Specific Immunity and Its Application
The Dual Nature of Specific Immune Response Overview
Reference: https://sites.google.com/site/rccmicrobiology/chapter-15-specific-immunity-and-its-application
- Development of the Dual Lymphocyte System
- 1. Lymphocytes arise from the same basic stem cell.
- Diverge and mature to B-cells and T-cells.
- Maturation of B-cells occur in specialized bone marrow sites.
- Maturation of T-cells occurs in the thymus.
- B-cells and T-cells migrate to precise, separate areas of lymphoid organs (for instance, nodes and spleen).
- 2. Entrance and Processing of Antigens and Clonal Selection
- Battery of cells that work together to screen, entrap, and eliminate in fluid compartments networked together with lymphatics, blood, and reticularendothelial system (RES).
- Macrophages usually the first to recognize and react (produce antibodies).
- Ingest and process antigens and present them to the lymphocytes that are specific for antigens.
- In most cases, B-cells also require additional assistance from special classes of T-cells.
- 3. B- and T-cell Activation of Lymphocytes And Clonal Expansion
- When challenged by antigen, B- and T-cells differentiate and multiply.
- Clone cells are made of particular lymphocyte to a attack pathogen as well as a few memory cells for later detection of antigen.
- B-cell and T-cells depart from this point.
- 4. Products of B- Lymphocytes: Antibody Structure and Function
- Plasma cells: active progeny of a dividing B-cell.
- Programmed to synthesize and secrete antibodies in tissue fluid.
- Antibodies and antigens attach and become marked for neutralization or destruction.
- Secreted antibody molecules are humoral, pertaining to elements in blood and other fluids.
- 5. How T-cells Respond to Antigen: Cell-Mediated Immunity (CMI)
- T-cell types and responses are extremely varied.
- T-cells activated by antigen and clone one of several types for cell-mediated immune function.
- Functional Types of T-Cells
- Helper cells that assist the immune system.
- Suppressor cells that suppress and regulate immune reactions.
- Cytotoxic, or killer cells, destroy specific target cells.
- Delayed hypersensitivity cells that function in certain allergic reactions.
- T-cells secrete cytokines (help destroy antigen and immune response) but do not produce antibodies.
- Markers on cell surface for self and non-self.
- A given cell can have several different receptors.
- Function of markers:
- Perceive and attach to non-self (antigens).
- Promote recognition of self molecules.
- Receive and transmit chemical messages among other cells of the system.
- Aid in cellular development.
- How Are Receptor Formed?
- Many receptors are glycoproteins with additional carbohydrate fragments added.
- As a cell matures genes for cell receptors will be transcribed and translated into protein products and modified and packaged by endoplastmic reticulum (ER) and Golgi complex.
- Inserted in membrane.
- Major Histocompatibility Complex (MHC)
- MHC is a set of genes for human cell receptors.
- MHC is also known as Human Leukocyte Antigen (HLA).
- MHC antigens are on cells except RBCs.
- MHC genes located on the sixth chromosome and in multigene complex of class I, class II, class III.
- Class I
- Code for markers for self molecules and the regulation of immune reactions.
- Required by certain T-cells.
- Each human being inherits a particular combination of class I MHC.
- MHC profiles differ from person to person.
- Class II
- Code for markers (receptors) for foreign antigens to recognize and react.
- System located mostly on macrophages and B-cells.
- Involved in presenting antigens to T-cells during cooperative immune reactions.
- Class III
- Code for secreted complement components such as C2 and C4.
- Lymphocyte Receptors and Specificity to Antigen
- Lymphocytes play important role of surveillance and recognition in immune system.
- Lymphocytes posses MHC antigens for recognizing self and receptors for foreign antigens.
- Wide variety of sources of antigens: microorganisms as well as chemical compounds in the environment.
- Central Theory of Immunity
- The Clonal Selection Theory and Lymphocyte Development
- Lymphocytes use only about 500 genes to produce a variety of specific receptors.
