Introduction and Cells of the Immune System by malj


                                                              Friday, May 09, 2003, 11 AM
                                                                               Dr. Simecka
                                                             Rachel Eason for Erica Ayoub
                                                                               Page 1 of 10
                     Introduction and Cells of the Immune System
Dr. Puttoff addressed the class before the lecture started. He spoke about 4 issues:
        (1)        Excused absences—there is a change in procedure regarding this.
                   They will now be dealt with by Dr. Martin’s office (located at rm
                   402). Please read the e-mails regarding the new procedures requesting
                   an excused absence.
        (2)         He is receiving huge amounts of e-mail regarding questions students
                   have. If you are not present at a lecture, CIL, post-exam review, etc.,
                   please do not send him an e-mail to ask a question about anything you
                   don’t understand. He is a busy man and does not have time to be
                   looking at a bunch of e-mail. He said to look it up in the text.
        (3)        Cheating—He also has received numerous e-mails regarding this, and
                   in turn, contacted administration himself. He has made changes in the
                   format of the CILs—scantrons will be completed and picked up first,
                   and then there will be a discussion about the questions. This will be a
                   formal examination and should prevent any type of cheating. If he
                   hears about one more case of cheating, the attendance points for the
                   course will also be changed to scored quizzes.
        (4)        Post-exam reviews—There have been requests for detailed
                   explanations of some of the questions missed. Again, he and other
                   professors do not have time for this, and the answers to these
                   questions can also be looked up in the text.
He introduced Dr. Jerry Simecka who will be in charge of the section on Immunology for
the course and also collaborate with him for the Microbiology portion of the course. Dr.
Simecka is head of the section of Microbiology and Immunology in the Department of
Molecular Biology and Immunology. He received his PhD at the University of Alabama
at Birmingham.

Dr. Simecka & Dr. Mathews has placed power points on the web along with an outline of
topics and a number of study questions from his section. His test questions may be more
difficult with use of clinical vignettes.

I. Introduction
        A. Immunology-the study of host response against pathogens/disease, some sort
            of irritant. It could be cancer, infectious agents, environmental agents, or
            anything that causes damage to the human. Looks at processes against these
        B. Pathogens—includes 4 major classes
                1. Extracellular—live outside of cells in the tissues
                2. Intracellular—bacteria or parasites that spend part of life cycle inside
                     the cell, a hiding place from the host.
                3. Viruses (intracellular)—replicate using the host’s genetic machinery.
                     A portion of their life is spent extracellularly.
                4. Parasitic worms
                                                               Friday, May 09, 2003, 11 AM
                                                                                 Dr. Simecka
                                                              Rachel Eason for Erica Ayoub
                                                                                 Page 2 of 10
               5. Each has a different immune mechanism to attack them. There is
                   some overlap of these immune processes. We should think about the
                   different types of pathogen and which immune response acts best
                   against them as we study this topic.
        C. Defenses and host response
               1. Physical barriers—we are exposed to a number of potential pathogens
                   daily and do not get sick. This is because we have physical barriers
                   such as skin, tears, mucous that protect us against them. In tears, there
                   are enzymes that attack and digest pathogens. Successful pathogens
                   must be able to cross the physical barriers first
               2. Innate immunity—if the physical barriers are breached, there is an
                   immediate response to a pathogen. It (innate immunity) is nonspecific,
                   recognizes a bacteria that is foreign and immediate responds to it.
                   There are two levels of innate immunity
                         a. Resident-occurs immediately at the site of recognition and
                              takes care of the problem
                         b. Induced (inflammation, activated macrophages, etc.)—initial
                              reaction does not work, so a greater response is generated.
               3. Adaptive immune response-if the innate system is not enough, this
                   system is activated. The major difference between the adaptive and
                   the innate system is that the adaptive system has specificity and
                   memory and the innate does not. This system recognizes a specific
                   pathogen and attacks only it. The innate recognizes anything foreign,
                   any sort of pathogen, and will attack it (it has mechanisms for this). It
                   is divided into 2 categories:
                         a. Humoral (antibody mediated)
                         b. Cell-mediated (effector T cells)
               4. There is a lot of overlap and interaction between the adaptive and
                   innate immune systems. The innate immunity system can help induce
                   adaptive immunity and adaptive immunity enhances innate immunity.
II. Innate immune system
        A. Think of phagocytes-cells that ―eat bacteria‖ –or engulf and destroy them.
            There are two major professional phagocytes
               1. Neutrophils
               2. Monocytes/macrophages—monocytes are present in the blood stream
                   and they become macrophages as they migrate out of the blood stream
                   into the tissues.
