Immune Response
Once the non-specific barriers to infection have been breached, the specific immune responses to pathogens come into play: acquired immunity (Figure 1)
Hallmarks of acquired immunity include - specificity (discrimination between self and non-self) and memory (rapid response to previously encountered antigen)
Two types of immune response:
Humoral - serum transfer, antibodies
Cellular - T lymphocytes and activated macrophages
Terminology: (Figure 2)
Antibody: soluble proteins produced by B cell, they interact with specific antigens
Antigen: a molecule capable of interacting with components of the immune systems (antibodies or immune cells)
Immunogen: molecule capable of inducing an immune response (immunogens are antigens but not all antigens are immunogens). Immunogens include proteins, glycoproteins and lipoproteins, many polysaccharides, some nucleic acids and techoic acids. Most antigens or immunogens have multiple antigenic determinants, the portion of the molecule that is actually recognized by the Ab or cell - for a protein ~ 4 - 6 amino acids.
Cells involved: (Figure 3, Figure 4)
all are derived from precursor cells in the bone marrow, immune responses usually involve the interaction of more than one cell, the cells communicate through direct contact or through secreted signals - cytokines (lymphokines are cytokines produced by lymphocytes)
Macrophages: large phagocytic cells. Play a central role in the immune response. They not only phagocytize and destroy pathogens and foreign material, but also process part of the ingested antigen and place it back on the surface of the macrophage. Thus they are one of the major antigen-presenting cells (APC). The antigen (either ingested or, in the case of viruses, produced internally) is bound to a molecule of MHC (major histocompatibility complex, marks the cell as "self") class I (internal peptides) or class II (exdocytosed external peptide) and presented on the surface of the cell, where it can be seen by other cells or molecules of the immune system.
B cells: Antibody producing cells. Are responsible for the production of the soluble antibodies which play a role in production against a variety of infections. B cells have antibody on their surface, if the corresponding antigen is bound, cell division - clonal expansion and formation of plasma cells and memory cells. B cells mature in bone marrow and peripheral lymphoid tissue (lymph nodes, spleen, gut-associated lymphatics)
T cells: T cells include both effector and regulator cells. They react with antigens but use a T cell receptor (TCR) rather than antibody. TCRs, like the antibodies on B cells, are highly specific, and there are probably as many specificities for TCRs as for Ab. However, the structure of the molecule is different, and TCRs recognize antigen associated with MHC. (Figure 5)
Different T cell types can be distinguished by different surface markers: CD4, CD8 and other markers. (Figure 6)
TH - helper T cells, CD4 - stimulate other cells, esp. B cells, to enhance the immune response
TS - supressor T cells, CD8 - down regulation
TC - cytotoxic T cells, CD8 - recognize and kill infected host cells
TD - delayed type hypersensitivity cells, CD4, recruit and activate non- specific effector cells, esp. macrophages
T cells mature in the thymus (where many self clones are eliminated) before migration to peripheral lymphatics, recirculate through blood and lymph
TC and TD cells will be discussed in more detail when we cover cellular immunity.
Humoral immunity: B cell response
Structure and classes of antibodies (Figure 7, Figure 8)- antibodies are found on surface of B-cells as membrane bound markers and are secreted
(Figure 9)
Antibody binds to antigen - affinity refers to how well they fit
avidity refers to the total binding strength (i.e. depends on valence as well as affinity)
IgG - major secreted Ab
IgA - secretions on body surfaces
IgM - multivalent
IgD - B cell receptor
IgE - usually bound to mast cells or basophils, allergic response
IgM on the surface first, then IgD on mature B-cells. A single B cell switches class but all the antibody produced has the same antigen binding site. The antigen on the surface and the antibody secreted by the cell have the same specificity.
Generation of diversity - (Figure 10) -millions of different specificities available, binding of antigen selects that clone and allow it to expand. If 1 gene = 1 antibody, enormous numbers of genes would be required. Instead, DNA rearrangement of a limited number of genes is used to create diversity.
V regions segment of DNA (~200)
D (diversity) ~10 (not found in light chains)
J = 4
C region is joined, C regions can rearrange during class switching (i.e. can have the same antigen binding site but change class of antibody)
=8000 heavy chains and 800 light chains = 6,400,000 combinations
Probably even greater diversity of T-cell receptors
Ab made, predominantly IgM made in response to first exposure to Ag, some IgG.
On second and subsequent exposure IgM pattern the same but more rapid and quantitatively greater IgG response (Figure 11, Figure 12)
2º vs 1º response:
1. shorter lag
2. Ab produced at a faster rate and is more persistent
3. Ab concentration higher at peak response
4. IgG rather than IgM predominates
5. Ab's produced have a higher affinity for Ag
Stimulation of B cells and production of Ab involves a complex series of events.
(Figure 13): Ag (e.g. influenza virus) --phagocytosis - processing by macrophage which "presents" Ag to B and T cells. Some B cells mature to plasma cell - some divide to produce memory cells
(Figure 14, Figure 15, Figure 16)
If Ag binds to B cell with low affinity - more Ag required to stimulate division - thus higher affinity Ab's tend to predominate.
This example shows response to a single antigen. Pathogens are complex and possess many antigenic determinants, e.g. typical Salmonella. (Figure 17)
Immunization:
The development of memory cells is the basis of active immunity and immunization strategies, i.e. vaccines. (Figure 18)
1º exposure - develop memory cells, ideally in response to a non-toxic form of the pathogen
2º response upon subsequent exposure to the wild type pathogen
Vaccines are usually one of three types
1. Component vaccines - toxoids, capsular polysaccharides etc.
2. Killed cells or virus
3. Live attenuated strain
Immunization can be passive as well as active through the transfer of serum or cells
In utero - transfer of IgG to fetus (Figure 19)
Serum transfer - g globulin, a-toxin
Transfer of spleen cells - cell mediated immunity
Short term protection only since memory cells are not stimulated to develop
How do antibodies afford protection? (Figure 20)
1. Antibodies can bind to a pathogen or a toxin for example and block attachment to the host target cell.
2. Antibody-antigen complexes can fix complement - leads to lysis or opsonization - C3b receptor - binding through this receptor makes phagocytosis more efficient
3. They interact with other components of the immune system to clear out the pathogen. One of the most important is by enhancing phagocytosis - opsonization. - phagocytes have an Fc receptor.
Summary of humoral immunity:
Ag is processed by macrophage and presented to T and B cells
B cells produce Ab
Ab binds to Ag
Ag may be inactivated, phagocytosis enhanced, or complement activated