- Clonal Selection Theory
- Clonal selection theory explains prenatal development of B and T cells using independent segregation, random assortment, and mutation.
- Each clone can only respond to one antigen.
- Undifferentiated lymphocytes undergo genetic mutations and recombinations while they proliferate in the embryo.
- Process leads to extreme variations in expression of receptor specificity.
- Mechanism process:
- As a immature, undifferentiated lymphocyte divides, the receptor genes recombine randomly to produce differing genetic codes in the two daughter cells (Gene assortment).
- Due to differences in how genes are spliced together, daughter cell A1 receives a combination of genes and a specificity that are different from those of daughter cell A2.
- Progeny of A1 and A1 will have varying receptor specificity and continue for millions of differing lymphocytes.
- Each genetically distinct group of lymphocytes that possess the same specificity is called a clone.
- Although B- and C-cells have different kind of receptors, they both have similar acquisition of specificity.
- Lymphocyte specificity is preprogrammed.
- Each genetically different type of lymphocyte expresses only a single specificity.
- Any lymphocyte that could possibly mount a harmful response to self molecules is eliminated or suppressed known as tolerance to self.
- The Specific B-Cell Receptor: An Immunoglobulin Molecule
- For B-cells, the receptor genes that undergo the recombination are in control of immunoglobulin (Ig) synthesis.
- Immunoglobulins: large glycoprotein molecules that serve as specific receptors of B-cells and as antibodies.
- Composition of Immunoglobulin
- Pair of Identical Heavy (H) Chains
- Pair of Identical Light (L) Chains
- The light chain is bonded to a heavy chain, and the two heavy chains are bonded together by disulfide bonds.
- Are symmetrical and Y shaped.
- Antigen binding site: site of immunoglobulin formed between the light and heavy chain.
- Variable regions (V): area where amino acid composition is highly varied from one clone of B lymphocytes to another.
- Constant region (C): area where there is little variability from antibody to another.
- Development of the Receptors
- During Lymphocyte Maturation
- Genes for immunoglobulins are in three different chromosomes.
- Undifferentiated lymphocytes has about 150 different genes that code for variable region of light chains and a total of 250 for variable and diversity regions (D) of the heavy chains.
- Only a few genes for joining regions (J) that join segments of the molecule together.
- Only the selected (V and D) receptor genes are active in mature cells and all other V and D genes are inactive and gives rise to singular specificity of lymphocytes.
- Process during development of lymphocyte:
- Each lymphocyte genetic blocks are independently segregated, randomly selected, and assembled.
- For heavy chains: one variable region (V) gene and diversity region (D) gene selected and spliced to one joining region (J) gene and one constant region (C) gene.
- For light chains: one variable (V), one joining (J), and one constant (C) are spliced together.
- Heavy chain combines with light chain to form half immunoglobulin.
- Two half immunoglobulins combine for a completed monomer.
- Transported to cell membrane and inserted as receptor.
- First receptor on a B-cell is a small-form IgM and a mature B-cell carries IgD receptors.
- Specificity is locked in for that lymphocyte and progeny for rest of its life.
- T-cell Receptors
- T-cell receptors are the same protein family as the B-cell receptor.
- Similar to B-cells in formation and structure.
- T-cell receptor relatively small and does not appear to have humoral function.
- 1. The Development of the Dual Lymphocyte System: The Stages of Origin, Differentiation, and Maturation
- Starts as stem cells in the yolk sac, liver, and bone marrow.
- Immature lymphocytes are released into circulation.
- Develop chances in specific anatomical regions.
- Mature B and T cells released to lymphoid organs.
- Lymphocyte differentiation and immuno-competence basically complete by late fetal or early neonatal period.
- Specific Happenings in B-Cell Maturation
- Stromal cells nurture the lymphocyte stem cells in bone marrow and provide hormonal signals that initiate B-cell development.
