McCance 8 M9.6 Adaptive Immunity

Adaptive Immunity

• Third line of defense that includes lymphocytes and serum proteins known as antibodies.
• Adaptive immunity is also referred to as acquired immunity, immune response, or simply immunity.
• External defensive barriers and inflammation must be compromised before adaptive immunity can be activated.
• Inflammation contains the initial injury and limits infection spread, while adaptive immunity enhances the initial defenses and offers long-term protection against reinfection.
• Components of innate and adaptive immunity are interactive and complementary.
• Products of the adaptive immune response activate components of the innate immune system.
• Both systems are required for protection against infectious disease.
• Adaptive immunity components develop slowly, are inducible, are specific, and are long-lived and systemic with memory.
• The components of inflammation are pre-existing in blood and tissues and activated upon tissue damage.
• The mediator products of inflammation must be removed quickly to limit damage and allow healing, while the effects of adaptive immunity are long-lived.
• Lymphocytes and antibodies induced by an infectious agent are specific to it, and a different agent induces a different battery of lymphocytes and antibodies.
• Memory allows the adaptive immune response to produce protective lymphocytes and antibodies rapidly, providing permanent long-term protection if reinfected with the same microorganism.
• Medically relevant aberrations in both inflammation and immunity include allergies, diseases that involve destruction of healthy tissue, and diseases caused by deficiencies in immune or inflammatory responses.

General Characteristics

• Adaptive immune system has its own vocabulary.
• Normal adults' immune systems are constantly challenged by a spectrum of substances that it may recognize as foreign or "nonself".
• Foreign antigens often associated with pathogens like viruses and bacteria, also found in noninfectious environmental agents like pollens and clinical derivations (drugs, vaccines, transfusions/transplanted tissues).
• Adaptive immune response products include antibodies/immunoglobulins and lymphocytes specific for particular antigens.
• Specificity and memory differentiate the immune response from other protective mechanisms.
• Specificity is defined by the nature of antigens recognized by the immune system, how they are recognized by antibodies and lymphocytes and the specific intercellular recognition molecules necessary for effective immune responses.
• In the fetus, lymphocytes undergo differentiation and proliferation before exposure to any infectious microorganisms which occur in the primary lymphoid organs (thymus and bone marrow).
• Lymphoid stem cells in humans enter the thymus differentiate into T lymphocytes (T cells), derived from the thymus.
• Other cells enter specific regions in the bone marrow and differentiate into B lymphocytes (B cells) which are derived from the bone marrow.
• Each cell type develops origin-specific cell surface proteins that identify them as T or B cells.
• Both B and T cells develop cell surface antigen receptors and each individual B or T cell is programmed to recognize only one specific antigen before encountering that antigen.
• With the extensive diversity of antigen receptors, it is estimated that each person has produced a population of B and T cells capable of recognizing at least 109 different antigens.

Generation of Clonal Diversity and Selection

• Lymphocytes leave the primary lymphoid organs as immunocompetent but naïve B and T cells.
• Immunocompetent cells have the capacity to respond to antigen, but are still naïve, as they have not encountered antigen.
• These cells enter blood/lymphatic vessels and migrate to the secondary lymphoid organs (lymph nodes, spleen) of the systemic immune system.
• Approximately 60% to 70% of circulating lymphocytes are immunocompetent T cells, and 10% to 20% are immunocompetent B cells.
• Clonal selection begins with the exposure of foreign antigen usually related to infection.
• Antigen reacts with, or selects, clones of B and T cells with surface receptors against that specific antigen and initiates further differentiation and proliferation into mature effector cells.
• The process requires cooperation among cells in the secondary lymphoid organs; most antigens need to be processed (antigen processing) by phagocytic cells (primarily dendritic cells).
• Dendritic cells also present (antigen presentation) the processed antigen on their surfaces to lymphocytes and these cells are generally called antigen-processing or antigen-presenting cells (APCs).
• Clonal selection involves APCs, subsets of B/T cells, intercellular adhesion by antigen receptors, adhesion molecules, the production/response to cytokines, and differentiation of immunocompetent B/T cells into highly specialized effector cells.
• B cells become plasma cells, which become factories for antibody production. T cells develop into several subsets that identify and kill a target cell (T-cytotoxic cell [Tc cell]).
• Other T cells regulate the immune response by helping the clonal selection process (T-helper cell [Th cell]) or suppress/limit the immune response (T-regulatory cell [Treg cell]).
• Both B and T cells differentiate into very long-lived memory cells that exist for decades or the life of the individual.
• Memory cells "remember" the initial antigen and are rapidly activated if a second exposure occurs to the same microorganism.

Humoral and Cell-Mediated Immunity

• The immune response has two arms, antibody and T cells, both of which protect against infection.
• Antibody circulates in the blood and in secretions and defends against extracellular microbes circulating in those fluids and microbial toxins.
• Interaction can result in direct inactivation of the microorganism or activation of inflammatory mediators that destroy the pathogen.
• Antibody is primarily responsible for protection against many bacteria and viruses.
• Effector T cells are found in the blood and in tissues/organs where they defend against intracellular pathogens and cancer cells. Some T cells produce cytokines that stimulate the protective response of other leukocytes, while others develop into Tc cells that directly attack and kill cellular targets.
• Humoral and cellular immune responses are interdependent at many levels and the acquired immune response depends on the functions of both responses and the interactions between them.

