Immunology Review Questions

General Characteristics

• Adaptive immunity works together with inflammation

• It has the ability to recognize foreign or "nonself" substances called antigens

• Antigens include pathogens, noninfectious environmental agents, drugs, vaccines, transfusions, and transplants

• Provides long-term protection

• It is slower to react than innate immunity but more specific

• Has memory

• End products of adaptive immunity include lymphocytes (T and B cells) and antibodies known also as Immunoglobulins (Ig)

• Each individual T or B cell specifically recognizes only one particular antigen, generation of clonal diversity

• The sum of the population of lymphocyte specificities may represent millions of foreign antigens

• The thymus is the primary lymphoid organ for T cells, and bone marrow for B cells

• Clonal diversity occurs in primary lymphoid organs

• Involves maturing of B and T cells

• Migrates to secondary lymphoid organs

• Clonal selection processes and presents antigens to immune cells by antigen-presenting cells (APCs)

• T-helper cells (Th) and APCs interact

• Interaction results in the differentiation of B cells into active antibody-producing cells (plasma cells) and T cells into effector cells

Humoral and Cellular Immunity

• Humoral Immunity's primary cells are B cells and circulating antibodies
• Humoral immunity causes direct inactivation of a microorganism or the activation of inflammatory mediators
• It primarily protects against bacteria and viruses
• Cellular immunity differentiates T cells
• It primarily protects against viruses and cancer
• Humoral and cellular immunity work together to provide immunity and memory
• They respond more rapidly and efficiently on subsequent exposure to the same antigen

Active vs Passive Immunity

• Active immunity produces antibodies or T cells after either a natural exposure to an antigen or after immunization, and is long lived
• Passive immunity preformed antibodies or T lymphocytes are transferred from a donor to a recipient
• It occurs naturally or artificially and is temporary or short-lived

Recognition and Response

• Recognition and response are required for a successful immune response, they involve highly effective interaction of cells
• Cluster of Differentiation (CD) was originally used to describe proteins on the surface of lymphocytes
• CD is currently a labeling system used to identify a family of proteins on many cells

Antigen

• A molecule that can react with antibodies or receptors on B and T cells

• It is mostly protein but can be other molecules as well

• Immunogenic antigen triggers an immune response Sites for binding to antibodies and lymphocytes:

  • Antigen's binding site: antigenic determinant (epitope)
  • Antibody or Lymphocyte's binding site: Antigen-binding site (paratope)

• Degree to which an antigen has immunogenic capability

  • Degree of foreignness to a host is most important
  • Size is extremely immunogenic when large

• Small-molecular-weight antigens are called haptens, which cannot trigger the immune response themselves but can when bound to a carrier protein

• Chemical complexity causes greater diversity and more immunogenicity

• Amount: High or low extremes can cause tolerance

• Tolerance is the ability to recognize ourselves as not foreign

  • Central tolerance: Lymphocytes with receptors against self-antigens are eliminated
  • Peripheral tolerance: Prevents recognition by lymphocytes and antibodies

Molecules that Recognize Antigens

• Circulating antibody
• Antigen receptors on B cells or B-cell receptors (BCR)
• Antigen receptors on T lymphocytes or T-cell receptors (TCR)

Antibody

• Also called immunoglobulin (Ig)

• Is produced by plasma cells

• Has several classes: IgG, IgA, IgM, IgE, and IgD

• They are characterized by antigenic, structural, and functional differences

• IgG is the most abundant class (80% to 85%)

• Transports across the placenta

• Accounts for most of the protective activity against infections

• Has four classes: IgG1, IgG2, IgG3, and IgG4

• IgA has two subclasses:

  • IgA1 molecules are predominantly in the blood
  • IgA2 molecules are predominantly in normal body secretions

• IgAs in body secretions are dimers anchored by the J-chain and "secretory piece."

  • The Secretory piece may function to protect IgAs against enzyme degradation

• IgM is the largest of the immunoglobulins and stabilized by a J-chain

• It is the first antibody produced during a response to an antigen and synthesized during fetal life

• Information on IgD function is limited

• IgD concentration is low in the blood

• It is located primarily on the surface of developing B lymphocytes

• Functions as one type of B-cell antigen receptor

• IgE is the least concentrated of the immunoglobulin classes in the circulation and acts as a mediator of many common allergic responses

• Its role is to defend against parasites

Antibody Molecular Structure

• Antigen-binding fragment (Fab) acts as recognition sites (receptors) for antigenic determinants, binds antigen and has two identical fragments
• Crystalline fragment (Fc) is responsible for biologic function and activates complement and opsonization Polypeptide Chains include two light chains and two heavy chains, being held together with disulfide bonds The heavy chain determines the type of antibody