- Gene modification and selection causes millions of B-cells to develop and travel to lymph nodes, spleen, and gut-associated lymphoid tissue.
- B-cell has distinctive rough appearance.
- Specific Happenings of T-Cell Maturation
- T-cell maturation are directed by the thymus gland and its hormones.
- Seven Class of T-Cell Receptors (Markers); Termed CD, Cluster Differentiations
- Receptors can recognize antigens, B-cells, other T-cells, and macrophages.
- T-cells also occupy lymphoid organs and specific sites.
- T-cells have smaller and fewer microvilli and rosette formation when mixed with sheep RBCs.
- 2. Entrance and Processing of Antigens and Clonal Selection
- Antigen (Ag): substance that provokes and immune response in specific lymphocytes.
- Antigenicity: property of behaving as an antigen.
- Immunogen: substance that can elicit an immune response.
- Must meet requirements of foreignness, shape, size, and accessibility.
- Characteristics of Antigen
- Foreign: not a constituent of the body.
- Whole microbes, or their parts, cells, substances from other humans, animals, plants, and various molecules all possess qualities of foreignness and potentially antigenic.
- Complex molecules such as protein and protein-containing compounds can be more antigenic than repititious polymers composed of a single type of unit.
- Common Antigen Chemical Categories
- Proteins and polypeptides (enzymes, albumin, antibodies, hormones, exotoxins)
- Lipoproteins (cell membranes)
- Glycoproteins (blood cell markers)
- Nucleoproteins (DNA complexed to proteins, but not pure DNA)
- Polysacharrides (certain bacteria capsules) and lipopolysaccharides
- Effects of Molecule Size and Shape
- Molecular Weight (MW)
- <1,000 MW seldom complete antigens.
- 1,000-10,000 MW are weak antigens.
- >10,000 MW (usually complex macromolecules) are most immunogenic
- Large size alone is not sufficient enough to determine antigenicity.
- Lymphocytes can recognize a portion of an antigen (antigenic determination).
- Antigen can have numerous determinants.
- Mosaic antigen: express multiple and various surface and core antigens.
- Haptens: small foreign molecules that consist only a determinant group and are too small by themselves to elicit an immune response.
- Must be attached to a larger carrier carrier molecule for immunogenicity.
- Examples: drugs, metals, and many chemicals.
- These often bind to large carrier molecules such as serum proteins.
- Special Types of Antigens
- Immune tolerance to self occurs during lymphocyte differentiation.
- Autoantigens: hidden molecules that escape immune tolerance (eyes, thyroid gland).
- Thyroid gland is walled off pre-immune tolerance.
- Alloantigens: cell surface markers and molecules that occur in some members of the same species but not in all.
- Basis for blood group and major histocompatibility profile.
- Heterophilic (Heterogenic) antigens: molecules with the same or a similar determinant group.
- Stimulate response from the same lymphocyte clone even when from different sources.
- Antibodies for heterophilic antigens can cross-react with a similar or identical antigen from another source.
- Antibodies after attacking agent may also attack they host as well such as with Group A streptococci and human heart tissue.
- Result for false-positives diagnostic tests.
- Play a part in such diseases as rheumatic fever.
- Host Responses to Antigens: A Cooperative Affair
- Microbes most commonly enter the respiratory tracts or gastrointestinal tract.
- Less frequently enter other mucous membranes, skin, and across the placenta.
- IV entry come localized in liver, spleen, bone marrow, kidney, and lung.
- Other routes, antigens are carried in lymphatic fluid and concentrated by the lymph nodes.
- Lymph nodes and spleen important in concentrating antigens and circulating them thoroughly through all areas populated by lymphocytes so that they come into contact with the proper clone.
- The Role of Macrophages: Antigen Processing and Presentation
- Antigen must be presented to lymphocytes by special macrophages or other cells called antigen-processing cells (APCs).
- Most common APC is a large dendritic cell that engulfs and modifies it to become more immunogenic and recognizable to lymphocytes.
