Update On Innate Like B Cells Biology Essay

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The immune system is composed of two types of defence systems; innate and adaptive, which create an immune response when encountered with foreign agents.

Innate immunity posses fast kinetics, however lacks memory and uses germline encoded receptors to detect antigen (Vilen et al, 2008), whilst adaptive immunity uses large variable receptors to generate a repertoire of cells through memory, thus posses delayed-kinetics, (Borghesi et al, 2007).

The cells in both systems vary (table 1), however research suggests innate-like B-cells are part of both systems. In this essay I will be looking at innate-like B cells.

Innate immunity is the first line of defence against pathogens, (Vilen et al, 2008). Fast kinetics provides an instant physical barrier via skin, mucus and cilla or a chemical barrier to enable phagocytes to destroy foreign agents, (Borghesi et al, 2007). Innate immune system operates via two mechanisms:

Oxygen dependant killing- where reactive oxygen (ROI) and nitrogen (RNI) are produced to damage membrane proteins.

Oxygen independent killing- where neutrophils and macrophages alter peptidoglycan in the membrane, depriving cells of Fe2+.

Innate cells include; phagocytic cells such as macrophages, NK cells and basophils. They recognise pathogen (Figure 1) associated molecular patterns- PAMPs on the surface of bacterial cells, via pathogen recognition receptors-PRRs. Caspases-8 is selectively required for B-cell activation by specific PAMPs, (Beisner et al, 2005).

Recognition takes place via 2 types of interactions: Direct (ligands or receptors attach) or Indirect (oposonins enhance binding to pathogens). Following recognition phagocytic cells enter the spleen where they activate B & T-cells, facilitating secretion of antibodies.

Complement factors and lysozymes aim to cause inflammation and degrade the cell walls of the pathogens, whilst acute phase proteins (CRP & mannose-binding protein) increase during cellular stress and limit host tissue damage.

Figure 1: Shows how recognition of pathogens takes place (Produced by Nisha Lad) (13)

1.2.2 Adaptive (acquired) immune system

Adaptive immunity is specific and acts as a second line of defence, thus provides a delayed kinetic response, (Borghesi et al, 2007). It affects lymphoid tissues and organs and involves memory lymphocytes which recognise and respond to self and non-self antigens via the major histocompatobility complexes (MHC).

Adaptive immunity is divided (figure 2); Natural acquired (contact with disease causing agents); Artificial acquired (develops via vaccines), which are subdivided into passive (transfer of Ab-short-lived) and active (lifelong induced by host).

Figure 2: Categories of adaptive immunity (6)

Helper T-cells (Th1 & Th2) aid in antibody production, by binding to MHC-II and present CD4 via cytokine (IL-2, IL-4, IL-5, IFN- TNF¢) production, whilst cytotoxic T-cells (Tc) bind to MHC-I and present CD8, which has a toxic impact and kills via apoptosis.

1.2.3 Humoral immunity

Humoral immunity is mediated by the secretion of antibodies (B cells) and cytokines (Interferons). It occurs at the site of infection and uses B-cell lineages and co-stimulators, (Leadbetter et al, 2008).

Innate-like B cells (B1 & MZ) are important in humoral immunity. They capture antigens in an early immune response, producing IgM, to neutralize invading pathogen before IgG antibodies derived from follicle B-cells undergoing GC-reactions, (Phan et al, 2005).

Immune surveillance:

Immune surveillance activates local immune cells to recognise foreign material. These activate myeloid cells, dendritic cells and granulocytes via receptors such as toll-like, nod-like or protease and alter properties of tissue, resulting in migration to the lymph nodes where they present to antigen-specific t-cell clones.

Cytokines are produced and migrate back into infected tissue. Here memory cells fight infection, via antibody production. This mechanism demonstrates that adaptive immunity can acts like innate immunity.

Natural antibodies (Nabs) are initially derived from phenotypically, functionally mature B lymphocytes, (Goodyear et al, 2005). NAbs are spontaneously and don't require immunization or exposure. They are circulating ligand receptors (IgM isotype), which bind with high avidity to phosphorylcholine (PC) to facilitate endocytosis of foreign antigens, via non-polymorphic Fca/m receptor interactions and resemble cells from the innate immune system.