        B. Natural Killer cells (NK cells)-another cell type that participates in the innate
            immune system. (This is the area of research of Dr. Mathew)
               1. Their main function is to kill virally infected and tumor cells. They
                   recognize cells that have become ill and then remove them
               2. Produce cytokines, small peptide hormones of the immune system that
                   allows it to communicate between cells. Cytokines can influence the
                                                                Friday, May 09, 2003, 11 AM
                                                                                 Dr. Simecka
                                                               Rachel Eason for Erica Ayoub
                                                                                 Page 3 of 10
                    type of immune response, enhance phagocyte function, especially the
                    macrophages. They are, thus, very important.
       C. Complement-Is a cascade of proteins in the plasma that recognizes pathogens
           and attacks them via the alternative pathway. This system also enhances
           phagocytosis and recruits other cells.
       D. Inflammation—accumulation of fluids and white blood cells to localize and
           remove irritants from a site of infection. It also sets up the area for repair of
III. Adaptive immunity
       A. Specifity and memory are major characteristics.
       B. Look at the response of an antibody. (see Figure 1 at end of notes.)
               1. On the x-axis is an individual measured over time. On the y-axis, is a
                    graph of antibody response. Give the person an antigen, a foreign
                    substance that can induce an immune response. Inject the individual
                    with the Ag, and we do not see any response for 3-5 days. Then we
                    will see an antibody response develop that will subsequently fade off.
                    If we give the individual a second dose of the same antigen, we will
                    see a lag period of only 1-2 days with a much greater response. If we
                    immunize the person at the same time with a completely different
                    antigen, this will take 3-5 days and have a similar response as with the
                    first time we gave the 1st antigen. The period in which the first antigen
                    was presented is termed the primary response (see graph). The second
                    time the same antigen is presented; it is termed the secondary
                    response. Pay attention to the lag period, with the primary response it
                    is 3-5 days and with the secondary response it is 1-2 days. Also note
                    that there is a much greater response, the second time the antigen is
                    presented. This indicates that there is memory response; this
                    individuals remembers that it saw the antigen before and responds to it
                    more rapidly and greater than before. Finally, this graph shows that
                    the response is specific: as a completely different antigen is given at
                    the same time as the initial antigen, the individual responds to that
                    antigen differently, like the primary response.
               2. There are a number of different classes of antibodies: IgG, IgM, and
                    IgA (will be discussed in greater detail on Monday). Usually in the
                    primary response, the Ab class is IgM initially, and then we see a IgG
                    response. In the secondary immune response, will see IgG and less
                    IgM (about the same as the first). There is a switch between being an
                    IgM dominant response in the primary response to an IgG dominated
                    response in the second immune response. IgM response here will be
                    faster (in the secondary response), but the important thing is that the
                    IgG response is much greater.
               3. Also affinity maturation, the affinity of the Ab for the Ag (strength of
                    binding, how specific the response is), is much higher in the secondary
                    response than in the primary response.
                                                              Friday, May 09, 2003, 11 AM
                                                                               Dr. Simecka
                                                             Rachel Eason for Erica Ayoub
                                                                               Page 4 of 10
       C. Major cell type is the lymphocyte with two major types of responses
              1. T lymphocytes-regulate immunity, kill infected cells, activate
                 macrophages, etc. He called them the ―conductors of immune
                 response.‖ There are 2 major T-cell populations
                       a. cytotoxic T cells (with marker on surface, CD8, so known as
                           CD8+ cells) kill virally infected and cancer cells, as well as
                           cells with intracellular bacteria. So do some of things that
                           NK cells do, but NK cells recognize cells that are sick and
                           these cells recognize cells that are infected with a specific
                           virus. They recognize the viral antigen that is present on the
                           surface of a virally infected cell. Thus, they recognize things
                       b. T helper cells (with marker on surface, CD4, so known as
                           CD4+ cells)
                              (1) H.I.V. causes depletion of this population of cells so
                                  monitor CD8+ to CD4+ ratio and CD4+ number to
                                  stage the disease and determine when the patient
                                  develops A.I.D.S
                              (2) They help direct/regulate immune response.