Antigen Binding

• Amino acid sequences of the variable regions of the heavy and light chains
• Framework regions control antibody folding
• Antigen binding is like lock and key, a noncovalent chemical interaction Antibody valence (number of binding sites):
  • IgG, IgD, circulating IgA and IgE-2
  • Secretory IgA-4
  • IgM-theoretically 10, likely 5

B Cell-Receptor Complex

• Is located on the surface of B cells
• Consists of antigen-recognition molecules:
• Membrane-associated IgM and IgD and is responsible for recognition and binding -Consists of accessory intracellular-signaling molecules:
• Ig-alpha and Ig-beta heterodimers responsible for sending message to mature and to make antibodies

T Cell-Receptor Complex

• Consists of antibody-like transmembrane protein (TCR), responsible for recognition and binding
• Accessory proteins for intracellular signaling, referred to as CD3, are responsible for sending message to activate and differentiate T cells

Molecules That Present Antigen

• Needed for an effective immune response and antigen is processed within cells
• Expressed on the cell surface in a specific manner, some antigens need special APCs; others can be processed by most any type of cell Major histocompatibility complex (MHC) includes:
  • Glycoproteins on the surface of all human cells (except red blood cells [RBCs])
  • Human leukocyte antigens (HLA) alleles are inherited in a codominant fashion to enable both maternal and paternal antigens to be expressed
• Are also called HLAS
• MHC class I genes: A, B, and C
• MHC class II genes: DR, DP, and DQ
• MHC class III genes: others control the quality and quantity of an immune response

Transplantation

• Cells in transplanted tissue from one individual have a different set of MHC surface antigens than those of the recipient
• The recipient can mount an immune response against foreign MHC molecules
• The more similar two individuals are in HLA tissue type, the more likely for a successful transplant
• Haplotype is a specific combination of alleles at the six major HLA loci on one chromosome (A, B, C, DR, DQ, and DP)
• CD1 are antigen presenting molecules, found on APCs and thymus cells, and present lipid antigens: M. tuberculosis and M. leprae

Molecules that Hold Cells Together

• Antigen-independent interactions between cells
• Results in intracellular signaling events independent of the TCR or BCR complexes
• Necessary complement to antigen-specific signaling
• Needed for effective immune response

Cytokines and Their Receptors

• Cytokines are low-molecular-weight proteins or glycoproteins that function as chemical signals between cells and secreted by APCs and lymphocytes Results in cytokine-induced:
  • Increased production of proteins
  • Lymphocytes proliferate and differentiate
• A combination of cytokines influences a given cell that ultimately determines that cell's response

Generation of Clonal Diversity

• All necessary receptor specificities are produced and takes place in the primary (central) lymphoid organs
  • Thymus produces for T cells, bone marrow for B cells
• Results in immature but immunocompetent T and B cells
• Migrates to secondary lymphoid organs to wait for antigens, primarily during the fetal stage but continues throughout life
• Rearrangement of smaller regions of DNA during T- and B-cell development
• DNA loci that encode immunoglobulins and TCRs are rearranged from somatic recombination, making each cell unique and able to react with different antigens

B-Cell Maturation

• Occurs in the bone marrow: The stem cells mature and develop surface markers, and Interleukin (IL)-7 receptor

• IL-7 is produced by stromal cells and critical in driving the further differentiation and proliferation of the B cell

• Results in production of BCRs, heavy and light chains with, light: V, J, and C genes and heavy: V, D, and J genes

• Changes in characteristic surface markers:

  • CD21 is a complement receptor, and CD40 is an adhesion molecule required for later interactions with Th cells

• Central tolerance eliminates a large number of autoreactive B cells if exposed to self-antigen-over 90%

• Peripheral tolerance means that autoreactive B cell clones persist and must be controlled by other means in the lymphoid organs

T-Cell Maturation

• The thymus is the central lymphoid organ of T-cell development

• T cells move from the thymic cortex to the medulla

• Changes include the development of the TCRs and the expression of surface molecules

• T cells are released into the blood and take up residence in the secondary lymph organs to await antigens

• Production of TCRs

• Contains a- and a B-chains, each of which has a variable region and a constant region Complementary-determining regions (CDRs) separated by framework regions (FRs) are within each V region, has the V region genes, and Joining (J) region genes

• The sequence for the development of a- and B-chains are different and allows for the identification of many antigens

• Produces changes in characteristic surface markers and initiates the expression of CD2 on the cell surface - a marker for T cells

• The developing T cells make surface proteins CD4 and CD8

• CD4 cells recognize antigens presented by MHC class II molecules and develop into T-helper cells

• CD8 cells recognize antigens presented by MHC class I molecules and become mediators of cell-mediated immunity and directly kill other cells (T-cytotoxic [Tc] cells)

• Central tolerance means that autoreactive T cells in the thymus are deleted

• Central tolerance includes:

