Immunology Fundamentals

General Characteristics of Adaptive Immunity

• Adaptive immunity works with inflammation to protect the body
• It recognizes "nonself" substances like antigens
• Antigens include: Pathogens, Noninfectious environmental agents, Drugs, Vaccines, Transfusions, Transplants
• Adaptive immunity provides long-term protection
• It is slower than innate immunity but more specific
• Adaptive immunity has immunological memory (responds more efficiently to subsequent exposure to the same antigen)
• End products of adaptive immunity are lymphocytes (T and B cells) and antibodies (immunoglobulins, Ig)
• Each T or B cell specifically recognizes only one particular antigen
• The sum of all lymphocyte specificities can represent millions of foreign antigens
• Primary lymphoid organs are the thymus for T cells and the bone marrow for B cells
• Clonal diversity occurs in primary lymphoid organs and involves the maturation of B and T cells
• These cells then migrate to secondary lymphoid organs
• During clonal selection, antigen is processed and presented to immune cells by antigen-presenting cells (APCs)
• T-helper (Th) cells and APCs interact, resulting in the differentiation of B cells into plasma cells and T cells into effector cells

Humoral and Cellular Immunity

• In humoral immunity, B cells and circulating antibodies are the primary cells
• This causes direct inactivation of a microorganism or the activation of inflammatory mediators
• Humoral immunity primarily protects against bacteria and viruses
• Cellular immunity differentiates T cells
• This primarily protects against viruses and cancer
• Humoral and cellular immunity work together to provide both immunity and memory.
• They respond more rapidly and efficiently upon subsequent exposure to the same antigen.

Active vs. Passive Immunity

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

Recognition and Response

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

Antigens

• An antigen is a molecule that can react with antibodies or receptors on B and T cells and is usually a protein
• An immunogenic antigen is an antigen that can trigger an immune response
• Antigen's binding site is the antigenic determinant (epitope)
• Antibody or lymphocyte's binding site is the antigen-binding site (paratope)
• Immunogenic capability is the degree to which an antigen can trigger an immune response
• A degree of foreignness to a host is the most important factor
• Large antigens are extremely immunogenic
• Small molecular weight antigens are called haptens and cannot trigger an immune response themselves, but can when bound to a carrier protein
• The greater the diversity, the more immunogenic is the antigen
• Very high or very low amount of a specific antigen can cause tolerance
• Tolerance is the ability to recognize ourselves as not foreign
• Central tolerance involves the elimination of lymphocytes with receptors against self-antigens
• Peripheral tolerance prevents recognition by lymphocytes and antibodies

Molecules that Recognize Antigens

• Types of molecules which recognize antigens include Circulating antibody
• Antigen receptors on B cells, also called B-cell receptors (BCR) and Antigen receptors on T lymphocytes also called T-cell receptors (TCR)

Antibody

• Also called immunoglobulin (Ig)
• It is produced by plasma cells
• Several classes of antibodies exist: IgG, IgA, IgM, IgE, and IgD
• They are characterized by antigenic, structural, and functional differences
• IgG is the most abundant class (80% to 85%), is transported across the placenta, and accounts for most of the protective activity against infections
• The 4 classes of IgG are: IgG1, IgG2, IgG3, and IgG4
• IgA has two subclasses: IgA1 and IgA2
• 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 ("secretory piece")
• Secretory piece may prevent enzyme degradation
• IgM is the largest of the immunoglobulins and its pentamer is stabilized by a J-chain
• It is the first antibody produced during a response to an antigen and is synthesized during fetal life
• Information on IgD function is limited
• Its concentration is low in the blood and found primarily on the surface of developing B lymphocytes
• It functions as one type of B-cell antigen receptor
• IgE is the least concentrated of the immunoglobulin classes in the circulation
• It acts as a mediator of many common allergic responses and defends against parasites

Antibody types by Characteristics

• IgG is the most prevalent, offers most of protective activity against infection and crosses the placenta
• IgA is mostly present in the secretions and offers protective activity in body secretions
• IgE is the most rare, acts as common allergic responses mediator, and defends against parasitic infections
• IgD is the most unknown and acts as one type of B-cell antigen receptor
• IgM is the largest and offers the first antibody produces during the initial, or primary, response to an antigen

Antibody Molecular Structure

• The antigen-binding fragment (Fab) acts as recognition sites for antigenic determinants, binds antigen, and has two identical fragments
• The crystalline fragment (Fc) is responsible for biologic function and activates complement and opsonization
• Polypeptide chains consist of 2 light chains and 2 heavy chains which are held together with disulfide bonds
• The heavy chain determines the type of antibody

Antigen Binding

• Consists of amino acid sequences of the variable regions of the heavy and light chains
• Framework regions control antibody folding
• Utilizes lock and key to form Noncovalent chemical interactions
• Antibody valence depends on the number of binding sites
• IgG, IgD, circulating IgA, and IgE have 2 binding sites
• Secretory IgA has 4 binding sites
• And IgM has theoretically 10, likely 5 binding sites

B Cell-Receptor Complex

• Located on the surface of B cells
• Consists of: Antigen-recognition molecules, Membrane-associated IgM and IgD, Responsible for recognition and binding
• Consist 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
• and Accessory proteins for intracellular signaling
• Accessory proteins are referred to as CD3, responsible for sending message to activate and differentiate T cells

Molecules that Present Antigen

• Needed for an effective immune response
• Includes the necessity to process antigen within cells
• After processing, the antigen molecules are 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) consists of 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
• MHC molecules are also called HLAS
• MHC class I genes: A, B, and C
• MHC class II genes: DR, DP, and DQ
• MHC class III genes are other genes that control the quality and quantity of an immune response
• Cells in transplanted tissue 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 greater the likelihood 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 the antigen-presenting molecules found on APCs and thymus cells
• CD1 present lipid antigens
• CD1 present Mycobacterium tuberculosis and Mycobacterium leprae
• Molecules that Hold Cells Together allow for Antigen-independent interactions between cells
• This then results in intracellular signaling events that are independent of the TCR or BCR complexes
• Necessary complement to antigen-specific signaling and is Needed for effective immune response