                              (3) There are two major classes of T helper cells divided
                                  based on the different cytokines they produce and
                                  determine their function (we need to know these
                                      (i)     TH1 cells → cell mediated immunity-
                                              IL-2, IFN-γ, TNF-β, and GM-CSF
                                      (ii)    TH2 cells involved with humoral immunity-
                                              (activate B cells and help produce more Ab)
                                              -IL-4, IL-5, IL-6, IL-13
IV. Adaptive immunity
       A. Humoral (antibody-mediated) immunity
              1. Antibody [Ab] (immunoglobulin) specifically binds to antigen [Ag]
                 and targets its destruction. See figure 2 for structure. The antibody
                 consists of 2 heavy chains that are identical and 2 light chains that are
                 identical. It has a region that binds to a foreign antigen called the
                 variable region. Another portion is called the Fc portion. The Fc
                 portion tells how the foreign Ag will be destroyed and the variable
                 region tells what will be destroyed. An individual can respond to any
                 viruses or foreign material it has not seen. This is because there is a
                 system to generate variable regions that will react with anything. The
                 heavy chain, particularly the Fc portion, determines the class of the
              2. Functions of antibodies:
                       a. Neutralization: Ab binding to Ag inhibits its activity. Toxin
                           works by binding to a receptor on a cell, entering it, and
                                                              Friday, May 09, 2003, 11 AM
                                                                                 Dr. Simecka
                                                              Rachel Eason for Erica Ayoub
                                                                                 Page 5 of 10
                             causing effects. The binding of the Ab to it and inhibits it
                             interaction with the receptor prevents this from happening.
                             Ab can also bind to a virus and prevent it from interacting
                             with a cell receptor.
                        b. Opsonization: phagocytes have receptors for the Fc portion
                             of an Ab and when an Ab binds to the bacteria, it marks it for
                             phagocytosis more effectively and efficiently. Certain
                             classes of Ab are better at doing this than others.
                        c. Complement activation: Ab binding to bacteria will help
                        d. Antibody-dependent cell-mediated cytotoxicity (ADCC):
                             Cells (NK cells, macrophages, neutrophils) recognize Ab
                             bound to target cell and release substances to destroy the
                             target cell. Is different from phagocytosis, which a cell is
       B. Cell-mediate immunity—Antigen-specific T cells play a major role
              1. Cytotoxic T cells-lysis of viral and tumor cells
              2. Activation of macrophages by TH 1 cells, e.g., produces cytokines
                  such as gamma-interferon to activate macrophages.
V. Acquired immunity
       A. Passive immunization (host does not generate own response, host given Ab)
              1. Host given antibody, e.g. antivenom, Ab specific for snake venom,
                  binds to snake venom toxins and neutralizes it. Another e.g., is
                  maternal Ab, which are given to fetus via placenta during pregnancy.
                  At 6 months, an infant seems to get ill more frequently. The maternal
                  Ab present in the infant are decreasing below levels that are protective,
                  and this is the period of transition when the child starts to generate his
                  own immune response
              2. Is rapid and transient
       B. Active immunization
              1. Host generates own humoral and cell-mediated immune responses, e.g.
              2. Involves a lag-time (requires 3-5 days before generates a response) and
                  is long-lived (perhaps, a lifetime).
VI. Development of an immune response
       A. Clonal selection theory-Nobel Prize for it (see figure 3)
          In bone marrow or developmental tissue (thymus), we have lymphocytes that
          randomly generate unique receptors in the absence of an antigen or foreign
          stimulus. The first step is that we need to remove cells with receptors that are
          specific for self, in order to prevent an immune response against self. If not
          done, will have a high death rate for the progenitor lymphocyte cells. Other
          cells survive that do not recognize self, but have unique surface receptors that
          are not specific. If Ag present now, a cell will become activated and produce
          many more cells like it. Select a clonal cell that is not reactive to self, but to
                                                             Friday, May 09, 2003, 11 AM
                                                                                Dr. Simecka
                                                             Rachel Eason for Erica Ayoub
                                                                                Page 6 of 10
          some specific Ag and expanding it to react quicker at a later time period. Can
          be B cells also—in the bone marrow. T cells in the thymus.
       B. Activation of lymphocytes requires more than antigen recognition (same
          concept holds for B cells)
              1. First thing that happens is—cell adhesion molecules (CAM) mediate
                  interactions between T cells and antigen presenting cells (APC). Is
                  non-specific and transient. APC include macrophages, dendritic cells,
                  and B cells
              2. Once the T cell is bound, it is looking for Ag it is specific for. It
                  recognizes peptide bound to Major Histocompatibility Complex
                  (MHC) molecules. Called HLA in humans. These are the first signals.