  • Clonal deletion: A TCR strongly reacts with MHC class I or class II and the T cell undergoes apoptosis
  • Negative selection: Developing T cell's TCR binds strongly with a self-antigen causing T cell to be deleted
  • Positive selection: Surface CD4 molecules bind to MHC class II molecules and become CD4 single-positive; and surface CD8 reacts with MHC class I molecules and become CD8 single-positive
  • This results in about 60% of immunocompetent T cells being CD4+ and 40% being CD8+ and peripheral tolerance can also occur

• The Second phase of the immune response produces effector cells (Th, plasma, and Tc cells) and memory cells

• There is induction of the population of T-helper cells and induction of immunocompetent B cells into plasma cells and immunocompetent CD8+ T cells into T-cytotoxic cells, which begins at birth and proceeds throughout life

Secondary Lymphoid Organs

• Include the spleen, lymph nodes, adenoids, tonsils, Peyer patches (intestines), and appendix
• High endothelial venules mean Lymphocytes bind to the endothelium through adhesion molecules

Antigen Processing and Presentation

• Antigens require processing and presentation by APCs, which include dendritic cells, macrophages, B lymphocytes

  • B lymphocytes present antigen to Th cells that facilitate humoral immune response
  • Macrophages present antigen to memory Th cells to initiate a rapid response to antigens (secondary immune response)
  • Dendritic cells processes antigen from a site of inflammation to T-cell-rich areas of lymph nodes

• For processing and presentation to occur, the antigen must be the appropriate type, lymphocytes must recognize presented antigen, and the antigen must be appropriately presented

• Antigen processing is the process by which exogenous and endogenous antigens are linked with the appropriate MHC molecules

• Pathways of antigen processing Class I MHC molecules generally present endogenous (inside cells) antigens Class II MHC molecules prefer exogenous (outside cells) antigens

T-Helper Lymphocytes

Th cells help the antigen-driven Maturation of B and T cells and Facilitates and magnifies interaction between APCs and immunocompetent lymphocytes Steps to the helper cell pathway are:

• Th cells interact through antigen-specific and antigen-independent receptors

• Th cells undergo differentiation

• Mature Th cells interact with plasma or T-effector cells

• APC-Th cooperation complex of an antigenic peptide presented by an MHC class II molecule is recognized by multiple molecules on the Th-cell surface-CD4 (Th) is class II restricted Costimulatory molecules are necessary for proper differentiation to occur

  • B7 on the APC and CD28 on the Th cell are most important, and CD48 on the APC and CD2 on the Th cell IL-2 is needed for a Th cell to mature into a functioning cell

• Subsets exist of T-Helper cells types:

  • Th1 cells provide help in developing cell-mediated immunity, which activates macrophages and Tc cells
  • Th2 cells provide help in developing humoral immunity and activate B cells
  • Th17 helps the inflammatory response
  • Treg cells limit immune response

• The differences are based on cytokine production

B-Cell Clonal Selection

• Results from the recognition of soluble antigen by BCRs, processing of antigen, and presentation by MHC class II antigens to Th2 cells
• When an immunocompetent B cell encounters an antigen for the first time, B cells with specific BCRs are stimulated to differentiate and proliferate A differentiated B cell becomes a plasma cell, used as a factory for antibody production, and leads to single class or subclass of antibody

Primary and Secondary Immune Responses

• Primary immune response occurs during the initial exposure
  • B-cell differentiation occurs during the latent period or lag phase
• After 5-7 days, an IgM antibody for a specific antigen is detected and an IgG response equal to or slightly less follows the IgM response
• In the primary response, the immune system is primed
• The Secondary (anamnestic) immune response is more rapid than the primary response Larger amounts of antibody are produced, rapidity is due to the presence of memory cells that do not have to differentiate
• IgM is produced in similar quantities to the primary response, but IgG is produced in considerably greater numbers during a secondary response

Cellular Interactions

TCR can only "see" processed and presented antigen BCR can react with soluble antigens Signals originate from the BCR complex and other surface co-receptors The antigen-bearing macromolecule is eventually presented on the cell surface and recognized by a Th2 cel

Class Switch

Is also called the isotype switch B cells use IgM and IgD as receptors During clonal selection, B cells can change antibody class:one of four IgGs, one of two IgAs, IgE, or an IgM DNA rearrangement (cut then mended) requires a CD40-CD40L interaction T-independent antigens bypass Th cells and directly stimulate B cells-cannot stimulate class switch

• B cells differentiate into antibody-producing plasma cells and into long-lived memory cells
• On reexposure, memory cells do not require much further differentiation and will rapidly differentiate into new plasma cells