B1 and MZ B-cells are shown to produce preimmune levels of natural IgM, however they are also involved in responses to thymus-independent (TI) B-cell responses (Goodyear et al, 2005).


CD5 B-cells were first discovered in humans and mice over 20 years ago (Hardy, 2006). 5-15% of lymphocytes are B-cells, which consist of a dense nucleus, little cytoplasm and are 6-10­m (Ollila et al, 2005). ¾ of newly formed B-cells are said to be self-reactive, (Bolland 2008). They function to produce high affinity antibodies, however polymorphic forms bridge both innate and adaptive immunity, (Milner et al, 2005).

B-cells are capable of producing an accelerated clonal response, to fight blood-borne infections, (Goodyear et al, 2005). They are predominantly part of the adaptive immune system and play a variety of immuneregulatory roles, through antigen presentation, cytokines and chemokines, (Dorner et al, 2009).

Milner et al, 2005 analysed human B-cell population and proposed that 9G4 B-cells represent a population of autoreactive B-cells which when restricted them to innate immunity playing a role in physiology. However if 9G4 B-cells were in the adaptive immune system, they would become pathogenic agents and result in diseases such as SLE.

1.3.1 B-cell development

Immature B-cells develop in the foetal liver at approximately 8-weeks. After birth they develop in the bone marrow and maturation takes place in the spleen. Theses B-cells are activated in the thymus and require two types of signals; antigen signals (cross linking of BCR) and co-stimulatory signals. They are regulated by 2 stages:-

Antigen independent- an initial phase where a diverse repertoire of antigen-specific B-cells develop in bone marrow (figure 3), (Barrow, 2002). B1 cells are thymus independent and make IgM upon activation. There are 2 types of T-cell independent activation;

Type 1 T cell-independent (polyclonal) activation

Type-2 T-cell independent (macrophages) activation.

Quinn et al, 2006 saw that T1 B-cell anergize in diabetic mice, however if they aren't anergized, develop into the T2 B-cells via BCR signalling in the spleen, (Su et al, 2004).

Figure 3: Antigen independent (Produced by Nisha Lad)

Antigen dependent- a secondary phase where B2 cells undergo clonal expansion in peripheral lymphoid organs. Once pathogens ingress, antigen presenting cells attach to MHC-II and move into the cell membrane where T-cells recognise peptides. B-cells are activated by a synapse via Th cells, producing antibodies which inhibit the pathogen (Gray et al, 2007).

Haemapoietic stem cells differentiate into common lymphocyte pregenitors (CLP) which develop from pro-B, pre-B stages, immature and mature B-cells (Figure 4). 75% of B cells become apoptic in the pre-B cell stage, (Ollila et al, 2005).

Figure 4: B-cell differentiation

Check points are in place to ensure transition from early immature (CD45), to maturation occurs correctly to prevent autoimmune disease, (Gray et al, 2007). The two check points include:

Tolerance checkpoint- occurs in early development, where antibodies with a high affinity are removed by clonal deletion.

Self-tolerance checkpoint- occurs in mature B cells, where BCR receptor signals influence maturation.

Signal transduction pathways such as IL-1 and TLR are important produce immune responses; however defects in IRAK-4 and MyD88 means signals can't be generated (Bolland, 2008).

B-cell lineages such as B1 B-cells, MZ-B cells and FO B-cell are involved in the production of antibody. They share potency as controllers and use Pax5 in operating B-cell activity via two antagonists (NOTCH and Blimp-1).

During B-cell differentiation two types of genetic changes take place; somatic mutation, whereby B-cells bind to antigen with avidly and class switching, which alters recognition sites on immunoglobulin heavy chains, (Ollila et al, 2005).

Recombination of genetic material (VDJ) creates polymorphic forms of antibody, (Berdelac A, 2006). Recombination creates VJ genes encoding binding sites for Light-chains and VDJ for Heavy-chains. Once rearranged, chains attach via disulphide bonds into the Variable and Constant region. VDJ are gene segments that are rearranged within the rag1/2 gene, to initiate DNA cleavage at the TCR loci. (Borghesi et al 2007).

Translocation then takes place where the H & L chain combines in the ER to form Ag molecules which are specific for the B-cells. IgM is the first antibody made, thus has the ability to switch to other heavy chain classes (G-A-E-D). Conformational surface and involve complementary determining region (CDR) loop to recognize antigens on the surface (Goodyear et al, 2005).

