Chapter 24 The Immune System

About this Chapter Anatomy & function of immune system, organs, & cells How the body defends itself Non-specific body defenses Specific defenses that target one pathogen Combined defenses against bacteria and viruses Allergies and autoimmune problems

Immune System Functions: Overview of Defenses Scavenge dead, dying or abnormal (cancerous) body cells Protect from pathogens & foreign molecules Parasites Bacteria Viruses

Immune System Functions: Overview of Defenses Figure 24-1: Viruses

HIV or Human Immunodeficiency Virus

Life Cycle

Infectious Causes of Gastroenteritis. Bok K, Green KY. N Engl J Med 2012;367:2126-2132.

Genomic Organization and Atomic Structure of the Norovirus Capsid. Figure 1. Genomic Organization and Atomic Structure of the Norovirus Capsid. The RNA genome of the prototype norovirus strain, Norwalk virus (shown at the top), is organized into three open reading frames (ORF1, ORF2, and ORF3) that encode the designated nonstructural and structural proteins. Most diagnostic primers used in reverse-transcriptase–polymerase-chain-reaction assay target conserved areas in the RNA-dependent RNA polymerase region (NS7POL). VP1, the major capsid protein (shown below), is further organized into the N-terminal (N), shell (S), and protruding (P) domains defined by the indicated VP1 amino acid residues. The P2 region of the P domain (blue) is exposed on the surface of the capsid protein and is the site where histo–blood group antigens (HBGAs) (magenta) interact with the virion (dashed box). 5, 13 Bok K, Green KY. N Engl J Med 2012;367:2126-2132.

Body Defenses: Overview Physical barriers: skin & epithelial linings & cilia Chemical: acids, mucous & lysozymes Immune defenses – internal Innate, non-specific, immediate response (min/hrs) Acquired – attack a specific pathogen (antigen) Steps in Immune defense Detect invader/foreign cells Communicate alarm & recruit immune cells Suppress or destroy invader

Lymphatic System: Overview of Immune Defense Organs & Cells Bone marrow Thymus Lymph nodes Spleen Lymph vessels Leukocytes: (white blood cells – WBCs)

Lymphatic System: Overview of Immune Defense Organs & Cells Figure 24-2 ab: Anatomy of the immune system

Key Cells & Overview of their Function in Immune Defense Lymphocytes: helper, plasma, cytotoxic & natural killer (NK) Basophils Mast cells Monocytes Macrophages Neutrophils Eosinophils

Key Cells & Overview of their Function in Immune Defense Figure 24-4: Cells of the immune system

Innate Immunity: Phagocytosis & Inflammation Physical & chemical barriers Phagocytosis: macrophages, neutrophils, NK cells Engulf and digest recognized "foreign" cells – molecules Inflammatory response

Innate Immunity: Phagocytosis & Inflammation Figure 24-6: Phagocytosis

Cells of the Innate Immune System The Innate Leukocytes include: Natural killer cells Mast cells Eosinophils Basophils Phagocytic cells: including macrophages, neutrophils and dendritic cells, and All these cells function within the immune system by identifying and eliminating pathogens that might cause infection

Chemical factors produced during inflammation Histamine Bradykinin Serotonin Leukotrienes Prostaglandins sensitize pain receptors, cause vasodilation of the blood vessels at the scene, and attract phagocytes, especially neutrophils

Inflammatory Response: Cytokines Signal Initiation Histamines: from mast cells  swelling, edema, b. v . dilation Interleukins: fever, b.v. gaps  WBC's & proteins  infection Bradykinin: pain & swelling Membrane attack complex proteins

Inflammatory Response: Cytokines Signal Initiation Figure 24-8: Membrane attack complex

Acquired Immunity: Antigen-Specific Responses Activate T lymphocytes: direct attack Activate B lymphocytes to become: Memory cells: 20 immune response to that antigen Plasma cells: antibodies – attack that antigen

Antigen Presentation to Immature T Cells Antigen presentation stimulates T cells to become either "cytotoxic" CD8+ cells or "helper" CD4+ cells. Cytotoxic cells directly attack other cells carrying certain foreign or abnormal molecules on their surfaces. Helper T cells, or Th cells, coordinate immune responses by communicating with other cells. In most cases, T cells only recognize an antigen if it is carried on the surface of a cell by one of the body’s own MHC, or major histocompatibility complex, molecules.

T Cell Dependent B Cell Activation A TH2 cell (left), B cell (right), and several interaction molecules

B Cell Activation

Stimulation of specific clone of B cells and its proliferation: Primary and Secondary Immune Response

Acquired Immunity: Antigen-Specific Responses Figure 24-13: Functions of antibodies

The Human Leukocyte Antigen (HLA) System Essential to immune function: HLA molecules present peptide antigens to the immune system (T-cells) Important for self versus non-self distinction

HLA Class I Monitors Inside of the Cell Tapasin CR CN The MHC class I and class II molecules present antigens from different sources. Class I molecules present intracellular antigens that are processed in the cytoplasm and pumped into the endoplasmic reticulum, where new HLA molecules are being assembled. Processing of the antigens is performed by the proteosome, a multimeric enzyme composed of 28 subunits. Two subunits are encoded by the LMP genes found within the HLA region of the chromosome. The subunits may change in response to IFN-. LMP2, LMP7 and a third component, MECL-1, are induced by IFN- and displace the constitutive components and favor the processing of new peptides, thus insuring that newly synthesized viral proteins will be amply represented on the cell surface. The proteosome also favors the cleavage of proteins into 8-10 amino acids with hydrophobic or basic carboxy termini that fit nicely into the peptide binding groove of the HLA molecule. Peptides that are processed in this manner are transported into the endoplasmic reticulum by TAP (transporter associated with antigen), which is comprised of two subunits, TAP-1 and TAP-2. TAP-2 as an ATP binding site, which regulates the active transport of peptides into the lumen of the ER. The TAP transporter has some specificity, preferring peptides of >8 amino acids with hydrophobic or basic amino acids at the carboxy terminus. This is the preferred peptide for binding in the MHC groove. The newly synthesized HLA molecule is maintained in a partially folded conformation by calnexin (not shown). When 2-microglobulin binds to the HLA molecule, the complex dissociates from calnexin and binds a complex of calreticulin and tapasin, which then bind to TAP-1. The proper binding of a peptide to the HLA molecule dissociates the complex, and the HLA molecule is then transported through the Golgi complex to the cell surface. Dr. Brian Freed