T-Cell Activation

• Initiates cellular immune response and binds antigen to TCRs Activation allows:
  • Direct killing of foreign or abnormal cells by (Tc cells or cytotoxic T lymphocytes [CTLS])
• Assistance or activation of other cells while T-regulatory cells (Treg) regulate the immune response to avoid attacking "self."
• It stimulates T-memory cells

Cellular Interaction

• Recognition of antigens that have been processed and presented by MHC class I molecules or CD8 T cells are class I restricted Appropriate signaling pathways are needed for the maturation of T cells B7 on the cell-presenting antigen, CD28 on the T cell, CD48 on the APC, CD2 on the T cell, a variety of other adhesion molecules, Requires cytokines, especially IL-2, produced by Th-1 cell
• Cellular differentiation produces active Tc cells with the capacity to identify antigens on the surface of infected or malignant cells and then to destroy these cells
• Causes memory T cells to have the capacity to respond rapidly if further exposure to the same antigen occurs

Superantigens

• Are not digested and processed by an APC Results in the activation of large populations of T lymphocytes, regardless of antigen specificity
• Superantigens induce an excessive production of cytokines, resulting in a systemic inflammatory reaction, including fever, low blood pressure, and, potentially, fatal shock
• Examples are Bacterial toxins from Staphylococcus aureus and Streptococcus pyogenes and some viruses

Antibody Function

Protects against infection by: Direct action through:

• Neutralization by inactivating or blocking the binding of an antigen to a receptor

• Clumping insoluble particles in suspension through agglutination

• Turning a soluble antigen into an insoluble precipitate through precipitation Indirect action through:

• Complement and phagocytes

• Neutralization is how some vaccinations that have been attenuated (weakened, inactivated) work

• Antibody titer is the level of circulating antibodies

• Toxoids are Bacterial toxins that are chemically inactivated but still retain immunogenicity

Indirect Effects

• Mediated by the Fc portion of the antibody molecule
• Includes opsonic activity, leading to enhanced phagocytosis
• Activation of the complement system, which may lead to complement-mediated destruction of the pathogen -Increases opsonic activity through the deposition of C3b

Secretory (Mucosal) Immune Response

• Lymphoid tissues protect external body surfaces
• Antibodies are present in tears, sweat, saliva, mucus, and breast milk
• Secretory immunoglobulins act locally Major Function: to halt viral and bacterial invasion before local or systemic disease develops; to prevent a carrier state. IgA is the dominant immunoglobulin and small numbers of IgG and IgM are present within the secretory system

Immunoglobulin E (IgE)

• Is a special class of antibody that protects against large parasitic worms and the primary cause of allergies
• The Eosinophil is the primary cell for granuloma formation around the parasite It causes degranulation of the parasite
• Tc lymphocytes destroy cancer cells or cells infected with a virus and induce apoptosis

Killing of Cancerous or Infected Cells

• Perforin penetrates, polymerizes, and forms pores in the target cell's plasma membrane
• Granzymes enter target cell through the perforin-lined pores, and activate cellular enzymes (caspases) that are involved in apoptosis Direct receptor interactions: Activation of Fas signals the target cell to undergo apoptosis

Other Cells That Kill Abnormal Cells

• Natural killer (NK) cells are a compliment to Tc cell mechanisms, do not mature in the thymus and lack antigen-specific receptors
• They kill abnormal cells that do not express MHC class I
• In antibody-dependent cell-mediated cytotoxicity, NK cells can attach to the IgG through Fc receptors and activate its normal killing mechanisms

T Cells That Activate Macrophages

• Chronic inflammation: T cells produce cytokines that activate macrophages
• T cell stimulation causes a Stimulated to macrophage to become a more efficient phagocyte.
• Increase production of proteolytic enzymes and other antimicrobial substances. Causes retention of macrophages at the inflammatory site and increased adhesion between Th1 and macrophages

T-Regulatory Lymphocytes

• Tregs suppress immune responses by decreasing Th1 and Th2 activity, and suppress antigen recognition and Th cell proliferation
• Provides peripheral tolerance Controls or limits the immune response to protect the host's own tissues against autoimmune reaction

Fetal & Neonatal Immune Function

• Newborns have a poorly developed immune response and antibody function of the newborn is deficient
• Capable of primary IgM response, but is unable to produce an IgG challenge
• Immunity is provided by maternal antibodies
• Trophoblastic cells transport maternal IgG across the placenta Newborn IgG levels are near adult levels

Aging and Immune Function

• Decreased T-cell activity where Thymic size is 15% of its maximum size
• Decreased production of specific antibodies
• Decreased circulating memory B cells
• Increased circulating immune complexes and autoantibodies

Review questions covering key concepts in immunology, including B-cell receptor production, T-cell maturation in the thymus, and the function of T-regulatory lymphocytes. This quiz tests understanding of immune system processes. It includes topics such as the role of MHC class II molecules.