The Humoral Immune Response

1.         Role of Humoral Immunity

a.         Many of the bacteria that cause infectious diseases multiply in the extracellular spaces of the body.

b.         Most intracellular pathogens must spread by moving from cell to cell through the extracellular fluids.

c.         The humoral immune response leads to the destruction of extracellular organisms and prevents the spread of intracellular infections.

d.         This is achieved by antibodies secreted by B lymphocytes.

e.            Humoral immunity is directed primarily against:

i.          toxin-induced diseases

ii.            infections in which virulence is related to polysaccharide capsules (e.g. pneumococci, meningococci, haemophilus influenzae).

iii.         certain viral infections.

2.         The Primary Response

a.         When an antigen is first encountered, antibodies are detectable in the serum after a longer lag period than occurs in the secondary response.

b.         The lag period is typically 7-10 days but can be longer depending on the nature and dose of the antigen and the route of administration.

c.         A small clone of B cells and plasma cells specific for the antigen is formed.

d.         The first antibodies to appear are IgM followed by IgG or IgA.

3.         The Secondary Response

a.         When there is a second encounter with the same antigen or a closely related one, months or years after the primary response, there is a rapid antibody response (the lag period is 3-5 days) to higher levels than the primary response.

b.         This is attributed to the persistence of antigen-specific ‘memory cells’ after the first contact.

c.         These memory cells proliferate to form a large clone of specific B cells and plasma cells, which mediate the secondary antibody response.

d.            Production of antibodies:

i.          during the secondary response, the amount of IgM produced is similar to that after the first contact with antigen.

ii.          a much larger amount of IgG antibody is produced and the levels tend to persist much longer than in the primary response.

e.         Affinity maturation:

i.          with each succeeding exposure to the antigen, the antibodies tend to bind antigen more firmly.

ii.            antibody binding improves because mutations occur in the DNA that encodes the antigen-binding site.

iii.         some mutations result in the insertion of different amino acids in the hypervariable region that result in a better fit and cause the antigen to be bound more strongly.

iv.         the subset of plasma cells with these improved hypervariable regions are more strongly selected by antigen and therefore constitute an increasingly larger part of the population of antibody-producing cells.

v.         helper T cells control isotype switching and play a role in initiating somatic hypermutation of antibody variable-region genes and directing the affinity maturation of antibodies.

4.            Antibody Function

a.         The primary function of antibodies is to protect against infectious agents or their products.

b.            Antibodies provide resistance because they can:

i.            neutralize toxins and viruses.

ii.            opsonize microorganisms.

c.            Opsonization is the process by which antibodies make microorganisms more easily ingested by phagocytic cells.

d.         This occurs by either of 2 reactions:

i.          the Fc portion of IgG interacts with its receptors on the phagocytic surface to facilitate ingestion.

ii.          IgG or IgM activates complement to yield C3b, which interacts with its receptors on the surface of the phagocyte.

e.            Complement proteins bound to the pathogen also opsonize it by binding complement receptors on phagocytes.

5.            Initiation of Antibody production

a.         Role of surface immunoglobulin:

i.          it transmits signals directly to the cell’s interior when it binds the antigen.

ii.          it delivers the antigen to intracellular sites where it is degraded and from where it is returned to the B-cell surface as peptides bound to MHC class II molecules.

b.            Thymus-dependent (TD) antigens:

i.            antibody responses to protein antigens require antigen-specific T-cell help.

ii.          B cells become effective targets for armed helper T cells when antigen bound by surface immunoglobulin is internalized and returned to the cell surface as peptides bound to MHC class II molecules.

iii.         T helper cells that recognize the peptide:MHC complex binds to it, leading to the expression of the B-cell stimulatory molecule CD40 ligand on the helper T-cell surface and to the secretion of the B-cell stimulatory cytokines, IL-4, IL-5, and IL-6.

iv.         these drive the proliferation and differentiation of the B cell into antibody-secreting plasma cells.

c.            Activation by Virus:

i.          An epitope on a viral coat protein is recognized by the surface immunoglobulin on a B cell and the virus is internalized and degraded.

ii.            peptides derived from viral proteins including internal proteins of the virus are returned to the B-cell surface bound to MHC class II molecules.

iii.         here, these complexes are recognized by helper T cells, which help to activate the B cells to produce antibody against the coat protein.

d.            Activation by vaccines:

i.            haemophilus influenzae B vaccine is a conjugate of bacterial polysaccharide and the tetanus toxoid protein.

