EXPRESSION ON B CELLS IN HEALTHY INDIVIDUALS AND IN CHRONIC LYMPHOCYTIC LEUKIMIA - Literature review Example

? CD180/RP105 EXPRESSION ON B CELLS IN HEALTHY INDIVIDUALS AND IN CHRONIC LYMPHOCYTIC LEUKIMIA by Literature Review Chronic Lymphocytic Leukemia and the Role of Toll-like Receptors Introduction Without the immune system, humans would be defenseless against the large number of foreign molecules, many of which are dangerous and may be potentially fatal. Components of the immune system such as the white blood cells protect the body through the creation of specific antigens. However, in some cases, the immune system itself can be a source of problems, such as in autoimmune diseases, where the immune system recognizes cells of the host body as invaders and attacks these. The cells that form an important part of the immune system can also function incorrectly. Chronic lymphocytic leukemia (CLL) is one example of a disorder where the cells of the immune system are functioning incorrectly. This is a cancer where the B cells of the immune system are highly activated, show increased levels of proliferation and decreased rates of apoptosis. This results in the accumulation of affected cells, which prevents the immune system functioning normally. This review considers the role that Toll-like receptors (TLRs) have on immune system functioning, with a specific focus on CD180 (also known as RP105) and its role on CLL. Toll-like Receptors The immune system plays a crucial role in protecting the body against pathogens and allows the body to effectively defend itself. One class of molecules that have been shown to have an important role in the effectiveness of the immune system is Toll-like receptors (TLRs). These molecules play a significant role in the human immune system by assisting in the recognition of specific patterns or motifs in invading microbes . The current model of TLR action hypothesizes that these bind to invading molecules that enter the cell, discriminating these from other molecules. This stimulates defenses in other parts of the cell where necessary . The type of molecule that is recognized by a TLR differs between specific receptors. For example, TLR9 is specific for CpG DNA, while TLR2 can recognize a range of lipoproteins (Figure 1) . Figure 1: The ability of certain TLR receptors to recognize specific molecules. Image from Akira et al. (2001) However, while the TLR pathway has been shown to be crucial for the defense and protection of the body, it also can have a significant role in immune system diseases and allergies. This can be due to high levels of signaling or deficiencies of molecules that are involved in the signaling pathway . Thus, TLRs play a significant role in the immune system and related diseases. Understanding their functions both collectively and individual is important to understand the occurrence and progression of many different diseases, as well as looking for treatment for these. Studies have revealed that one potentially important TLR in many immune system diseases is CD180, also known as RP105. This molecule is expressed on the outer membrane of B cells that is known to be a leucine-rich repeat (LLR). LLRs are known to be important in the way in which pathogens within the immune system are recognized. A homolog of the protein has been found on mouse B cells, and has been associated with a decreased rate of cell death. Experimental evidence shows that cells that were negative for CD180 were susceptible to apoptosis induced by corticosteroids, while those that expressed CD108 were not . In mice, almost all mature B cells expressed CD180; however, this is not true in humans. For example, in individuals suffering from systemic lupus erythematosus (SLE) almost 16% of patients tested were not expressing CD180 in a significant quantity. Individuals who did not have SLE had a significantly lower average level of CD180 expression than those who were affected with SLE . In humans, CD180 is involved in the recognition of B cells and signaling of lipopolysaccharides. However, little more is known about its function . In mice, almost all mature B cells expressed CD180; however, this is not true in humans. For example, in individuals suffering from systemic lupus erythematosus (SLE) almost 16% of patients tested were not expressing CD180 in a significant quantity. Individuals who did not have SLE had a significantly lower average level of CD180 expression than those who were affected with SLE . CD180 has been predicted to have significant biological significance as a consequence of being a TLR, as well as the role that it appears to have in signaling and recognition of potentially harmful molecules . However, there are some differences between CD180 and normal TLRs, as CD180 does not have a TIR domain . Consequently, some authors consider CD180 to be an TLR-related, accessory molecule . The expression of CD180 has been linked to the activation of B cells and higher levels of activity for a number of immune system diseases. For example, studies in SLE show that as disease activity decreased, the amount of CD180 that was being expressed also decreases . This suggests that CD180 has a significant role in the progression of immune system diseases. Furthermore, elucidating more about the relationship between CD180 and the progress of specific disorders may have a role in the development of treatments. Chronic Lymphocytic Leukemia Chronic lymphocytic leukemia (CLL) is the most common form of leukemia in adults, representing approximately 30% of all cases within the United States. It is approximately twice as common in males than it is in females, although the factors that drive this difference are not known. There is also a racial difference, with CLL being more common in Caucasians . As the disease progresses, the