Module 5 - the Immune System (A and B)

bolded is what Dr. Ahangari said will possibly be important


defense mechanisms

  • innate immunity

    • nonspecific

  • adaptive immunity

    • specific


innate immunity

  • nonspecific defense mechanism of the body

  • includes external and internal defenses

  • defenses are always present in the body

    • first line of defense against invasion by potential pathogens

  • phagocytosis, chemotaxis, fever


phagocytosis

  • part of innate immunity

  • “eating” of a pathogen

  • 3 major phagocytic cell groups

    • neutrophils in blood

    • monocytes in blood and macrophages in connective tissues

      • cells of the mononuclear phagocyte system

    • organ-specific phagocytes in liver, spleen, lymph nodes, lungs, brain

      • in spleen, called Kupffer cells; in brain, called microglia

    • phagocytes remove foreign particles from blood → blood is usually sterile after a few passes through liver and spleen


chemotaxis

  • part of innate immunity

  • movement of toward chemokines

    • chemokines: a subclass of cytokines

      • chemical attractants that attract leukocytes during infection

  • neutrophils arrive first at infection site

  • monocytes arrive later, can transform → macrophages

  • all connective tissues have a resident population of all leukocyte types that move to infection


fever

  • increase in body temp set-point in response to the hypothalamus

  • temp is regulated in hypothalamus in response to PGE2

    • pyrogen triggers PGE2 release → hypothalamus responds with body temp increase

  • pyrogen: a fever-inducing substance

    • can be endogenous (internal) or exogenous (external)

      • e.g. LPS (lipopolysaccharide, a bacterial substance) is an exogenous pyrogen

  • cytokines are part of innate immune system

    • produced by phagocytes

    • cause increase in thermoregulatory set-point in hypothalamus

    • e.g. interleukin 1,2, IL-6, tumor necrosis factor-alpha

    • get released into general circulation → migrate to circumventricular organs of brain (where blood-brain barrier is reduced) → bind w/ endothelial receptors on vessel walls or interact with local microglia → activate arachidonic acid pathway

  • PGE2 release:

    • comes from arachidonic acid pathway

    • mediated by phospholipase A2 (PLA2), COX-2, and PGE2 synthase

      • COX-2 converts arachidonic acid → PGE2

      • enzymes^ usually mediate synth and release of PGE2

      • PGE2 is ultimate mediator of fever response (irritates temp center of hypothalamus)


adaptive immunity (specific)

  • specific defense in the body

  • involves antibodies, haptens, lymphocytes


antigens

  • aka immunogens

  • molecules that stimulate immune response

  • usually proteins or polysaccharides

  • include parts of bacteria (coats, capsules, cell walls, flagella, fimbrae, toxins), viruses, other microorganisms

  • lipids and nucleic As can be antigenic

    • but only if combined with proteins and polysaccharides

  • stimulate production of specific antibodies with specific binding sites


haptens

  • low-molecular weight molecules with an antigenic determinant

  • but not antigenic themselves unless they complex with an immunogenic carrier

    • e.g. bind to protein → become antigenic determinant on the proteins


lymphocytes

  • 3 major types: T cells, B cells, natural killer (NK) cells

  • NK cells are part of innate immune system

    • play major role in defending host from tumors and virally infected cells

      • level of NK cells increases with tumor or infection

    • activated in response to interferons → release cytotoxic granules which destroy altered cells


local inflammation

  • a response of an organism to a pathogen

  • bacterial infection → capillaries rupture → activate platelets → platelets move toward affected area → stops bleeding

  • after platelets, mast cells are activated → release histamine → acts as vasorelaxator in skin area → neutrophils come out of blood vessels toward affected area


B lymphocytes

  • part of the adaptive immune system

  • secrete antibodies that bind to antigens in a specific fashion


antibodies

  • aka immunoglobins (Ig)

  • part of gamma globulin class of plasma proteins

  • 5 distinct bands of proteins: albumin, alpha-1 globulin, alpha-2 globulin, beta globulin, gamma globulin

    • IDed by electrophoresis

  • 5 Ig subclasses: IgG, IGA, IgM, IgD, IgE

    • most serum antibodies are IgG

    • most antibodies in external secretions (e.g. saliva, milk) are IgA

    • IgE antibodies are involved in certain allergic rxns

  • structure: 4 polypeptide chains

    • 2 heavy (H), 2 light (L)

    • both chains have variable and constant regions

    • connected by disulfide bridges

    • antigen binding sites are at the ends of the “Y”