                  These molecules are important in antigen presentation. They are what
                  you match for tissue grafts—called MHC because first recognized in
                  rejected skin grafts. There are two types that are structurally and
                  functionally different
                         a. CD8+ T cells: recognize peptide bound to MHC I:
                             endogenous antigen
                         b. CD4+ T cells: recognize peptide bound to MHC II:
                             exogenous antigen ***Remember by 8 x1=8 and 4 x 2=8
                         c. T cells only recognize peptide, don’t recognize entire protein.
                         d. Process of Antigen processing-degrades proteins into
                             peptides. Where peptides arise determines if are MHC I
                             (from inside cell) or MHC II (outside cell, in phagocytes)
              3. Cells become anergic if they don’t do anything else (only see Ag).
                  Will forget if Ag is presented again, will not respond to it. Require a
                  second co-stimulatory signal—CD28 on T cells binding to B7 on APC
              4. Same thing occurs with B cells, it recognizes an entire Ag and requires
                  a co-stimulatory signal that is delivered by T helper cells. Look for
                  this in reading.
VII. Immunopathology
       A. Autoimmunity—loss of self-tolerance –will attack some organ or part of
          body. Different targets determine what autoimmune disease it is, e.g. lupus or
          rheumatoid arthritis.
       B. Immunodeficiency—there is something wrong with the immune system, the
          individual cannot respond properly. The most common inherited form is a
          deficiency of IgA. IgA is associated with mucosal secretions, and individuals
          with this, cannot respond to GI and respiratory infections. Another common
          immunodeficiency that is acquired is A.I.D.S., in which individuals lose T
          helper cells.
       C. Hypersensitivity-the immune system responds, but in a stronger, inappropriate
          manner. E.g., Allergies, asthma, reaction to poison ivy
       D. Blood transfusion reactions & graft rejections—you are given an individual
          foreign material (trying to save his/her life) and he/she is responding to it.
VIII. Lymphoid Tissues
                                                          Friday, May 09, 2003, 11 AM
                                                                           Dr. Simecka
                                                          Rachel Eason for Erica Ayoub
                                                                           Page 7 of 10
       A. Primary—refer to immune system development
             1. Hematopoietic tissues
             2. Bone marrow
                       a. B cell development in adults (liver in fetus)
                       b. Myeloid cell development
                       c. T progenitor cells migrate to thymus
             3. Thymus
                       a. T cell development
                       b. Removal of self-reactive T cells
                       c. Reduced activity with aging (elderly not respond to
                           vaccinations well and have not as good response to viral
       B. Secondary—infrastructure where develop immune response to an infection or
             1. Provide the microenvironment
             2. Lymph nodes
             3. Spleens—for Ag that are blood-borne. If removed or lost, an
                 individual is more susceptible to blood borne infections. (was on a
                 board exam)
             4. Mucosal associated lymphoid tissues (MALT)—along mucosal
                 surfaces, largest site of immune system (would cover ¾ of a tennis
                       a. Peyer’s patches
                       b. BALT

IX. Two major lineages
      A. Myeloid cells
             1. Monocytes and macrophages
             2. Neutrophils (PMNs)
             3. Mast cells-allergies and parasites, other inflammatory responses
             4. Basophils- allergies and parasites?
             5. Eosinophils-allergies and parasites
      B. Lymphocytes
             1. T cells [T cell receptor (TCR), CD3]
                       a. TH cells (CD4)
                       b. CTL (cytotoxic T lymphocytes (CD8)
             2. B cells [surface immunoglobulin (slg)]
             3. NK cells (Fc receptor, no TCR or slg)
      C. Other cells
             1. Interdigitating dendritic cells- potent Ag presenting cells to T cells—
                  both myeloid and lymphoid derived populations
             2. Langerhan’s cells—skin
                       a. pick up Ag in skin and bring to lymph nodes to T cells
                       b. maturation to APC during migration
                                             Friday, May 09, 2003, 11 AM
                                                               Dr. Simecka
                                             Rachel Eason for Erica Ayoub
                                                               Page 8 of 10
3. Follicular dendritic cells-germinal centers
   ***Captures immune complexes and presents antigen to B cells, not T
   cells. Called dendritic cells due to morphology, not function. Unlike
   langerhan’s and interdigitating dendritic cells, which present to T cells.
Friday, May 09, 2003, 11 AM
                 Dr. Simecka
Rachel Eason for Erica Ayoub
                 Page 9 of 10
Friday, May 09, 2003, 11 AM
                 Dr. Simecka
Rachel Eason for Erica Ayoub
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