immune system begins to become less functional, and is unable to fight infections. This occurs because the abnormal cells that are produced as part of the disease outnumber the number of healthy, correctly functioning cells. CLL is often not evident, and individuals may have the disease but be asymptomatic during the early stages. In these cases, the presence of CLL is first determined through a blood test, where an amplified amount of white blood cells is observed. Some symptoms of CLL include loss of weight, anemia, shortness of breath and a swollen spleen. The disease primarily occurs in the elderly , with 72 being the median age of patients at the time of diagnosis . The term leukemia refers to cancer that occurs within the white blood cells, also known as leukocytes. Unlike other variants of cancer, there is no tumor or solid mass associated with LLC. The disease causes the number of white blood cells to accumulate in the blood and bone marrow, which can spread to other systems such as the spleen or the lymph nodes. People with LLC may still have production of some normal white cells, however, the number depends on the severity of the disease. One of the key determinants of CLL is the presence of a higher than normal white cell count. The exists in stages, which are determined on the basis of the number of white blood cells, lymph node groups, and whether the amount of red blood cells has been affected. Prognosis for CLL patients is variable depending on the stage of the disease. People diagnosed with an early stage of the disease may live more than ten years . The disease was originally thought to have a homogenous presentation across the population; however, research now suggests that the disease is variable between one person and the next. There remains no cure for CLL; however, understanding of the disease processes continues to increase , with significant increases in knowledge occurring within the last ten years . Chemotherapy drugs are often used for the treatment of CLL, and occasionally radiation may be used if the patient has painful, enlarged lymph nodes. Additionally, a blood transfusion may be required if the patient has a low blood count. In some cases, a stem cell or bone marrow transfusion may be used. This is the only form of therapy that has the potential to cure the disease; all others can only slow the progression of CLL . Pathology The key cell type involved in CLL is B lymphocytes or B cells that are present in lymphatic tissues, the blood and the marrow . These cells are involved int the immune systems and produce antigens, which help the body to fight invaders. CLL cells have strong phenotypic resemblance to the activated human B cells . In an individual with CLL, these cells are monomorphic, small and round . Because of this, CLL is thought to develop from normal B cells that have been stimulated by either auto-antigens or exogenous antigens . B cells are one of the most prevalent types of lymphocytes (white blood cells), and this is part of the reason that CLL has such a strong impact on the immune system. The immune system is an essential system within humans, and its presence and optimal functioning is important to ensure that people are protected against potentially harmful infections and against pathogens. The role of B cells in a healthy body is the production of antibodies, although B cells have many different specific functions, depending on their differentiation, where they are in the body and their developmental history. For example, different classes of B cells express different antigens. However, in an infected individual, most of these B cells do not divide and also have a decreased rate of cell death, instead they are halted in the G0/G1 part of the cell cycle. Consequently, the affected cells accumulate and begin to outnumber the healthy cells . Although CCL was previously recognized as occurring because of accumulation rather than increased proliferation, current research indicates that proliferation is also higher than previously believed. This varies among individuals and is also closely related to disease progression. For example, in some patients, proliferation of the affected B cells is low, and consequently, accumulation of the cells is slow, and there are few symptoms of the disease. Such individuals can live many years with the disease. In contrast, in other individuals, proliferation of affected cells can be very fast, and this results in a rapid progression of the disease and increase in severity of symptoms . There appears to be a genetic component to the presence of CLL, as individuals with this or other abnormal lymphoid disorders have a significantly higher chance of having CLL. However, the disease is also prevalent in cases where no family history is present, and there is virtually no difference between the familial and sporadic presentations . While early research suggested CCL was a homogenous disease, evidence now indicates that it is heterogeneous, with many different clinical outcomes . The variability in clinical presentations of the disease has been linked to variation in many surface molecules that are present on the cell, which influence the way that it interacts with cells around it as well as rates of proliferation and apoptosis . Current evidence suggests that stimulation of the B cells by antigens drives the increased proliferation and decreased apoptosis observed in affected cells . Experimental results indicate that antigenic pressure can lead to the development of CLL, and that this can also have a significant effect on the progression of the disease . However, what antigens are responsible for disease presence and progression are unknown . CD180/RP105 B cells in individuals with CLL retain many of the functions from their origin, including that of