- APCs engulf, process, and present on the surface of an APC and bound to the MHC receptor so it is easily accessible to the lymphocytes during presentation.
- Presenting of Antigen to the Lymphocytes and Its Early Consequences
- T-cell-dependent antigens, usually protein based, require recognition steps between the macrophage, antigen, and lymphocytes.
- Helper T-cells are first cell to assist the macrophage in activating B-cells and other T-cells.
- Helper T-cells bind to MHC II on macrophage and with one site on antigen.
- Macrophage produces a cytokine, Interleukin-1 (IL-1) and activates helper T-cell.
- Helper T-cell produces Interleukin-2 (IL-2) to stimulate committed B- and T-cell activity.
- Few antigens trigger a response from B-cells without macrophages or helper T-cells.
- These cells are T-cell independent antigens.
- Usually simple molecules with many repeating invariable determinant groups.
- Few antigens follow this pattern and most antigens require helper T-cells.
- 3. B Activation of B Lymphocytes: Clonal Expansion and Antibody Production
- Steps For B-cell Activation
- A. Clonal selection and binding of antigen.
- Pre-commited B-cell of particular specificity picks up the antigen or presented with the antigen by the macrophage complex so that the antigen is bound to the B-cell receptor.
- MHC/Ag receptor on B-cell is bound the helper T-cell ensuring recognition.
- B. Instruction by Chemical Mediators
- B-cells receive development signals from macrophages and T-cells (IL-2 and IL-6) and growth factors (IL-4 and IL-5).
- Chemical stimuli cause a signal to be transmitted internally to the B-cell nucleus.
- B-cell activation results and undergoes DNA synthesis, organelle bulk, and size in preparation for entering the cell cycle and mitosis.
- C. Clonal Expansion
- Stimulated B-cells multiply but some cells do not completely fully differentiate and become memory cells which react to antigen at later periods.
- Reaction also expands clone cells for exposure to the antigen.
- Most numerous progeny that are large, specialized, terminally differentiate B-cells are called plasma cells.
- D. Antibody Production and Secretion
- Primary action of plasma cell is to secrete antibodies with the same specificity as the original receptor to surrounding tissues.
- Plasma cell can produce 2,000 antibodies per second.
- Plasma cell antibody production regulated by T suppressor cells.
- Plasma cells do not survive long and deteriorate after they have synthesized antibodies.
- 4. Products of B Lymphocytes: Antibody Structure and Functions
- Structure of Immunoglobulins
- Basic shape is of four polypeptides bonded by a disulfide bond.
- Structure of IgG (as a model)
- Two functional fragments.
- Antigen binding fragments (Fabs): two arms that bind to antigen.
- Distal end binds folds into groove for one antigenic determinant.
- Crystallizable fragment (Fc): remaining portion of Ig.
- Hinge region between Fab and Fc allow for swiveling of Fab fragments to accommodate varying distance and position.
- Antibody-Antigen Interactions and the Function of the Fab
- Receptor site of antigen is composed of a hypervariable region, extremely varied region of amino acids.
- Complementary fit is required to be held effectively.
- Similar to enzyme and substrate interaction (some antibodies can be used as enzymes).
- Immunoglobulins are so specific for antigens, they can distinguish a few atoms of a functional group.
- Opsonins
- Stimulate opsonization, a process in which microorganisms or other particles are are coated with specific antibodies so they will be easily recognized by phagocytes.
- "Soap" on a rope.
- Agglutinate
- Stimulate agglutination of cells or particles into large clumps.
- Neutralization
- Antibodies fill surface receptors of a virus or active site of molecule to prevent it from functioning normally.
- Antitoxins
- Antibody that neutralizes bacterial exotoxins.
- Functions of the Crystallizable Fragment (Fc): Interactions with Self
- Fc has different binding function than Fab.
- In most classes of immunoglobulin, Fc has an effector molecule that binds to receptors on the membrane of cells (macrophages, neutrophils, eosinophils, mast cells, basophils, and lymphocytes.
