Compare and contrast the development and function of B1 and B2 cells throughout life.
B cells are the effector cells of antibody mediated immunity, the humoral response. B cells develop from a common lymphoid progenitor cell in the specialised niche of the bone marrow and are stimulated from a naive state to an active effector form by the recognition of antigen by membrane bound immunoglobulin in tandem with co-stimulation from CD4 positive helper T cells (either TH1 or TH2). B cells which have been activated then differentiate into the antibody secreting plasma cells and memory cells by undergoing rapid division and differentiation within a germinal centre, a process known as clonal expansion.
The continuous production of B cells results in a heterogeneous population of cells equipped with distinct antigen receptors capable of meeting the vast array of antigens to which they will be exposed. This population contains several sub classes, including the conventional B cells broadly referred to in most texts (B2 cells) and the natural antibody producing B cells predominant in early life (B1 cells). These cells are similar but have are functionally distinct, possessing differing surface molecules which uniquely prepare them for particular roles in the immune response. These dissimilarities are defined by the respective differences in development of these B cell types, where selective pressures of the developmental niche shapes the same lymphoid progenitor cells into quite separate mature B cells.
EARLY DEVELOPMENT OF B CELLS:
Progenitor cells – same for B1/2, -> b cell lineage, how? Differences.
The development of a B cell begins with pluripotent haematopoetic stem cells, the precursor to all blood cells. These cells then differentiate into multipotent progenitor cells (MPP’s) which retain the ability to become lymphoid or myeloid cells but can no longer self renew – a typical trait of stem cells. Progression of stem cells towards mature B cells is accompanied by the up regulation of characteristic traits including FTL3, IL-7a, Rag1/2 brought about by the transcription factor Ikaros – crucial for lymphocyte development. Ikaros alter the chromatin structure of the genes which encode these traits, allowing them to be more readily transcribed and expressed (Georgopoulos, 2002).
MPP’s express the surface receptor tyrosine kinase FLT3, which binds it’s ligand on the surface of bone marrow stromal cells. FTL3 is responsible for the direction of progenitor cells to the bone marrow where they can be further exposed to the selective pressures which define their differentiation.
Signalling through FLT3 prompts the MPP to first progress to an early lymphocyte progenitor (characterised by to become either a T or B cell precursor) before becoming a B cell committed common lymphoid progenitor cell (CLP). During the development of B cells in the bone marrow B cells are restrained by the constitutively chemokine CXCl12 binding CXCR4 on the CLP, maintaining contact with stromal cells necessary for survival and differentiation. CXCR4 is also an important regulator of plasma cell migration to the bone marrow (Hargreaves et al, 2001, coordinated change).
Prior to the CLP stage the stem cell is IL-7 receptor negative. When committing to the lymphoid rather than myeloid lineage the CLP expresses Lin− stem-cell antigen (Sca)-1loc-kitloCD127[IL-7Rα]+ (Kondo et al, 1997) gaining an IL-7 receptor in the process.
The progression of a HSC through these various intermediary stages to become a CLP is a recent development of the previous, simpler understanding of the development of lymphocytes. It is a process whereby the cell sequentially loses the potential to become other, non lymphoid cell types and is committed to either the T or B lineage (Ye & Graf, 2007) – a process which is summarised in figure 1.
CLP ->B-> mature B:
The development of a B lymphocyte from the attachment to FTL ligand until the eventual relocation to the periphery takes place on the connective tissue stromal cells; more specifically reticular cells on the outer edges of the medullary vascular sinuses (the extavascular spaces between these sinuses act as the stage for haemopoeisis). These reticular cells abound in the bone marrow, however it is unclear if they are the only type of stromal cell to partake in B cell development although it is likely that they are the most important (Nagasawa, 2006).
The CLP is now exposed to a number of secreted and transcription factors in the bone marrow niche. IL-7 was the first cytokine demonstrated to be crucial in lymphocyte development, and acts mainly in the proliferation of pro-B cells. Its action is most likely to be achieved by inducing the expression of myeloid cell leukaemia sequence 1, which facilitates the survival of B lymphocytes. Additionally, IL-7 contributes to the specification of B cells as in its absence the cell cannot progress beyond the CLP stage.
—————– VCAM-1,VLA-4, CAMs = Kit SCF ———————————————————-
The successful development of the necessary retinue of mature B cells requires proliferation of these progenitor cells. This is achieved through the interaction of numerous cell adhesion molecules (CAM’s) and more specifically the binding of VCAM-1 on the B cell to stromal VLA-4. This binding initiates the association of CD117 on the B cell with stem cell factor found on the stromal cell. Stem cell factor is the main proponent of B cell progenitor proliferation during development, and is likely to act synergistically with IL-7 which enhances this proliferation (McNiece, Langley, Zsebo, 1991).