TLRs. TLRs have been showing to have a role in the development of tumors. When a TLR is stimulated, this triggers signals in the cell, which eventually results in the transcription of specific genes. TLR signaling pathways are important in humans, as they are required for the differentiation and proliferation of B cells . While all TLRs retain their expression in affected CLL B cells, the prevalence of expression varies. In particular, TLR4 and CD180 are both expressed in higher quantities in affected B cells than unaffected ones . Consequently, TLRs are thought to have a significant role in CLL. The process of activation of B cells occurs through two receptors, TLR4 and CD180. Recent research has indicated that CD180 plays a regulatory role in the cell, inhibiting the signaling of TLR4 . CD108 is able to affect the signal pathway of TLR4 due to the homology between the two products . The expression of the CD180 gene has been shown to be lower during B cell activation, suggesting that the activation of B cells represses CD180 expression . Studies have indicated that B cell activation can be stimulated, and that this results in a significant decrease in CD180 expression and the prevalence of the CD180 gene product . Expression in Healthy and CLL Affected Individuals Research indicates that CLL cells express CD180 in a heterogeneous manner. In a study of 78 patients, suffering from CLL, and 31 healthy individuals who did not have the disease, the authors found that in one third of the patients with CLL the expression of CD180 was not significantly different from the control cells. In contrast, two-thirds of patients had variable expression of CD180 that was significantly different than that of the control . Another study found that the expression of CD180 is higher in individuals that have CLL than those that do not . One study has shown that expression of CD180 has been observed in approximately 60% of individuals suffering from CLL . Thus, CD180 appears to play a significant role in many affected CLL B cells, but a smaller role in non-CLL B cells. Like normal B cells, some CLL cells have been shown to be able to be activated by CD180, suggesting that some level of functionality for CD180 remains in these cells. Nevertheless, in other CLL cells, this has not been observed . CD180 has been shown to have a role in the responsiveness of a cell to lipopolysaccharides (LPS). Cells that do not have CD180 exhibit hyporesponsiveness to LPS .The biological function of CD180 appears to be the same in affected and unaffected individuals, and consequently, the role of CD180 in cells remains mostly unknown . Stimulation of CD180 has been shown to increase the rate of B cell proliferation and differentiation . Combined with the increased prevalence of CD180 in affected CLL B cells, this result suggests that CD180 plays a significant role in the disease process. Furthermore, it may be possible to repress function of CD180, and decrease cell proliferation. This might not act as a cure for the disease, but could potentially slow down the reproduction of the affected cells, and consequently decrease the speed at which CLL and the associated symptoms progress. Anti-CD180 has been used to activate CD180 in B cells that are not affected by CLL .. There is significant potential for TLRs, like CD180, to have clinical role. TLR agonists are currently the subject of clinical trials, with the hope that these will have a significant role in decreasing the prevalence of leukemic B cells . Additionally, research has shown that CD180 has a role in the signaling pathway of CLL. This suggests that in the future CD180 expression may have a role in clinical treatment of the disease, although there is still a long way to go before the mechanism is understood fully. Future Perspectives Literature on the role that CD180 plays in CLL, and the way that this expression differs between types of cells is a relatively new field. Consequently, there are many new avenues for future research. For example, studies have shown a difference in expression of CD180 between cells of patients that have CLL and those that do not, but attempts have not been made to align these differences with variables associated with individual patients. An examination of this may help researchers to understand the variable nature of the disease, and why CD180 expression is elevated in most, but not all, suffers of CLL. Understanding the signaling pathway that is present in CLL cells and how CD180 interacts with this is an important component of current and future research into treatment for CLL. If this pathway can be understood in greater detail, there is the potential for the development of new therapies that can reduce the effects of this cancer. Conclusion Relatively little is known about CD180, beyond the fact that it is expressed highly in CLL affected B cells, and has significantly lower expression in non-affected cells. It is likely that the gene and its product plays some role in the progression of CLL, however, research that is more detailed is needed before the full relationship is elucidated. Studies have linked CD180 expression to increased disease progression in both CLL and SLE; although it is not yet known which factor is the causative agent. Further studies need to determine whether the expression of CD180 is a causal factor in the progression of these diseases, or if CD180 expression is increasing as a side-effect of disease progression. CD180 has potential therapeutic implications, as it plays a role in the way in which B cells proliferate. Studies in the role of CD180 in the immune system are not limited to CLL, and any information obtained about the pathways that CD180 is involved in, as well as its function, will benefit a large number of immune system disorders. References Read More