- In opsonization, antibodies' Fc fragment attaches to foreign cells and viruses to expose it to phagocytes.
- Some Fc ends have receptors for fixing complement.
- Some Fc ends cause the release of cytokines.
- Antibody of allergy (IgE) bind to basophils and mast cells, which causes the release of allergic mediators such as histamine (inflammatory response).
- Size and amino acid composition determine antibody's permeability, distribution throughout body, and its class.
- Accessory Molecules on Immunoglobulins
- J chain: joins monomers of IgA and IgM, and the secretory component.
- Helps antibody to move across the mucous membrane.
- Only on certain immunoglobulin classes.
- The Classes of Immunoglobulins
- Isotypes: structural and functional classes of Igs.
- Different classes mostly based on Fc fragment.
- IgG, IgA, IgM, IgD, IgE
- IgG
- Monomer produced by memory cells responding to second exposure.
- Most prevalent antibody circulating throughout the tissue fluids an blood.
- Functions: neutralizes toxins, opsonizes, and fixes complement.
- Only antibody capable of crossing the placenta.
- IgA
- Monomer that circulates in small amounts in blood.
- IgA coats surface of membrane and is free in saliva, tears, colostrum, and mucus.
- Most important specific local immunity to enteric, respiratory, and genitourinary pathogens.
- IgA given passively to newborns by breastfeeding.
- Secretory IgA (IgA Dimer)
- Significant component of the mucous and serous secretions of salivary gland, intestine, nasal membrane, breast, lung, and genitourinary tract.
- Formed in plasma cell by two monomers attached by a J-piece.
- To facilitate the transport of IgA across the membrane, a secretory piece is later added by the gland cells themselves.
- IgM
- Huge molecule composed of five monomers (pentamers).
- Attached by central J chain.
- First class synthesized by plasma cell following first encounter with antigen.
- Function: complement fixing and opsonizing.
- Circulates mainly in blood and too large to pass placenta.
- IgD
- Found in miniscule amounts in serum.
- Does not fix complement, opsonize, or cross placenta.
- Function: serve as a receptor for antigen on B-cells, usually along with IgM.
- Triggering molecule for B-cell activation.
- Also can play role in immune supression.
- IgE
- Uncommon blood component (unless host is allergic or has a parasitic worm).
- Fc region with mast cells and basophils.
- Function: stimulate inflammatory response by release of potent physiological substances from basophils and mast cells.
- Inflammation response involve RBCs such as eosinophils and lymphocytes to the site of infection.
- Involved in anaphylaxis, asthma, and certain allergies.
- Evidence of Antibodies in Serum
- Antiserum: serum containing specific antibodies.
- Put antiserum to electrophoresis, the major groups of proteins migrate in a pattern with their mobility and size.
- Albumins show up in one band and globulins in four.
- Most globulins represent antibodies.
- Gamma globulin: composed primarily of IgG.
- Beta and alpha 2 globulins are a mixture of IgG, IgA, and IgM.
- Monitoring Antibody Production Over Time: Primary and Secondary Responses to Antigens
- Level expressed by titer (concentration of antibodies)
- Primary response: first exposure to antigen.
- During latent period, there is a lack of antibodies for antigen but are being processed in lymphoid tissue for the correct B clones.
- IgM is first to be secretes by naive plasma cells.
- Later comes IgE or some other class.
- Secondary response: second exposure to antigen (also called anamnestic response).
- Antibody synthesis, peak titer, and length of antibody persistence are increase greatly.
- Response attributed to memory B cells for antigen.
- Booster shots: additional doses of vaccine to increase serum titer.
- Monoclonal Antibodies: Useful Products from Cancer Cells
- Polyclonal antibodies: mixture of different antibodies because it reflects dozens of immune reactions from a wide variety of B-cell clones.
- Monoclonal antibodies (MABs): pure preparation from single clone and have single specificity to antigen.
