Chapter 24 The Immune System

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

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)

Transplantion

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

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

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