Cell collaboration in the immune response. Primary and secondary responses.

The vast majority of the production of antibodies depends on the collaboration between helper T cells and B lymphocytes. When the thymus is extirpated in a new born pig, the development of the cell and humoral (by antibodies) responses are prevented, with the sole exception of those antibodies induced by T- independent antigens. Thus, the production of antibodies can only be possible when there is an effective cooperation between B and helper T lymphocytes (CD4+).
Cooperation between B and T lymphocytes. Antibody production by B lymphocytes presentation. B lymphocytes are not only immunoglobulin producers; they are also effective antigen presenting cells (APC). B lymphocytes have, then, two important roles in the humoral response: They act as antigen presenting cells. They produce antibodies. B lymphocytes have SLA II in their membranes, so they can recognize the antigen even in its native form (free antigen, without being associated to the SLA or transformed) through their surface immunoglobulins.
		How is a B lymphocyte activated? The antigen in its native form reacts directly with the surface immunoglobulins of B lymphocytes, without any intervention of antigen presenting cells or T lymphocytes. Later, the antigen is ingested, fragmented, associated to the SLA II and then it is expressed in the membrane or the lymphocyte. Thus, it works as the rest of the APCs, with two main differences: a) Antigens can be recognized in their native form by surface immunoglobulins and b) Phagocytosis do not occur. Once the antigen is expressed in the membrane of B lymphocytes (and if there is an appropriate stimulus from a CD4+ lymphocyte), the production of immunoglobulins will start. This cooperation is essential for the initiation of antibody production against the majority of antigens.The collaboration between B and CD4+ lymphocytes takes place when both cells come in contact, thanks to the SLA II and the antigen, and to the liberation of lymphokines, especially interleukin-4.
Diagram of Ag presentation by B lymphocytes. Reaction with native Ag (1); con el Ag en su forma nativa (1); Ag engulfing (2); Ag fragmentation (3); Union to SLA II (4) and expression in the membrane (5)
Antibody production starts with IgM and then, if the antigenic stimulus continues, the constant region of mu chains (IgM) is changed to gamma (IgG), epsilon (IgE) or alpha (IgA), but the variable chains (those that bind to the antigen) will remain (chapter 4). This process is similar to that originated by the antigen presentation by APC, but is more effective due to the fact that B lymphocytes only react with the antigen, while macrophages phagocyte every kind of particles. Moreover, a smaller quantity of antigen is required.
		B lymphocytes, when stimulated by an antigen, change their structure and function. The B lymphocyte proliferate, originating several clones; then it is transformed, developing the rough-surfaced endoplasmic reticulum and becoming a plasmatic cell.
The sole exception to this system are T independent antigens, which can produce antibodies without the collaboration of T lymphocytes. These antigens, usually present in some bacteria, are generally polyssacharides or lypo-polysacharides, NEVER PROTEINS. They can react directly with the BcR, by crosslinking the cell-surface immunoglobulin, stimulating several BcR at the same time, and so they induce enough stimulus to initiate the antibody production. But they are only able of producing IgM and not any other immunoglobulin.
Cooperation among APC and T and B lymphocytes. Antibody production through antigen presentation by phagocytic presenting cells.
Antigens can also be bound by macrophages and dendritic cells. These act as antigen presenting cells. These APCs belong, as lymphocytes, to the exclusive group of immune cells that express in their membranes SLA II (every nucleated cell presents SLA I, but not SLA II). Thus, they are the only cells able to present antigens (epitopes) to the helper T lymphocytes CD4 +.
Antigen binding occurs thanks to an unspecific mechanism (opposite to what happens with B lymphocytes), that usually needs a large quantity of antigenic material. The antigen is engulfed inside a vesicle (1) and transported to the lysosomes, where it will be digested by different enzymes (2). Fragments of the digested antigen will be associated to SLA II (3) (non-covalent interaction) and transported to the macrophage membrane (4) where they will be recognized by T lymphocytes CD 4+ (TcR receptors can not recognize antigens if not associated to SLA). When these cells interact (APC and T lymphocyte) both are activated, and cytokines released (chapter 6). This allows the stimulation and proliferation of T lymphocytes CD4+ (clonal expansion of CD4+). At this stage, CD4+ lymphocytes can stimulate B lymphocytes for antibody production. This stimulation is mediated by SLA II and the antigen (both cells must recognized at least different epitopes of the same antigen) and enhanced by the liberation of interleukin 4 (IL-4). Thus, the activation of T lymphocytes CD4+ requires the performance of antigen presenting cells (APC) and the class II histocompatibility antigen (SLA II)

B lymphocytes activated by these mechanisms undergo a proliferation process. Part of the resulting cells are transformed into plasmatic cells which secrete antibodies, and some others remain as memory cells. These memory cells are long-lived. This is in contrast to other lymphocytes and plasmatic cells which have a very short-life). This long life is regulated by the bcl-2 gene, which is only present in the memory lymphocytes.
Characteristics of the primary response: Slow response IgM predominates over IgG Low titres and short lasting Characteristics of the secondary response: Faster and more effective than primary response Larger titres are produced, and these last longer		When an antigen is presented to the immune system for the first time, a primary response is produced. The Primary response is mainly produced in the lymph nodes and spleen. Memory lymphocytes are produced during the primary response, and they will remember each epitope´s structure for possible future infections. When an animal has already been in contact with any antigen, and has produced memory lymphocytes, if the antigen enters the organism again, a secondary response is produced. During the secondary response IgM levels are similar to those of the primary response, but IgG levels are much higher and remain longer. Other immunoglobulins are also produced, such as IgA and IgE, in the secondary response. The secondary response appears mainly in the bone marrow, followed by the spleen and lymph nodes.

T independent antigens follow the same response pattern both in primary and secondary response. In both cases, only IgM is produced.