The adaptive capability of the immune system has helped the human species to survive millions of bacterial, viral, fungal infections and a variety of other sources of infection and disease. Not only is this attack on the living invaders that enter our body, but also towards any foreign agent that is non-self in nature. The composition of this adaptive system, the B and the T cells, have each some very important functions to cater to. The B cells in this regard are important in creating antibodies towards the antigen that is introduced into the body.
The human adaptive immune system is a very fine example of lymphocytic clone aggregations, having a unique antigen receptor. This receptor on a B cell is the antibody. The activity and the development of the B cells start to take place in the early fetal life and continue to do so throughout life. These cells are then categorized into central and peripheral cells. While the central cells may be nascent or may not have any specific antibody developed in them, the peripheral cells are almost always exposed to some form of antigen and therefore create antibodies. Here there are two options for the B cell to take.
Either it can become an antibody secreting cell, or it may become a memory cell. Each cell is able to invoke an immune reaction; however the rates of reactions may be slow or fast depending upon the cell type. (BD Biosciences, 2007) The role of eosinophils in allergic reactions and manifestations is well established. There are many functions that eosinophils carry out in the airways during inflammation. Activated ones release various cytotoxic molecules such as major basic proteins, eosinophil peroxidase, eosinophilic cationic protein or ECP, lipid mediators and cytokins.
These molecules lead to damage to the tissue and the changes which are later on referred to as allergic reactions. It is well known that eosinophils also retain the capability of producing various chemokines which include IL-3, IL-4, IL-5, IL-6, IL-16, the tumor necrosis factor, and the GM-CSF. Other chemokines include eotaxin, IL-8, macrophage inflammatory protein, MCPs and RANTES. The Th2 system is also responsible in coordinating the effects of eosinophils. IL-4 and IL-5 cause IgE synthesis and eosinophil proliferation respectively are very important in local infiltration and activation of the eosinophils in any site.
Other Th2 cytokines such as IL-10 and IL-13 cause airway hyper-reactivity and allergic inflammation. Where initially the information about the mechanisms of B cells was very limited, this is not the case now. For example, we now know that B cell immunological responses are a complicated series of events involving antigens, cell-surface ligands, and soluble growth and differentiation factors or cytokines which bind to the specific receptor sites on the cells. (Callard and Kotowicz, 2000) The cytokines have been found to be one of the most potent activators of the B cell line.
Of the 40 total known cytokins, more than 17 retain ability to activate B cells. The source of these cytokines in many of these cases are the T cells, however, B cells, monocytes, non-lymphoid cells such as endothelial cells and fibroblasts can also produce various cytokines. (Callard and Kotowicz, 2000) There are however, certain features of cytokines that make them unique in the way they act on cells. For example, cytokines are not specific for any particular type of cell and certainly not for B cells.
(Callard and Kotowicz, 2000) However, they are able to activate many tissues and types of cells. Second, the cytokines can have multiple effects on the B cells, which can depend on the stage of the development and differentiation of B cells. Such high variability in the ability to influence cellular responses fascinates researchers till today. (Callard and Kotowicz, 2000) Asthma, also known as hyper-reactive airway disease, is a chronic condition where there are recurrent episodes of wheezing, breathlessness, chest tightness and coughing particularly during night or early morning.
This is a complicated chemical interaction between mast cells, eosinophils, T lymphocytes, macrophages, neutrophils and epithelial cells. While there are many clinical and pathological stages of the disease, these can all be summarized into three stages; airway inflammation, intermittent airflow obstruction and bronchial hyper-responsiveness. Eosinophil count is usually elevated in such cases. (Morris, 2007) With the complex immunological sequence of events and the roles of many immunological factors, asthma has become one of the most complicated illnesses of man.
(Morris, 2007) As this condition is immunological in nature, there is a very important and significant role that cytokines play in the progression of the disease. IL-25 is a cytokine that belongs to the family of the IL-17 family of cytokines. This cytokine is known to initiate type II immunological reaction and drives certain other cytokines such as IL-4, IL-5 and IL-13. IL-25 is present in many cells including activated Th2 cells, bone marrow derived mast cells and, alveolar macrophages.
(Kleinsheck et al, 2007) IL-25 has been implicated in causing allergic reactions, and the IL-17 family is known to cause chronic inflammatory reactions. Studies conducted on mice have shown that over expression of IL-25 in mice induces eosinophilia. (Cheung et al, 2006) due to the many similarities of IL-25 with the IL-17 family, it shows a very prominent role in affecting B cells and therefore in immunologic and allergic reactions. IL-17E, the other name of IL-25 has been found in large quantities in bronchial mucosa among asthmatic patients. (Letuve et al. Year??????))