The CLP has now become a definitive, B cell committed cell, the early pro B cell defined by the cell undergoing DJ heavy chain rearrangement at the IgH locus. Successful gene rearrangement allows expression of the pre B cell receptor and continued maturation. The initiation of DJ rearrangement is precipitated by E2A transcription factor and early B cell factor (EBF). It is likely that IL-7 initiates E2A expression which then works in tandem with another transcription factor, PU.1 to up regulate EBF which is the actual effector in this process. Evidence for this comes from the observation that EBF will progress the B cell lineage in the absence of PU.1 and E2A where the presence of EBF is assured (in a lab setting). This observation suggests that PU.1 and E2A are the facilitators whereas EBF is responsible for manifesting the components of the pre B receptor including VpreB, λ5 and mb-1.
Maturing B cells must complete their development in the peripheral lymphoid organs, where they complete genetic rearrangement of light and heavy chains and present both IgM and IgD membrane bound immunoglobulin. These cells recirculate throughout secondary lymphoid tissues such as the spleen and Peyer’s patches where they may encounter antigen and undergo further development in the form of affinity maturation and class switching within a germinal centre. This developmental process is true for conventional follicular B2 cells; however the fetally derived B1 cells differ from B2 cells both developmentally and functionally.
B1 B cells differ initially in that they are produced mainly in the foetus before birth (rather than postnatally), and repopulate in the peripheral areas in which they reside whereas B2 cells are produced constitutively in the bone marrow throughout life (Rodriguez & Dorshkind, 2006). B1 cells act as innate like lymphocytes, with easily activated low affinity responses which cannot be boosted unlike the adaptive response of B2 cells which boasts an enhanced IgG mediated secondary memory response.
There is uncertainty as to the specifics of B1 cell ontogeny and there are two proposed models of development. The Lineage model proposes that a HSC becomes two distinct precursor cells unique for each pathway which are phenotypically different and anatomically separate (Herzenberg & Tung, 2006). The selection model suggests that there is only one B cell precursor which has the potential to become either a B1 or B2 cell depending on antigen selection (Berland & Wortis, 2002). In both cases the models agree on the functions of B1 cells as innate like cells but differ on their genesis. It would be unwise to find one model to be definitive at this stage without further evidence and consideration.
There is further doubt as to the presence of two types of B1 cells (B1a/b) which have been observed in mice but which have not been entirely clearly defined in humans. The current delineation of these cells is based on expression of the CD5 marker, those B1 cells which do express CD5 are B1a cells whilst those which do not are B1b cells (Hardy, 2006).
A necessary step in B2 development is the interaction of the developing cell with cytokines Il-7 and thymic stromal lymphopoetic (TSLP) a process known to selectively enhance the production of cells expressing a pre BCR. Conversely, B1 cells in the foetal liver rely mostly on IL-7 for development but can also respond to TSLP even in the absence of a pre BCR (Vosshenrich et al, 2004). Additionally, B1 precursor cells are absent of the DNA polymerase terminal deoxynucleotidyl transferase, which is normally responsible for N addition in the VDJ recombination of follicular B cells (Allman & Pillai, 2008).
The functional roles of B1/B2 – predominant when?
The B1 and B2 cell dichotomy provides two B cell subtypes which offer different functional roles in the immune response which are required at different times throughout life. While both types of B cell act using the antibody response, it is the types and quantities of immunoglobulin which are produced and to what threat which determines their unique functional roles.
B1 roles in immunity:
Foetal liver derived B1 cells role is in early life host defence, where the adaptive immune system is in a nascent stage – exposed to a multitude of completely unknown pathogens to which the adaptive response is unable to effectively combat. This necessitates the release of antibody of a wide specificity, the so called “natural antibodies” which are constitutively produced by B1 cells and found in the serum. These are antibodies encoded by genes which have been rearranged but have not been further diversified by the antigen dependent somatic hypermutation characteristic of activated B cells.
IgM is ideal for a general response to pathogens early in life due to its low affinity and high cross reactivity. In the absence of T cell help, IgM is still secreted in large quantities and is particularly adept at dealing with bacterial infections as it is proficient in the activation of the classical pathway of the complement system. The staple form of pentameric IgM attaches to the polysaccharide membrane of bacteria, to which the C1q complex can attach and go on to opsonise the bacteria, stimulate mast cell degranulation and recruit granulocytes such as neutrophils to the site of infection. This partnership with C1q allows natural IgM to direct apoptotic cells to be phagocytosed, giving it a role in normal cellular housekeeping as well as immunity (Ehrenstein & Notley, 2010).
Further evidence as to the necessity of B1 cells in bacterial defence comes in their interaction with streptococcus pneumoniae. Mice lacking CD19 were unable to produce natural antibody and were notably more susceptible to infection by streptococcus pneumoniae (Haas et al, 2005).
Conventional B2 cells differ firstly in their anatomical location as they recirculate continuously through secondary lymphoid organs. Secondly, their B cell receptors undergo antigen dependent selection in the periphery, a complex process of gene rearrangement encompassing: somatic hypermutation, gene conversion and class switching. This process lends the BCR an extremely high degree of specificity which is responsible for the highly effective memory response of which B1 cells are incapable
Use IgG rather than IgM.
B2 cells response to infection, memory, specificity.
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