  • combo of Ig with antigen does not cause destruction of antigen or pathogen

  • Igs ID targets for immunological attack and activate nonspecific immune processes that destroy invaders

  • able to stimulate phagocytosis

    • opsonization


the complement system

  • a system of serum proteins activated by Igs to destroy bacteria

  • proteins are designated C1-C9

    • present inactive in plasma and other body fluids

    • become active by attachment of Igs to antigens

  • 3 components:

    • recognition: C1

    • activation: C4, C2, C3 (in that order)

    • attack: C5-C9

      • complement fixation: complement proteins attach to cell membrane, destroy victim cell

  • classic pathway:

    • bacteria activates IgB and IgM → IgB and IgM activate C1

    • C1 catalyzes hydrolysis of C4 → C4a and C4b

    • C4b binds to cell membrane, becomes an active enzyme

    • C3 is cleaved → C3a and C3b

      • through intermediate step, involves splitting of C2

    • C3b converts C5 → C5a and C5b

    • C3a and C5a stimulate mast cells to release histamine

    • C5a also acts as chemokine → attracts neutrophils and monocytes to site of infection

    • C5-C9 insert into bacterial cell membrane → form membrane attack complex

      • attack complex is large pore that can kill bact. cell through osmotic water influx

  • note: complement proteins kill cell, not Igs directly

    • Igs serve as activators of the process

      • (Igs are the “lock on target” and pull the trigger, but are not the actual bullet)


T lymphocytes

  • part of active immunity

  • CD8+ T cells assoc. with MHC class I

  • CD4+ T cells assoc. with MHC class II

  • subsets: helper, cytotoxic, memory, suppressor/regulatory, NK


helper T cells

  • middlemen of adaptive immunity

  • when activated: divide rapidly, secrete cytokines

    • cytokines regulate immune response

  • differentiate into Th1, Th2, Th17, or other subsets depending on the cytokine signal received → secrete different cytokines


cytotoxic T cells (Tc)

  • aka CD8+ cells (express CD8 glycoprotein at surface)

  • destroy virally infected and tumor cells, implicated in transplant rejection

  • interact with Th cells → transform into suppressor T cells

    • suppressor T cells prevent autoimmune diseases


memory T cells (Tm)

  • a subset of antigen-specific T cells that persist long-term after infection has resolved

  • quickly expand to large numbers of effected T cells upon re-exposure to cognate antigen → provide immune system with “memory” against past infections

  • 2 subtypes: central (TCM) and effector (TEM)

  • may be either CD4+ and CD8+


regulatory T cells (Treg)

  • important for maintenance of immunological tolerance

  • major role: shut down T cell mediated immunity toward end of immune reaction, and suppress auto-reactive T cells that escaped (-) selection in thymus

  • aka CD4+ cells, formerly suppressor T cells

  • 2 major classes:

    • naturally occurring (Cd4+CD25+FoxP3+) Treg cells arise in thymus

    • adaptive (aka Tr1 or Th3) may originate during normal immune response


natural killer T cells (NK)

  • special kind of lymphocyte

  • bridge adaptive and innate immune systems

  • recognize glycolipid antigen by CD1d (a molecule)

    • unlike conventional T cells that recognize peptide antigen presented by MHC molecules


diseases caused by immune system

  • autoimmunity

    • failure of an organism to recognize its own constituent parts as “self”

    • failure of recognize goes down to sub-molecular levels

    • result: immune response against its own cells and tissues

    • e.g. type I diabetes, rheumatoid arthritis, lupus, Graves’ disease

  • complex diseases

  • allergy

    • immediate hypersensitivity

      • results when an allergen provokes production of IgEs

      • IgEs attach to tissue mast cells, stimulate release of chemicals (e.g. histamine) from mast cells

      • can be treated with antihistamine

    • delayed hypersensitivity

      • cell-mediated response of T lymphocytes

      • e.g. contact dermatitis

      • patient has the disease for their entire life


clinical points

  • NSAIDs/aspirin inhibit COX-2 → prevent PGE2 formation → inhibit fever


clinical cases

  • 25 y.o. female has weight loss, nervousness, anxiety, hypertension, sleep disorder. Blood test shows everything is normal (Na, K, glucose, Ca, etc). What do you think?

    • hyperthyroidism

  • 25 y.o. female has hypertension, muscle spasms, muscle weakness, headache. Blood test shows increased blood [Ca]. What is your opinion?

    • hyperparathyroidism

  • 25 y.o. female has hypertension, headache, polyuria, weight loss, nephropathy. Urine test shows glucose. What is the cause of hypertension?

    • type I diabetes (diff dx btwn type I and II is weight loss)