HLA Class II Monitors Outside of Cell Peptides Extra-cellular Proteins DM monitors peptide specificity for DR The presentation of peptides on MHC class II molecules is quite different. HLA-DR and related class II molecules are also assembled in the endoplasmic reticulum, but the associate with a third protein known as the invariant chain, which prevents peptide binding. The invariant chain is processed within endosomes to CLIP (class II-associated invariant chain peptide). In the presence of HLA-DM molecules, CLIP dissociates from HLA-DR or DQ molecules and allows binding of new peptides that have been endocytosed from the extracellular environment. Thus, MHC class II molecules differ from MHC class I molecules in that they preferentially present extracellular antigens rather intracellular ones. HLA-DM serves to ‘edit’ peptide binding, promoting association with high affinity peptides over lower affinity peptides. DM Dr. Brian Freed

Antigen–presenting cells (APCs): monocytes, macrophages, dendritic cells, B cells Teaching slides: www.barbaradaviscenter.com

Humoral Versus Cellular Immune Response

Class II (2.2 Mb) Class III (0.7 Mb) Class I (1.1 Mb) Complement & cytokines Class II (2.2 Mb)

HLA Genetic Nomenclature Gene low high resolution typing “subtype”=01 Allele: HLA-DRB1*0401 Haplotype: HLA-DRB1*0401 HLA-DQB1*0302 HLA-DRB1*0301 HLA-DQB1*0201 DRB1*02 Genotype: HLA-DRB1*04 HLA-DQB1*0302 J. Noble

T Lymphocytes: Cell Mediated Immunity T cell receptors: cell activated to antigen Major histocompatability complex (MHC) Helper T cells: Cytotoxic T cells: perforins, granzymes, (apoptosis) & Fas

Defenses against Bacteria: Complement P Activates: Make membrane attack complex  kill bacteria Inflammation: + recruit phagocytes, B & T lymphocytes (Acquired response  antibodies, cytotoxic Ts … if needed)

T Lymphocytes: Cell Mediated Immunity Figure 24-16: T lymphocytes and NK cells

Antigen Presentation Antigen presentation stimulates T cells to become either "cytotoxic" CD8+ cells or "helper" CD4+ cells. Cytotoxic cells directly attack other cells carrying certain foreign or abnormal molecules on their surfaces. Helper T cells, or Th cells, coordinate immune responses by communicating with other cells. In most cases, T cells only recognize an antigen if it is carried on the surface of a cell by one of the body’s own MHC, or major histocompatibility complex, molecules.

Defenses against Bacteria: Complement P Activates Figure 24-17: Immune responses to bacteria

Viral Defense: Summary of Innate & Acquired Responses Circulating antibodies inactivate or target virus (opsins) Macrophage  inflammation, interferon, cell activation Helper, cytotoxic T, NK & B cells  plasma c. antibodies

Viral Defense: Summary of Innate & Acquired Responses Figure 24-18: Immune responses to viruses

Allergic Response: Inflammation Reaction to Non-pathogen First exposure: sensitization Activation Clone B cells Form antibodies Memory cells Re-exposure Many antibodies Activated Ts Intensified Inflammation

Allergic Response: Inflammation Reaction to Non-pathogen Figure 24-19: Allergic responses

Blood Types: Like Antibodies & antigens will agglutinate Antigens on RBCs (A, B, AB or none = O) Antibodies in plasma (anti A, anti B, anti AB) Rh antigens & antibodies

Although there are over 600 known red blood cell antigens organized into 22 blood group systems, routine blood typing is usually concerned with only two systems: the ABO and Rh blood group systems. Antibody screening helps to identify antibodies against several other groups of red blood cell antigens. Some of the other groups are the Duffy, Kell, Kidd, MNS, and P systems

Blood Types: Like Antibodies & antigens will agglutinate Figure 24-20a: ABO blood groups

Autoimmune Diseases: Failure of “Self-Tolerance” Type I diabetes mellitus – immune system attacks - cells Graves disease – antibodies mimic TSH hyperthyroidism Multiple Sclerosis – autoimmine attack on myelin nerve sheath Rheumatoid arthritis – autoimmune attack on joint cartilage Myasthenia gravis – ACh-receptors at endplate attacked by immune system

Interaction of Nervous, Endocrine & Immune Systems Much yet to understand Neuroimmunomodulation All three share some: Signal molecules Receptors Overlapping responses Fight or flight Chronic stress

Interaction of Nervous, Endocrine & Immune Systems Figure 24-21: Model for interaction between nervous, endocrine, and immune systems

Summary Body defends itself with barriers, chemicals & immune responses WBCs and relatives conduct direct cellular attack: phagocytosis, activated NK & cytotoxic T cells and produce attack proteins (i.e. antibodies, complement, & membrane attack complex)

Summary Cytokines, communicate cell activation, recruitment, swelling, pain, & fever in the inflammation response Defense against bacteria is mostly innate while viral defense relies more on acquired immune responses Autoimmune diseases are a failure of self-tolerance