Active vs. Passive Immunity

• Adaptive immunity can be either active or passive, depending on whether antibodies or T cells are produced by the individual in response to antigen or are administered directly.
• Active immunity is produced by an individual either after natural exposure to an antigen or after immunization.
• Passive immunity does not involve the host's immune response at all, and rather occurs when preformed antibodies or T lymphocytes are transferred from a donor to the recipient.
• Passive immunity can occur naturally (maternal antibodies passing across the placenta to the fetus), or artificially (using immunotherapy for a specific disease performed in a clinic).
• Individuals exposed to infectious agents (hepatitis A virus, rabies virus) often given immunoglobulins prepared from individuals with antibodies against that particular pathogen.
• Active acquired immunity is long-lived, while passive immunity is only temporary as the donor's antibodies/T cells are eventually destroyed.

Recognition and Response

• The foundation of any successful immune response is the specific recognition of antigen by antibody or receptors on the surface of B or T cells, and followed by complex intercellular communication.
• CD (cluster of differentiation) format is used for labeling a large amount of different proteins found on the surface of many cells.
• A large number of CD molecules and cytokines contribute to the acquired immune response.

Antigens and Immunogens

• There are clinically important differences between antigen (molecule that can react with binding sites on antibodies/antigen receptors on B and T cells), and immunogen (antigen that is immunogenic and will induce an immune response to produce antibodies/functional T cells).
• The precise portion of the antigen configured for recognition and binding is called its antigenic determinant or epitope.
• The matching portion on the antibody or lymphocyte receptor is the antigen-binding site or paratope.
• Antigenic determinants may be linear (stable when the molecule is denatured and consists of adjacent amino acids) or conformational (destroyed when the molecule is denatured or processed and consists of the amino acids that are only adjacent when the molecule is folded appropriately).
• Macromolecules usually contain multiple and diverse antigenic determinants and trigger a mixture of specific antibodies against several of these determinants.
• Criteria influence the degree to which an antigen is immunogenic including foreignness to the host, appropriate size, adequate chemical complexity and sufficient quantity.
• A self-antigen generally does not elicit an immune response and the immune system has an ability to distinguish between "self" and foreign antigens.
• Tolerance is a state of nonresponsiveness in which the immune system passively allowed self-antigens to persist, but is now actively prevented/limited in its recognition by lymphocytes and antibodies.
• Pathogens can mimic self-antigens.
• Large molecules are most immunogenic.
• Low-molecular-weight molecules may become immunogenic by functioning as a hapten, bonding with a larger molecule that functions as a carrier.
• Antigens that induce an allergic response, allergens, are discussed in chapter 9.
• The best immunogens have chemically different components.
• Antigens that are present in large/small quantities may be unable to elicit an immune response.
• Extremes of quantity may induce tolerance.
• Additional factors affecting immunogenicity include route of antigenic entry/administration and delivery with adjuvants (substances that stimulate the immune response), and genetic makeup of host.

Molecules that Recognize Antigen

• Circulating antibody and antigen receptors (B-cell receptor, or BCR) and T lymphocytes (T-cell receptor, or TCR) recognize antigen directly.

Antibody

• An antibody/immunoglobulin is a serum glycoprotein produced by plasma cells in response to an immunogen challenge.
• Immunoglobulins have five molecular classes (IgG, IgA, IgM, IgE, and IgD) characterized by differences in antigenicity, structure, and function.
• Within each class are subclasses including IgG (four subclasses, IgG1, IgG2, IgG3, and IgG4 and IgA (two subclasses, IgA1 and IgA2).
• IgG is the most abundant constituting 80% to 85% of those circulating in body and maternal IgG is transported across the placenta that protects the newborn for approximately 6 months.
• IgA is divided into two subclasses, IgA1 (predominately in the blood) and IgA2 (predominately found in secretions).
• sIgA molecules are dimers anchored together through a J chain and secretory piece. Secretory piece attaches to the IgA dimer inside mucosal epithelial cells and protects these immunoglobulins against degradation by enzymes found in the secretions.
• IgM is the largest of the immunoglobulins that exists as a pentamer stabilized by a J (joining) chain. It is the primary synthesized antibody in neonatal life.
• Information on the role of IgD is limited and functions as an antigen receptor on the surface of early B lymphocytes.
• IgE is normally at low concentrations in circulation. It functions as a mediator of many common allergic responses and as a defense against parasitic infections.
• Structural analysis began with Porter's studies using papain to cleave IgG into two identical antigen-binding fragments/Fab and a crystalline fragment/Fc.
• The Fab portions contain recognition sites for antigenic determinants and confer specificity toward an antigen while the Fc is responsible for most biologic functions of antibodies that have bound antigen including activation of the complement cascade and opsonization.
• An antibody consists of four polypeptide chains: two identical light (L) chains and two identical heavy (H) chains with heavy chains used for class (gamma[IgG], mu [IgM], alpha [IgA], epsilon [IgE], or delta [IgD]).
• Light chains are of either the kappa (K) or the lambda (λ) type. One type of H chain and one type of L chain are made by a single plasma cell at a time using noncovalent bonds and disulfide linkages.
• Disulfide bridges set occur between the heavy chains in the hinge region and lends flexibility so that the Fab regions can move.
• Within an immunoglobulin class/subclass, constant regions have relatively stable amino acid sequences while variable regions in heavy/light chains differ greatly and determine the antigen-binding specificity that is localized into the complementary-determining regions (CDRs) are called framework regions (FRs).
• The antigen-binding site is formed by antibody folding so that the CDRs of the variable heavy (VH) and light (V₁) chains move into close proximity, resulting in a binding site lined by CDRs in each of those chains to create topography appropriate for most strong antigen binding.