ii.          the B cell recognizes and binds the polysaccharide, internalizes, and degrades the toxoid protein to which it is attached, and then displays peptides derived from it on surface MHC class II molecules.

iii.         helper T cells generated in response to earlier vaccination against the toxoid recognize the complex on the B-cell surface and activate the B cell to produce antibody against the polysaccharide.

iv.         this antibody can then protein against H.influenzae B infection.

e.         Some antigens such as some bacterial polysaccharides, polymeric proteins and lipopolysaccharides have special properties that enable them to stimulate naive B cells in the absence of T-cell help.

f.            Thymus-independent antigens fall into two classes, which activate B cells by different mechanisms: TI-1 and TI-2.

g.         TI-1 activation:

i.          TI-1 antigens contain an intrinsic activity that can directly induce the proliferation of B cells.

ii.          at high concentrations, these molecules cause the proliferation and differentiation of most B cells – polyclonal activation.

h.         TI-2 activation:

i.          the TI-2 antigens are bacterial cell wall polysaccharides that have highly repetitive structures.

ii.          TI-2 antigens can only activate mature B cells; immature B cells are inactivated by repetitive epitopes.

iii.         TI-2 antigens act by extensively crosslinking the cell-surface immunoglobulin of specific mature B cells.

I.            Properties of different classes of antigens that elicit antibody responses:

6.            Accessory cells in Humoral Immunity

a.         To dispose of neutralized microorganisms and to attack resistant extracellular pathogens, antibodies can activate a variety of accessory effector cells bearing Fc receptors.

b.            Accessory cells:

i.            macrophages and neutrophils: ingest antibody-coated bacteria and kill them.

ii.          natural killer cells

iii.            eosinophils and mast cells: triggered to secrete stored mediators when their Fc receptors are engaged.

c.         These accessory cells are activated when their Fc receptors are aggregated by binding to the multiple immunoglobulin Fc pieces of antibody molecules bound to a pathogen.

7.            Activation of Fc receptors

a.            Phagocytes are activated by IgG antibodies which bind to specific Fc receptors on the phagocyte surface.

b.         As phagocytic activation can initiate an inflammatory response and cause tissue damage, it is essential that the Fc receptors on phagocytes be able to distinguish antibody molecules bound to a pathogen from the majority of free antibody molecules.

c.         This condition is met by the aggregation of antibodies that occurs when antibodies bind to antigens or antigenic particles, such as virus and bacteria.

d.            Mechanisms of Identification:

i.          Fc receptors on the surface of an accessory cell bind an immunoglobulin with low affinity while they bind antibody-coated particles with high affinity.

ii.          subtle conformational changes in antibody molecules that accompany binding to antigen enables better binding to Fc receptors.

e.            Activation of Phagocytes:

i           Many bacteria resist phagocytosis by macrophages and neutrophils.

ii.            antibodies binding to these bacteria allow them to be ingested and degraded through interaction of the multiple Fc domains arrayed on the bacterial surface with Fc receptors on the phagocyte surface.

iii.         Fc-receptor binding also signals the phagocyte to increase the rate of phagocytosis, fuse lysosomes with phagosomes, and increase its bacterial activity.

f.            Activation of Natural Killer cells:

i.          natural killer cells are large granular non-T, non-B lymphoid cells that have CD16 receptors on their surface.

ii.          when these cells encounter cells coated with IgG antibody, they rapidly kill the target cell.

g.            Activation of Mast cells:

i.          mast cells are found in high concentrations in the submucosal tissues lying just beneath body surfaces, including those of the gastrointestinal and respiratory tracts, and in connective tissues along blood vessels.

ii.          mast-cell activation occurs when the bound IgE is crosslinked by binding multivalent antigen.

iii.         this activates the mast cell to release the stored histamine, causing a local increase in blood flow and vascular permeability.

iv.         this leads to fluid accumulation in the surrounding tissue and an influx of blood-borne cells such as neutrophils.

v.         such local inflammatory responses serve to bring increased antibody and increased numbers of phagocytes, effector lymphocytes and eosinophils to a site of infection in a period of a few minutes to a few hours.

vi.         thus, mast cells form a part of the front line of host defenses against pathogens that enter the body across epithelial barriers.

h.         Role of Mast cells:

i.          their location near body surfaces allows them to recruit both specific and non-specific effector elements to sites where infectious agents are likely to enter the internal milieu.

ii.          they also increase the flow of lymph from sites of antigen deposition to the regional lymph nodes, where naive lymphocytes are first activated.

iii.         their ability to trigger muscular contraction can lead to the physical expulsion of pathogens from the lungs or the gut.