The Biology And Homeostasis Of B Cells Biology Essay

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B-cells, like other lymphocytes derive from pluripotent hematopoietic stem cells that differentiate into mature B-cells Blom and Spits 2006. Based on the expression of IgD, CD27, CD10, CD38, CD138 and CD23, B-cells are classified into immature transitional B-cells (CD19+CD10+CD34-CD27-), naïve B-cells (CD19+IgD+CD27-), memory B-cells (CD19+CD27+), plasmablast (CD19+CD138+CD38+) and plasma cells (CD19+CD138+CD38 (Sanz et al., 2008). When the naïve B-cells come into contact with an antigen, they differentiate into plasma cells (Lindsley et al., 2007). B-cells are also classified according to their function and anatomy into marginal zone B-cells (CD19+CD27+IgD+C27+) or class-switched memory B-cells (CD19+CD27+IgD-IgM-).

The continuous maintenance of serum antibody levels, is accomplished by the long-lived plasma cells (LLPCs) while memory B-cells (MBCs) drive responses upon antigen re-exposure (Elgueta et al., 2010). Memory B-cells also survive long term and replenish the pool of long-lived plasma cells to maintain antibody titers in the absence of antigen or pathogen (Kafuye-Mlwilo et al., 2012). Continuous differentiation of MBCs into plasma cells is needed to maintain long-term antibody titers.

Although generation of protective antibodies is central to immunity against malaria, several studies from endemic areas indicate that antibody responses to malaria is short-lived (Traore et al., 2009). However the mechanisms involved in this defective B-cell response to malaria is poorly understood.

2.2 Malaria infection and B-cell function

In Western Kenya, malaria infection is endemic. This endemicity leads to early and repeated exposure to malaria parasite which may disrupt both innate and adaptive immune responses in children. Various immune dysfunctions such as hypergammaglobulinemia, propricidal cell death, auto-antibody production, circulating immune complexes and loss of primary and memory antibody responses to Plasmodium falciparum have been reported during malaria infection in children (Donati et al., 2004) suggesting possible disruption of B-cell responses. This disruption may involve alteration in chemotaxis, B-cell homeostasis, and consequently humoral immune responses (Chelimo et al., 2005; Asito et al., 2008).

Other studies have also shown increased frequencies of circulating naïve B-cells (Asito et al., 2008), atypical memory B-cells (Weiss et al., 2009) and immature B-cells (Bohnhorst et al., 2001), indicating disturbance of peripheral blood homeostasis. These information imply that malaria infection interferes with expansion of effective humoral immune responses against Pf thus necessitating the need for more studies on young children to explain how repeated and early exposure to Pf predispose young children in endemic regions to develop life threatening acute malaria. Despite the fact that children from endemic areas bear the brunt of malaria-related morbidity and mortality only few studies have examined effects of chronic Pf infections on B-cell development.

2.3 The role of cytokines in humoral responses

Cytokines are non-antigenic specific glycoproteins synthesized and then secreted in response to a stimulus. Cytokines' role in humoral immunity revolves around regulating immune responses. It is only the cytokines with the ability to affect B-cells that impact on humoral responses and are mainly cytokines of T-cell origin. Cytokines like Interleukin 2(IL-2) and Interferon-γ (IFN-γ) are produced by Th1 cells whereas Interleukin 4 (IL-4), IL-5, IL-6 and IL-10 are produced by Th2 cells reviewed in (Parker et al., 1993) and they regulate each other. Interleukin 4 (IL-4) is involved in the differentiation of B-cells, controlling the specificity of IgG class switching and also involved in the development of memory B-cells (Nelms et al., 1999). Interleukin-6 (IL-6) may stimulate proliferation and immunoglobulin secretion of differentiated B-cells (Chen et al., 1998). The tumor necrosis factor (TNF) cytokines such as B-cell activating factor (BAFF) and APRIL also play important roles in humoral responses.

2.4 TNF Cytokines (BAFF, APRIL and TWEAK) and humoral responses

By producing antibodies that provide defense from pathogens, the B-lymphocytes serve as the effectors of humoral immunity. Integration of signals from the B-cell receptor (BCR), members of TNF cytokines (APRIL and BAFF) and their receptors are needed for the establishment and maintenance of B-cell pools (Rennert et al., 2000). The B-cell activating factor (BAFF) functions to stimulate B-cells as well as their secretion of antibodies (Schneider et al., 1999). Interaction between BAFF and its high affinity receptor BAFF-R is important in the long-term survival of B-cells (Yan et al., 2001). The B-cell activating factor (BAFF) is also needed for the survival of plasmablasts (O'Connor et al., 2004) and memory B-cells(MBCs) (Avery et al., 2003). The regulated expression of all the three BAFF binding receptors, B-cell maturation antigen (BCMA), transmembrane activator and calcium-modulator and cyclophilin ligand interactor (TACI) and BAFF-R is linked to B-cell differentiation(Waldschmidt and Noelle 2001).

The specific interaction of BAFF with each of these receptors and their expression levels play a discrete role in B-cell development and differentiation (Darce et al., 2007). A proliferation inducing ligand (APRIL) plays a role in antibody response of B-lymphocytes to T-independent type II antigens (Mackay and Ambrose 2003). Both BAFF and APRIL function to induce the class switching (Castigli et al., 2005). The high affinity APRIL receptor BCMA is essential for the survival of long-lived plasma(O'Connor et al., 2004).

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