The response of IL-25 is different from other members of the family, as others cause the activation of the neutrophils. The IL-25 response also causes eosinophilia with increased mucous secretion. Many researches now show that B cells have role in the properties of IL-17E properties. (Letuve et al. Year?????? )) Associated with it are usually increases in other immunoglobulin levels as well. These include IgG, IgE and IgA respectively. IL-25 levels increase the levels of B cells in the serum, spleen and lymph nodes, which suggests that it has important role in the development of B lymphocytes.
(Letuve et al. Year?????? )) MAPKs or the mitogen activated protein kinases are comprised of molecules that play a critical role in cell signaling and gene expression. It consists of three members, which are extracellular signal-regulated kinase(ERK), p38 and c-Jun N-Terminal kinase or JNK respectively. The MAPKs are activated by phosphorylation and via transcriptional and non-transcriptional regulation, are able to cause a wide variety of intracellular responses. The p38 MAPK is also known as the stress induced kinase which plays an important role in the inflammatory responses.
Researches have shown that inhibitors of p39 MAPK are able to effectively reduce rheumatoid arthritis and inflammatory pain. (Ji and Suter, 2007) Current researches have shown that asthmatic patients display abnormal responses to common allergins that are present in the environment. (Pelaia et al 2005) the role of T cells is pivotal in the inflammatory responses in asthma. It is the ERK signaling module that is responsible for the differentiation of Th2 cells. (Pelaia et al 2005)ERK stimulation is also thought to contribute in differentiating the naive T cell population into Th2 cell types.
IL-4 is also thought to contribute to this process, which converts Th0 cells into Th2 cells stimulated IgE synthesis by the B lymphocytes and promotes eosinophil adhesion to vascular endothelium. JAK mainly mediates the activity of the the IL-4 which shows that the relationship between the pathways of ERK and JAK are interrelated and of significance. (Pelaia et al 2005) MAPK is one of the mechanisms defined that transmits extracellular signals into intracellular mechanisms.
(Seger and Krebs, 1995) This mechanisms in essentiality involves activations of several membranal signaling molecules along with sequential stimulation of several cytoplasmic protein kinases. MAPK then causes the activation of many molecules and mechanisms that lead to proliferation, differentiation and development of cells. MAPK pathway was initially considered as restricted to growth factor signaling. It is now known however, that signaling pathways can also be initiated via phorbol esters, ionophors, heat shock and ligands. (Seger and Krebs, 1995)
Research now states that Th2 secretory activity is under the influence of the p38.p38 causes the phosphorylation of GATA-3, which is a transcription factor, which leads to synthesis of IL-5 and IL-13. (Palaia et al, 2005) It is also seen to cause significant and varying changes in the eosinophilic population. It can cause inhibition of the eosinophil apoptosis, can help in the differentiation of the cell and cause cytokin release. It is also responsible for causing airway eosinophilia which is a very common presentation in asthmatic patients. (Palaia et al, 2005) Migration towards the target site is also carried out by p38.
But eosinophils are not the only population that is under the influence of the p38. p38 has also shown neutrophil migration and recruitment patterns and helps in the up regulation of the intercellular adhesion molecule-1 (ICAM-1) along with the release of TNF-?. The p 38 is able to cause monocyte differentiation as well which again stimulates the production of TNF-? and macrophage inflammatory protein-2 or MIP-2 from human macrophages. (Peliaia et al,2005) CD 23 is another modality that has gained increased attention during the last couple of years in research.
There are many names given to it and these include B6, BLAST -2, FceRll, Leu-20 and low affinity IgE receptor. (Sarfati and Delespesse, 1999) CD 23 belongs to the family of SiGlec or the sialoadhesion family also known as the immunoglobulin supergene family. CD 23 is a Type II integral membrane glycoprotein with molecular weight of 45 kDa. (Sarfati and Delespesse, 1999) Alternate splicing of exon 2 generates two isoforms differing by 6 aa in the cytoplasmic region, where as the proteolytic cleavage of CD 23 generates soluble CD23 fragments of various molecular weights.
The cellular expression of CD 23 lies in B cells, monocytes, and FDC apical light zone which includes T cells, platelets, eosinophils, neutrophils and Langerhan cells. (Sarfati and Delespesse, 1999) CD 23 is constantly expressed in the human serum by B and T lymphocytes. Inflammation or infection causes an increase in the production. There are two Recent studies have shown that CD 23 is strongly “expressed on the surfaces of follicular dendritic cells and its interaction with CD 21 on the surface of B cells undergoing the germinal centre reaction” .