Cytokines and Their Receptors

• Function as chemical signals between cells in low-molecular-weight proteins or glycoproteins
• Secreted by APCs and lymphocytes
• Cytokines increase the production of proteins and cause Lymphocytes to 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
• This process takes place in the primary (central) lymphoid organs: thymus for T cells and bone marrow for B cells
• Results in immature but immunocompetent T and B cells
• Cells in the fetus migrate to secondary lymphoid organs to wait for antigens and usually begins at birth and proceeds throughout life
• Smaller regions of DNA are rearranged during T- and B-cell development and can result in the Rearrangement of DNA loci that encode immunoglobulins and TCRs
• Somatic recombination occurs during this stage meaning that Each cell is unique and able to react with different antigens

B-Cell Maturation

• Occurs in the bone marrow
• Stem cells mature and Develop surface markers
• Utilizes Interleukin (IL)-7 receptor, IL-7 is produced by stromal cells and is critical in driving the further differentiation and proliferation of the B cell
• Production of BCRS depends on Heavy and light chains
• Light V, J, and C genes and Heavy: V, D, and J genes
• Resulting in Changes in characteristic surface markers: CD21, CD40
• Utilizes Central tolerance: A large number of autoreactive B cells are eliminated if exposed to self-antigen-over 90%
• In peripheral tolerance. Autoreactive B cell clones persist and must be controlled by other means in the lymphoid organs

T-Cell Maturation

• 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
• After this process T cells are released into the blood and take up residence in the secondary lymph organs to await antigens
• Production of TCRs consist of α- and -chains, each of which has a variable region and a constant region
• Contains Complementary-determining regions (CDRs) separated by framework regions (FRs) are within each V region. V region genes and Joining (J) region genes
• The Sequence for the development of α- and -chains are different
• Allows for the identification of many antigens
• Produces changes in characteristic surface markers, Initiates the expression of CD2 on the cell surface CD2 is a marker for T cells.
• 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 for Autoreactive T cells in the thymus are deleted
• Clonal deletion occurs when A TCR strongly reacts with MHC class I or class II, the T cell will undergo apoptosis
• Negative selection of 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
• Surface CD8 reacts with MHC class I molecules and become CD8 single-positive
• Note This positive selectionprocess results in about 60% of immunocompetent T cells being CD4+ and 40% being CD8+
• This leads to peripheral tolerance

Clonal Selection

• Second phase of the immune response
• Produces effector cells (Th, plasma, and Tc cells) and memory cells
• Leads to Induction of population of T-helper cells and of Induction of immunocompetent B cells into plasma cells and immunocompetent CD8+ T cells into T-cytotoxic cells
• Process begins at birth and proceeds throughout life

Secondary Lymphoid Organs

• Include: Spleen Lymph nodes, adenoids, tonsils, Peyer patches (intestines), and appendix
• High endothelial venules are when Lymphocytes bind to the endothelium through adhesion molecules

Antigen Processing and Presentation

• Antigens require processing and presentation by APCs: 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 process antigen from a site of inflammation to T-cell-rich areas of lymph nodes
• For processing and presentation to occur, antigen must be the appropriate type, lymphocytes must recognize presented antigen, and 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 consist of Class I MHC molecules, which generally present endogenous (inside cells) antigens
• The other Pathway consist of Class II MHC molecules which prefer exogenous (outside cells) antigens.

T-Helper Lymphocytes

• Th cells help the antigen-driven maturation of B and T cells
• Facilitate and magnify interaction between APCs and immunocompetent lymphocytes
• Steps for process:
  • Th cells interact through antigen-specific and antigen-independent receptors
  • Th cells undergo differentiation
  • Mature Th cells interact with plasma or T-effector cells
• Utilizes an 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
  • 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 Th1/Th2/Th17/Treg
    • Th1 cells provide help in developing cell-mediated immunity and activate Macrophages and Tc cells
    • Th2 cells provide help in developing humoral immunity and activate B cells
    • Th17 helps the inflammatory response
    • Treg cells limit an immune response

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
• Differentiated B cell becomes a plasma cell and act as the factory for antibody production
• Only consist of a Single class or subclass of antibody

Primary and Secondary Immune Responses

• Primary immune response occurs during the initial exposure
• During the latent period or lag phase, B-cell differentiation occurs
• After 5-7 days, an IgM antibody for a specific antigen is detected
• An IgG response equal to or slightly less follows the IgM response
• The immune system is primed
• 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

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.
• Antigen-bearing macromolecule is eventually presented on the cell surface and recognized by a Th2 cell.

Class Switch

• 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)
• CD40-CD40L interaction is needed
• T-independent antigens Bypass Th cells and directly stimulate B cells-cannot stimulate class switch.

Cellular Differentiation

• 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 by, Binds antigen to TCRs.
• This Allows for direct killing of foreign or abnormal cells (Tc cells or cytotoxic T lymphocytes [CTLS]),
• Assistance or activation of other cells
• Utilizes T-regulatory cells (Treg), Regulate the immune response to avoid attacking "self."
• Relies on T-memory cells
• During cellular interactions must rRecognize antigen that has 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, B28 on the T cell, DC48 on the APC, CD2 on the T cell, Variety of other adhesion molecules
  • Requires cytokines, especially IL-2, produced by Th-1 cell,

Test your knowledge of immunology! This quiz covers humoral and cell-mediated immunity, active and passive immunity, antigens, and T cell development.