This second type of immune response is slower to react, but is more effective over the long time. This reaction is driven by T- and B-lymphocytes, which need to be previously activated.
Bone marrow (BM) is the place where B-cells originate but also maturate. The role of B-cells is to secrete antibodies. Antibodies are made up of immunoglobulin (Ig) and carbohydrates, which maintain the structure of the antibody together.
Antibodies are made of 2 identical heavy chains and 2 identical light chains, bound together with disulfide bonds (6). The N-terminal of each chain consists of a variable domain, which will bind to antigens. On the other hand, the C-terminal of the heavy and light chain forms the constant region (Fig. 1). This constant region determines the class of the antibody. There are five
classes of immunoglobulins; IgG, IgA, IgM, IgD and IgE (Fig. 2).
Fig. 1. Schema of an IgG. In grey, the constant region; in red, the variable region with the antigen-binding site in blue.
Surrounded with a thin black line, are the light chains, the heavy chain is surrounded by a thick black line.
The orange line represents disulfide bonds.
These Ig can be secreted or fixed to the B-cell
membrane. This means that the antibody expresses a hydrophobic trans-membrane domain, which allows it to attach to the B-cells membrane and act as a B-cell receptor (7, 8).
Fig. 2. View of the five different Ig classes. The light chain is in yellow, and the heavy chain is in a different color, which represents the sub-class (γ, α, µ, δ, or ϵ). The green line represents the disulfide bonds.
From (Freeman, 2002).
Next to B-cells, T-cells are the main lymphocytes of the acquired immune system.
All cells receptors are bound to the cell surface and are not secreted. The T-lymphocytes originate from the BM and maturate in the thymus, an organ located behind the sternum, and divided into several distinct functional areas, the cortex, the cortico-medullary junction and the medulla. Progenitor T-cells issued from bone marrow reach the thymus through blood vessels at the cortico-medullary junction. Once there, they proliferate, differentiate and migrate to the cortex. In the cortex, the double negative CD4/CD8 thymocytes mature into double positive CD4/CD8 thymocytes. These double positive CD4/CD8 thymocytes encounter the cortical thymic epithelial cells, which express a peptide-MHC complex. The surviving T-cells are those, expressing functional T-cell receptors and are able to bind this peptide-MHC complex. Once this first selection is completed, a second selection is made in the cortico-medullary junction, where the double-positive T-cells mature into single positive. These single positive T-cells return to the medulla, where they leave the thymus for the periphery. (9, 10).
The masterpiece, which regulates the immune system, is the major histocompatibility complex (MHC) molecule, or human leukocyte antigen (HLA) in humans. The MHC is encoded by chromosome 6 and contains over 200 genes (11).
The MHC genes encode 2 different MHC proteins; each has its own structure and its own function (Fig. 3). The MHC-I gene codes for the α-chain and the β-chain, called β2-microglobulin, of the molecule, is coding by a gene situated on chromosome 15.
There are around 20 MHC-I genes and 3 of them, HLA-A, HLA-B and HLA-C are the so-called the classical HLA-I, and are expressed by all somatic cells (12, 13). MHC-I is expressed constitutively on the surface of most of cells. MHC-II includes 3 locus, HLA-DP, HLA-DQ and HLA-DR, the class II gene encode for the α-chain and β-chain of the molecule. MHC-II is expressed constitutively by a limited number of immune cells, such as B-cells, DCs, macrophages and activated T-cells, and under stimulation of different cytokines, MHC-II can be expressed by many cell types.
Fig. 3. Left: structure of MHC-I;
right: structure of MHC-II.(14)
The function of MHC-I and MHC-II is to present a short part of a peptide issued from a pathogen, and to trigger the acquired immune response. But the processing of MHC-I and MHC-II happens in different cell compartments, and the origin of the presented peptide is different. MHC-I presents peptides issued form the cytosol.
Proteasome cleave these intracellular antigens into peptides, and inside the Golgi apparatus, these peptides are bound to the MHC-I and export to the cell surface. In contrast, extra-cellular antigens are phagocyted, and cleaved into peptide in the phagolysosome. The MHC-II, present inside a vesicle, is transported to the phagolysosome where the peptide is bound to the MHC-II and exported to the cell surface (14).
The specific part of an antigen, which is recognized by a receptor, is called epitope. The epitope recognized by T-cells receptors are specific amino acid sequences of the pathogen peptide derived by intra-cellular proteolysis. T-cells receptors are associated with the CD3 complex, which helps to transmit the activating signal through the cells. Two different types of T-cells exist; CD4+ T-cells, which are mainly cytokines secreting T-cells, and CD8+ T-cells, which are mainly cytotoxic cells. CD4+ T-cells can be divided into several sub-populations; the type 1 helper T (Th1) cells, which secretes IL-2 and IFN-γ and the type 2 helper T (Th2) cells, which produces IL-4, IL-5, IL-6 and IL-10. Infected cells are destroyed by CD8+ cells or so called cytotoxic T lymphocytes (CTL). Once the viral peptide is bound to the MHC, the infected cells will express it, the CTL binds to this viral peptide-MHC complex and with the help of co-stimulatory molecules, kills the infected cells. To destroy the infected cells, CTL secretes perforins and granzymes;
perforins create pores into the infected cells, which allow granzymes to penetrate the cells and mediate apoptosis through the caspase pathway. The other way is the binding of Fas ligand expressed by the CTL to Fas receptors expressed by the infected cells and mediated apoptosis.
Two main characteristics render this acquired immune response more effective than the innate immune response. First, once the T- or the B-lymphocytes are activated, they are able to proliferate clonally, in order to be redundant with regard to the specific antigen of pathogens; this will increase the immune reaction.
Second, among these cells, some of them called memory T-cells, can be activated rapidly in case of a new infection by the same pathogen. In this case, the second
response of the immune system will be much faster and stronger compared to the first one. This allows the destruction of the pathogen before it causes a disease (7, 8, 12, 13, 14).