Borghesi et al 2007 described that B1 B-cells fail to develop in rag deficient SCID (severe combined immune deficient patients), thus providing a hallmark for adaptive immunity. Over-representation of VH3 gene has been seen in most autoimmune diseases (Goodyear et al, 2005).

1.3.2 Receptors

Innate receptors recognise lipids, dsDNA and lipopolysaccharide molecules, thus detect via conserved ligands, whilst adaptive receptors recognise proteins expressed on pathogens, thus detect both conserved and non-conserved ligands, (Borghesi et al 2007).

B-cell receptors (BCR) and T-cell receptors (TCR) are in the integral membrane. They differ in structure, genes and epitope. TCR have memory recognition and allow the body to be primed for a rapid response to invasion or re-infection. However BCR receptors attach to antigen and release toxins via receptor-mediated endocytosis where the antigen is fragmented within the cells, (Leadbetter et al, 2005).

BCR recognise fragments on the surface of TCR, resulting in B-cells differentiation, where plasma cells secrete large amounts of antibody.

1.4 Innate-like lymphocytes:

Innate-like lymphocytes are localized to areas such as the gut, skin and spleen where high antigen exposure is presented in a naturally activated state, in-order to provide rapid recognition to antigens and modulating an immune response to inhibit or promote inflammation; however their function is still unclear (Rolf et al, 2007).

Theses innate-like lymphocytes follow a strict development mechanism, where positive selection in the thymus results in recognitions of self antigens, if errors occur in recognition autoimmune diseases arise, (Leishmann et al, 2002).

Innate-like lymphocytes include (Galli et al, 2003):

Marginal zone (MZ) B-cells- found within the spleen

B1 B-cells

Natural Killer T-cells (NKT)- heteogenous subset of lymphocytes

¤ T-cells- also known as dendritic epidermal T cells (DETC), found on the dermis of the skin.

CD8¡¡€ TCR¡¢€­ are constituted type B intraepithelial lymphocytes (IELs) found in the gut. IELs maintain the epithelial and are involved in wound healing (Cheroute, 2005)

Yamagata et al, 2006 showed that techniques such as microarray analysis determine gene expression and profile lymphocytes, (Denning et al, 2007).

Innate-like B-cells act as first line of defence for many infections, (Silverman, 2005), thus act in an innate manner. They resemble NK cells and express gp49 inhibitory receptor.

Invariant and semi-invariant receptors are used by innate-like B-cells, thus characterise and hallmark innate immunity. These receptors are produced via the metabolic pathway, thus cannot be easily altered, (Kearney et al, 2005).

Innate-like B-cells express distinct phagocytes and morphology; receptors that are germline encoded. They don't contain or loose nucleotides that they acquire during VDJ joining. This indicates that they are evolutionary created with memory, (Kearney et al, 2005).

1.4.1 B1 + B2 B-cells

There are two types of innate-like B-cells; B1 and B2 (table 2). B1 B-cells are predominantly in the peritoneal and pleural cavity and express VH3609 heavy chains, (Kearney et al, 2005). They are found in low levels in the lymph nodes and spleen; however express high levels of IgM, than IgG. Polyspecific receptors allow binding to a variety of antigens with high affinity.

B1-B cells consist of 2 subpopulations:

B1a B-cells- are natural antibodies (80%) protect during initial infection, by expressing CD5 a negative BCR signal IgM and bind with low affinity bacteria. B-cells are polyreactive and mediate innate response and target antigen presenting cells in systemic circulation.

B1b B-cells- neutralise antibodies which slow the kinetics. IgM antibodies create a memory response and produce IgA that are secreted in the lumen of the intestine (Fagarasan, et al 2003), thus mediate an adaptive response.

B1b cells produced solely in the spleen, where Hox-11 is required for maintenance, so recruitment of IgM-mediated immune responses can occur. Goodyear et al, 2005 found that asplenic mice had defective or absent B1 responses.