- Possible by hybridizing cancer cells and plasma cells in vitro.
- Hybridoma: method of creating MABs.
- 5 (&3). T Activation of T Lymphocytes and How T-Cells Respond to Antigen: Cell Mediated Immunity (CMI)
- As B-cells have been responding, T-cells are engaged known as the cell-mediated immunity.
- Cell-mediated immunities require the direct involvement of T lymphocytes throughout the course of the reaction.
- Reactions involve subsets of T cells dictated by CD receptors.
- All mature cells have CD2 (cause of rosetting), CD4 and CD8 found only on certain classes.
- T-cells require some type of MHC (self) before they can be activated and all produce cytokines.
- Function: whole T-cells act directly in contact with antigen and stimulate other T, B-cells, and phagocytes.
- The Activation of T-cells and Their Differentiation into Subsets
- Mature T-cells react to processed antigens that are presented by macrophages.
- T-cell is initially sensitized when antigen is bound to its receptor.
- Sensitization leads to final differentiation into helper, suppressor, cytotoxic, or delayed hypersensitivity T-cells.
- Same as B-cells, activated T-cells transform into lymphoblasts before mitotic division of memory cells and effector cells.
- Memory T-cells longest lived blood cells.
- T Helper (T_h) Cells
- Assist in immune reactions to antigens.
- Directly by receptor contact and release cytokines such at IL-2 to stimulate B-cell and T-cell activation and growth.
- IL-4,-5,-6 for various activities of B-cells.
- Most prevalent T-cell in the blood and lymphoid system.
- T Suppressor Cells (T_s) Cells
- T suppressor cells inhibit the immune response.
- Carry CD8 receptor and are primarily regulatory.
- Inhibit B-cells and other T-cells by various protein inhibitors to antigen processing cells and lymphocytes from reacting to antigens.
- Benefit is to restrict random immune responses that could be destructive or uncontrolled.
- Role of development of self and foreign antigens.
- Abnormalities of suppressor cells believed to be linked with autoimmune disorders and cancer.
- Cytotoxic T (T_c) Cell: Cells That Kill Other Cells
- Cytotoxicity: capability to kill a specific target cell.
- To be activated, it must recognize foreign receptors presented to it.
- After activated, cytotoxic T-cells deliver a dose of several cytokines that injures target cell.
- Perforins: pore-forming proteins that attack the target cell membrane and creates holes in target cell.
- Loss of selective permeability is followed by target cell death, apoptosis.
- Can kill: fungi, protozoans, complex bacteria (mycobacteria), virally infected cells (due to telltale receptors), cancer cells, and foreign human/animals cells (cytotoxic CMI important factor for graft rejection).
- Natural Killer (NK) Cells
- Lack specificity for antigens.
- Circulate through spleen, blood, and lungs.
- First killer cells (Cytotoxic is also a killer cell) to attack cancer.
- Destroys cells similar to to T-cells.
- Activities sensitive to cytokines such as IL-12 and alpha and beta interferon.
- Delayed Hypersensitive T (T_d) Cells
- Delayed responses to allergens.
- Active vs Passive Immunity
- Active: individual makes antibodies (&memory cells) from self.
- Can be life-time.
- Passive: immune substances from other (human or animal source).
- Can last a few months to years.
- Natural vs Artificial Immunity
- Natural: immunity acquire from natural biological measures.
- Through placenta (99% immunity) and nursing (1%, mostly intestinal protection).
- Artificial: immunity from artificial medical methods.
- Immunization (immunoprophylaxis): process of producing immunity.
- Active immunization synonymous with vaccination.
- Passive immunization a person is given antibodies (immune therapy).
- Vaccination: exposes individual to microbial (antigenic) stimulus.
- Immunotherapy: Artificial Passive Immunity
- Antibodies for infectious agent.
Reference: https://sites.google.com/site/rccmicrobiology/chapter-15-specific-immunity-and-its-application