CELLS OF THE IMMUNE SYSTEM

 cells and B Lymphopoiesis


B cells are another important population of lymphocytes. From the 10th week of fetal life, B cell precursors originating from the lymphoid stem cell start out to differentiate into B cells. Early B lymphopoiesis in humans is first induced in the fetus's liver, then within the bone marrow and MALT microenvironment, but it is unknown which cells comprise this niche. If it to take in simplistic form, there are several stages of the B lymphopoiesis or B-cell commitment.

The germline DNA of B-cell lymphoid undergoes somatic recombination and splicing that leads to the formation of different DNA complexities in committed B cells. The somatic recombination follows in the specified order: the joining of D and J (at the pro-B cell stage), random selection of V and formation of VDJ and addition Cμ to VDJ (at the pre-B cell stage). Splicing enables the cutting of introns (e.g., switch regions and L segment). Subsequently, the pre-B cell undergoes multiple divisions and turns into an immature B cell. L chain rearrangement occurs at the immature B cell stage. Analogous to T lymphopoiesis, gene products, RAG-1 and RAG-2, expressed at stages of B lymphopoiesis, are necessary for both H chain and L chain gene rearrangement.

Pro-B cells already express accessory antigen receptor molecules (Igα and Igβ), a part of coreceptor (CD19+), but not yet BCR. Pro-B cells require direct contact with stromal cells and IL-7 secretion to develop.

Pre-B cells lose the lymphoid stem cells marker, CD34-. The "help" of IL-7 is still required though. At this stage, rearrangement of the genes for H chains and L chains is finished.

Immature B cells start out to express μ chain for BCR (IgM+) and one more part of a coreceptor, CD21+.

Transitional B cells express eventually completed μδBCR (IgM+IgD+) and migrate to the peripheral blood and lymphoid organs.


It is known that there are four major features of B lymphopoiesis, as follows:

(1) The clonal division into different clones by unique BCR (with a single antigenic specificity), which is linked to accessory antigen receptor molecules, Igα (ÑD79à+)/ Igβ (ÑD79b+), and a coreceptor, CD19+/CD21+/CD81+.
(2) Two types of B-cell selection:
positive selection, when BCRs have a low affinity for self-HLA molecules and soluble self-antigens or are edited in V gene region to replace self-antigen directed BCRs by non-self-antigen directed BCRs, and
negative selection, which induces apoptosis in about 75% B cells (clonal deletion), which bind self-HLA molecules and cell-associated self-antigens too tightly. However, some B cells escape from apoptosis and come into an unresponsive state (clonal anergy). Positive selection leads to HLA restriction, and negative selection results in self-tolerance.
(3) The division of all B cells into three populations, B-1 cells, B-2 cells, and Marginal Zone B cells. These populations have different activities, but all can differentiate into antibody-producing cells, short-lived plasma cells, while B-2 cells also develop into long-lived plasma cells, which then return to the bone marrow.
(4) The ability to constitute lifelong memory B cells after naïve B-2 cells encounter antigens in those cases if helper T cells take part in the adaptive immune response.

The remaining 25% of mature naïve B cells enter the bloodstream and lymph flow to settle in lymphoid follicles of the secondary organs of the immune system and MALT. Chemokines CXCL13 (BLC), CCL19 (ELC), and CCL21 (SLC) upregulate B-cell homing.

B-1 cells (IgM+CD5+CD21+) arisen from stem cells during fetal life, have restricted clonal diversity, settle peritoneal and pleural cavities, produce IgM, and do not form memory cells. Analogous to γδT cells, they are a link between the innate and adaptive immunity.

Transitional B cells settle in the T independent zone of secondary organs of the immune system (lymphoid follicles) and become follicular B cells, or B-2 cells. B-2 cells, a prevalent (up to 95% of all B cells) highly diverse B-cell population, are the main participant of an advanced B-cell-mediated response to antigens, enable the production of all antibody isotypes, and formation of memory B cells.

Marginal Zone (MZ) B cells (IgM+CD1d+CD21+) are located in the spleen at the interface between the circulation and lymphoid tissue. The splenic Marginal Zone B cells can rapidly respond to blood-borne antigens and molecular patterns, being the intermediate population between B-1 and B-2 cells.

Priming will start when a naïve B-2 cell encounters an appropriate antigen. Due to differentiation in the course of immune response, naïve B cell becomes activated B cell, effector B cell and then turns into a plasma cell that produces immunoglobulins. In addition, memory B cells and regulatory B cells (Breg) are formed. A common phenotypic marker of memory B cells, which are highly heterogeneous, is IgD- IgM+IgG+IgA+CD27+.

B cells make up 10–25% of peripheral circulating lymphocytes.

V.V.Klimov