B1 cells

Conventional B2 cells

Major sites

Peritoneal and pleural cavities

Secondary lymphoid organs

Source of new cells

Division of existing B1 cells

Bone marrow


Little or none


Response to carbohydrate antigens



Response to protein antigens



Surface IgD

Little or none


Class switching

Little or none





Table 2: Difference between B1 and B2 cells (66) (Produced by Nisha Lad)

T-15 idiotype has been expressed in B1 B-cells in mice and shown to secrete Nab by binding to phosphorycholine (PC), (Kearney et al, 2005).

B2-B cells appear mainly in secondary lymphoid organs and circulation, (Ollila et al, 2005). In mouse models innate B1 cells are seen to be mobile, however B2 are sessile components and restricted to the spleen. B2 B-cells are involved in t-dependant germinal centre reactions, where high numbers of memory cells are produced.

1.4.2 Marginal zone (MZ) B-cells

MZ B-cells are primarily found in the spleen and responsible for the early antibody response to blood-borne pathogens; however they also maintain host homeostasis, (Lopes-Carvalho et al, 2005).

MZ B-cells bind to complement coated antigens and mount to bacterial capsules, activating thymus independent (TI-2) antibodies to rapidly proliferate IgM, IgG3 and up-regulated co-stimulatory molecule (CD86).

During haemostasis MZ B-cells are found within the MZ region of the spleen where there are a large number of macrophages, whereas the FO B-cells re-circulating through the body.

The majority of MZ B-cells express the CD27 memory marker. Expression increases IgM, CD21, CD1, CD9, however it decreases IgD, CD5 and CD23. These characteristics aim to differentiate FO-B cells from B-cells. High levels of CD1d are responsible in presenting to NKT-cells.

MZ B-cells were first demonstrated in tyrosine kinase Pyk-2 deficient mice, where reduced IgM titre to all antigens, reduced IgG2a antibody titres to TI-1 & TI-2 antigen and reducing IgG3 antibody titres, (Song et al, 2003).

Figure 7: Structure of spleen (Rolf et al, 2007)

The spleen (figure 7) consists of approximately 100million lymphocytes and is crucial in B-cell maturation. MZ B-cells differentiate into antibody-forming cells in the red pulp and secreted high levels of IgM and IgG during the first week after challenge. White pulp area separates FO-B and T-cell areas, whilst red pulp consists of blood vessels and macrophages, (Gatto et al, 2004).

During childhood low levels of MZ B-cell mean a higher sensitivity to infections such as Streptococcus pneumonia (Kretschmer et al, 2003).

1.5 Diseases:

Deregulation of the immune system can result in autoimmune disease (AID), where the body attacks its own tissue. Theses arise due to abnormalities in B and T- cell maturation and signalling. Patients with AID generally have mutation in the memory B-cells which preferentially express IgM, thus this inhibits the isotype switch mechanism resulting in IgM accumulation.

Systemic Lupus Erythematosis is a multisystem AID that occurs due to production of autoantibodies against dsDNA. It affects the brain or the kidneys and shows an increase production of IFN-¡ (Waldner et al, 2009). Type 1 diabetes is an organ-specific AID that results due to destruction of ¢-cells of the pancreas. T-cell development and TLR result in its manifestation.

Sjogrens syndrome is a rheumatologic disease caused by accumulation of memory-B cells which cause attack to the exocrine glands. A large number of primary immunodeficiencies are caused by impaired B-cell development, or by failure to produce a response to t-cell signals. (Ollila et al, 2005).

Other autoimmune diseases include Wegners (vasculitis) Myositis syndrome, Lupus, MS, Glomerularnepheritis and Myastenia gravis.

B-cell depletion therapy has been shown to be highly effective as treatment in autoimmune disorders thus they are beneficial therapeutic targets, (Dorner et al, 2009).

1.6 Conclusion:

After looking at innate-like B-cells I can distinguish that they are vital for the immune system and they hold great promises for the future development of new vaccines, however further research is still required as theses cells are not fully understood.

I can conclude that innate-like B-cells consist of properties that bridge the two immune systems. These cells are useful in disease, as an adaptive response via memory cells can create a higher amplified signal and act like a primary innate response.

There are many future directions that B-cells can undergo: therapeutic targets- where B1a and MZ B-cells mount to antibodies responses in the absence of T-cells. This would be useful in diseases such as Alzehimers and brain tumors, where T-cell activity can have fatal consequences. Marcrophage lineages could also be determined and autoimmunity could also be clearly understood, (Dorner et al, 2009).

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