B-Cell Receptor Complex

• Number of functional antigen-binding sites is called antibody valence.
• Most antibody classes have a valence of 2, but sIgA has valence of 4, IgM has a theoretical valence of 10, but can simultaneously use only about 5 because of large antigen binding one site blocks other sites.
• B-cell receptor (BCR) is a complex of antibody bound to cell surface and other molecules that involved in cell signalization and its role is to recognize antigen and communicate in order to signal the cell nucleus.
• Immunocompetent B cells' are produced from genes used by plasma cells for soluble antibodies, and produced membrane-associated IgM monomers, and possibly IgD.
• Signaling complex is made with two-chain Iga and Igß chain heterodimers that consist of tyrosine kinase, and its antibody portion of BCR complex binds recognition to antigen. The Igα complex portion provides for intracellular signals that are required to activate the B cell to be complete plasma complex.

T-Cell Receptor Complex

• The T-cell receptor (TCR) complex is composed of an antibody-like transmembrane protein and a group of accessory proteins (CD3) that signal.
• The most common TCR resembles a Fab and composed by two ɑ and chain proteins that include V-regions, with gene locations independent with antibody chains. They do with help, as like, BCR for recognition as are in action on the ɑ and b cells. 1-2 chain with CD3 make up, complex. All of each compound is important, it can lead 2 immune deflictions for T-cell mutations with (CD).

Molecules That Present Antigen

• Most antigens must be processed by APCs and presented on the cell surface by specialized molecules for an effective immune response.
• MHC in humans also are called HLA related to their role in transplantation..
• Special cells process/present antigen: APCs; others process and present antigen almost any cell.
• Several cell surface molecules have the responsibility for appropriately presenting antigen

Major Histocompatibility Complex

• MHC is glycoproteins found as surface of the cells but w less red of blood for humans. They get devided to too general classes, class 1 or 2, based by function for antigen cell population or structures at cell. The MHC class the proteins 2a chain/small/large and another has b2- microglobulin, heterodimers.
• Gene and chain protein B get encoded from genetic loci. A short chromosome helps with HLA that is a molecule. Properties or classes of every complex has already been given.
• The MHC has primary (A,B and C) genes, loci or class 1, where to take, primary the class 2 genes the area or within, are to contain or consist of three independent loci/ DR loci (alpha and β), DP, and DQ.
• MHC is also greatest of genetic polymorphism and with a different alleles number, forms the genetic at great measure, within a human for alleles to express each different MHC and each region is too various for numbers..
• But, not every HLA expresses each person because only two alleles exist for locus to inherit every human from both parents, codominat for that make up two proteins of one to have express surface of code molecules. This way MHC clinically means transplantation.
• Cell in translated is translated with cell or translate organ are from first a different have MHC surface antigens from that host with an the immune response against to foriegn translated cells- leading translated issues. The best option, HLA HLA-B HLA-C and translated one well, a HLA genetic loci like translated well.
• It will minimize a chance for immune cell interaction with tissues to have different alleles with differences found already the transplant issues are type with same. As so with the HLA tissue type and success will be higher and more chances!
• But because of so many various alleles which are a lot, it can found between two people of common group that will lead is same egg related identical will be more identical also make twins genes!
• Haplotype is a term of combo each of genetics and alleles are primary so that a rejection is for is that a number with have role in capability of antigens from not translated. However, antigens have and with the share of what makes genes with translated code which is more.

CD1

• In the 250th point: other present genetics are few in molecule that are genetic molecule codes are group type with have chromosomes at molecular that have lipid (a).
• It is high with membrane types and lipid antigen.s Because it is related with tb this helps by being a big number and having so much lipid for cell structures so help.

Molecules That Hold Cells Together

• Efficient development has molecules with efficient several actions the development for cells to signal that without BCR or TRC the necessary is for cells to perform cellular actions.

Cytokines and Their Receptors

• There has been big information but to point, what is essential from with is as in chapter 7 - this will lead in low level membrane function within receptor.

Generation of Clonal Diversity

• This chapter will be the main subject matter but the immune response phase two can have is called: Diversity, Cloner for more that for clones a is one important