL-10, IL-12) and antigen-presentation through MHC molecules Migration: From tissue infection sites to 2o lymphoid tissues

Mast cells: parasite killers Origin : bone marrow Antigen receptors: No Function: to kill parasites Sensor: IgE receptor Effector machinery:cytotoxic granules, lipid mediators, cytokines and chemokines Present in connective tissues

Eosinophils: worm (parasites) killers Origin : bone marrow Antigen receptors: No Function: killing of antibody-coated parasites through release of killing mix (granule contents) Effector machinery:cytotoxic granules, lipid mediators, cytokines and chemokines

Basophils: relatives of mast cells and eosinophils Origin : bone marrow Antigen receptors: No Function: important effector cells in allergic disorders and immune responses to parasites Sensor: IgE receptor Effector machinery:cytotoxic granules, lipid mediators, cytokines and chemokines

T lymphocytes: master regulators of the immune system Origin: Bone marrow Maturation: Thymus Differentiation to effector cells: secondary lymphoid tissues (Lymph nodes, spleen, Peyer’s patch, and tonsils) Antigen receptors: Yes Function: regulates humoral and cell-mediated immune responses Mechanisms: cytokines, cell surface molecules, granules (cytotoxic T cells)

B lymphocytes: antibody producers Origin and maturation: Bone marrow Differentiation to plasma B cells: secondary lymphoid tissues (Lymph nodes, spleen, Peyer’s patch, and tonsils) Antigen receptors: B cell receptor (cell surface immunoglobulins) Function: Production of antibodies (IgM, IgE, IgA, and IgG) Regulated by T cells

B lymphocytes Antigens+ T cell help

Circulating blood cells Figure 1-12

Neutrophils: disposable phagocytes to clear pathogens Figure 1-13

Macrophages engulf bacteria and produce inflammatory cytokines Figure 1-14

The lymphatic system Figure 1-15

Naïve lymphocytes encounter pathogens’ antigens in lymph nodes Figure 1-16 Activates lymphocytes Beginning of adaptive response

Antigens+DCs T cells Figure 1-17 B cells undergo differentiation to PC

Figure 1-18

Figure 1-19 Spleen does not have Afferent Lymphatics Spleen filters blood to search for antigens

Figure 1-20

Antigen receptors of B cells and T cells Figure 1-21

Antibodies neutralize pathogens in an antigen-specific manner Figure 1-22

Figure 1-23 Gene rearrangement to form antigen receptors on lymphocytes (immunoglobulins and T cell receptors)

Figure 1-24 Antibodies (B cells) bind whole proteins while TCR (T cells) binds small peptides

Peptides are presented to TCR by MHC class I or II molecules on APC (antigen presenting cells: B cells, dendritic cells and macrophages) Figure 1-25

Viral antigen presentation to CD8+ T cells via MHC class I molecules Figure 1-26

Bacterial antigen presentation to Th1 or Th2 CD4+ cells Figure 1-27

Selection and expansion of antigen specific T and B cells Figure 1-8

Figure 1-28 Generation and selection of T cells The thymic selection processes are to generate T cells with functional TCRs that are not autoreactive.

Antibodies neutralize and opsonize Figure 1-29 part 1 of 2

Figure 1-29 part 2 of 2

Typical time course of adaptive immune responses Primary response Slow (2 weeks) Weak Secondary Fast (several days) Vigorous

The impact of vaccination

Unwanted immune response: allergies

Unwanted immune response: autoimmune diseases

The goal of a balanced immune system [Pathogens]= 0 [tumor cells]= 0 Immunity

Allergy and hypersensitivities Immune response to allergens [Pathogens]= 0 [tumor cells]= 0

[tumor cells] >> 0 Cancer [tumor cells] >> 0 Immune response to tumor cells

Autoimmune diseases Immune response to self antigens [Pathogens]= 0 [tumor cells]= 0

[tumor cells] >> 0 Immunodeficiency [Pathogens] >> 0 [tumor cells] >> 0 Immunity to pathogens and cancer cells e.g. AIDS patients

Immune responses can be both beneficial and harmful Figure 1-34