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Absent Joining Chain Effect on Immune Response

Critical Review of a Journal
Kallberg, E. and Leanderson, T., 2006. Joining-chain (J-chain) negative mice are B cell memory deficient. European Journal of Immunology, 36, 1398-1403.
The journal article falls under the main subject area of cellular immune response, where the effect of the absence of joining chain locus on T- cell dependent immune responses on mice was explored. While the authors’ previous study establishes the production of impaired IgM secretion from mice with inactivated joining chain locus, (Erlandsson,, 20010), this particular study further investigated such findings in detail by determining the exact genetic background of the mice. Thus, this particular study aimed to further validate the authors’ previous findings on early crosses of mice with absent joining chain and its concomitant effect on T-cell dependent immune response. The T- cell dependent B cell responses were analyzed using four experiments, namely: the immune response to the hapten 4-hydroxy-3-nitrophenyl and chicken gamma globulin (NP-CGG); analysis of the ratio between NP-specific ? and ? antibodies; analysis of somatic mutations, and carrier priming experiment. It was found that mice with absent joining chain loci are deficient in “T helper cell activation during T cell –dependent B cell immune responses”, (Kallberg and Leanderson, 2006).
This study was aptly technically described and appeals to an audience in the medical field such as immunologists, physicians, laboratory and clinical directors, etc. It consists of the following format: abstract, introduction, results, discussion, materials and methods, acknowledgements and references.
The title appropriately indicates the effect of J-chain deficiency on B memory, which is the focal point of this study. Its well structured abstract completely and vividly presented the major points and the conclusion of the study. The objective, which can be found in the latter part of the introduction, however, was not clearly identified in the abstract and the text, but needs to be carefully ascertained by the reader.
The experimental results of the four experiments produced findings that correlate to and support the hypothesis of the study, i.e., J-/- mice have compromised T-cell dependent immune response. The specific findings are as follows:
Joining- chain deficient mice have compromised secondary immune response to 4-hydroxy-3nitrophenyl.
Although J-/- mice responded in the same way with the control group during the analysis of serum IgG anti-NP at all time points, there was a wide difference observed on after the 14th day point, which was clearly supported and plotted in the graph (Figure1). After the secondary response to NP-CGG, it was found that the recall response in mice without joining chain loci are lower than the control animals, which was further correlated to a lower number of B memory cells. All raw data of the results pertaining to these findings were well supported by graphs (figures1-3).
Mice without joining-chain have inefficient repertoire switch
Results showed that only 30% of the NP-binding antibodies in J-/- mice were expressed, while 90% of the antibodies of the control animals were expressed, confirming the negative effect of the joining chain on the efficiency of T-cell immune responses. This was supported by a bar graph of the results and a graphical illustration of the NP expression on splenic B memory cells.
J-/- mice have a lower somatic mutation rate
The data were presented in a table showing the total mutations of J-/- mice with only 5 and 17 for IgM and IgG respectively, compared to 19 for IgM and 28 for IgG of the control animals.
J-chain deficient mice have a defective priming of T-helper cells
The results of a carrier priming experiment confirmed that the T lymphoid, and not the B lymphoid compartment in J-/- mice was affected. This was statistically proven by the unpaired t-test results which obtained a value of p< 0.001, which means that the difference between the J-/- mice and the control group is statistically highly significant.
All of the four findings are new discoveries in the area of cellular immune response. These findings were supported by raw data which were tabulated and plotted into graphs. The use of the unpaired t-test was appropriate because the data required a systemic linear layout, (Valiela, 2001, p. 93).
It was clearly pointed out in the discussion of the results that J-/- mice produce phenotypically deficient T helper cell characteristics as evidenced by their responses to the four experiments. Thus, these findings confirm that the effect of the “joining chain deficiency interferes specifically with the T-helper-dependent development of a sublineage of immune B cells that contributes marginally to the primary, but significantly to the secondary immune response”, (Kallberg and Leanderson, 2006). These major points were supported by data from other previous researches. Linton and others (1989) studied the lineage and finds “the existence of a distinct precursor cell subpopulation that is responsible for the generation of B cell memory”. A parallel study previously conducted shows that “mice devoid of J-chain expressing cells are partially immune compromised,” (Erlandsson, 2001). However, there are issues that still remain to be solved and therefore warrant further investigation. The reason for the high degree of variability in the immune response at day 14 after immunization in J-/- mice needs to be established. Moreover, the specific role that the J-chain molecule plays in its interference with B cells which contribute to both primary and secondary immune responses, needs further study.
Materials and Methods
Four experiments were conducted to test the hypothesis: analysis of immune response to the hapten NP-CGG, analysis of ratio between NP-specific K and ? antibodies, analysis of total frequency of somatic mutations and a carrier priming test. These tests were appropriate for this study as evidenced by the reliability of the data obtained, all of which supported the hypothesis. However, the predictive value of positive ELISA test results would have been improved if they were validated with an independent supplemental test that is highly specific, such as the Western Blot . This is because the ELISA test “can give a positive result when there are no antibodies (false positive), and it can give a negative result when there are antibodies (false negative)”, (Myers and Well, 2003, p. 98). In a parallel study conducted by Erlandsson and others (2001), the reliability of the ELISA test was further improved by the use of the Western Blot.
In the final analysis, the strength of this study lies on its significance and contribution in cellular immune response. The importance of B cell memory in protective immunity has been evidenced by previously published researches and clinical studies. Furthermore, it was already established that “J-chain expression was a clonal property already established in naïve, peripheral B lymphocytes, (Erlandsson,, 2001). In the same vein, the key regulators of the germinal center that are important in the induction of B cell memory and molecular consequences of cellular immune response with regard to B cell compartment have been defined (Williams and Ahmed, 1999). In humans, studies have indicated the presence of J – chain –negative plasma cell population and their ability to produce polymeric immunoglobulin A, (Kutteh,, 1982). This particular research served to further validate these findings, and at the same time, provide more exact, specific information regarding the influence of the joining chain on B cell memory, by postulating that the absence of the joining chain on mice negatively affects the efficiency of B cell memory, and thus, lower cellular immune response. The findings in this study are new, yet pivotal discoveries in the area of cellular immune response, and could serve as bases for future researches of this nature.
Erlandsson, L. Akerblad, P., Vingsbo-Lundberg, C., Kallberg, E., Lycke, N., and Leanderson, T., 2001. Joining chain expressing and non expressing B cell populations in the mouse. Journal of Experimental Medicine, 194, 557-570.
Kallberg, E., and Leanderson, T., 1994. Expansion of kappa and B cells during the primary immune response to 4-hydroxy-3-nitrophenyl acetate in BALB/c mice. Immunoll.Lett., 41, 287-290.
Kallberg, E., and Leanderson, T., 2006. Joining-chain (J-chain) negative mice are B cell memory deficient. European Journal of Immunology, 36, 1398-1403.
Fraenkel, R.E., and Wallen, N. E., 2001. Educational Research: A guide to the Process. Mahwah, NJ: Lawrence Erlbaum Associates.
Kutteh, W. H., Prince, S.J., Mestecky, J., 1982. Tissue origin of human polymeric and monumeric IgA. The Journal of Immunology, 28 (2), 990-995.
Linton, P.J.L., Decker D.J., and Klinman, N. R., 1989. Primary antibody-forming cells and secondary B cells are generated from separate precursor cell subpopulations. Cell, 59 (6), 1049-1059.
Moxley, J.M., 1992. Publish, Don’t Perish: The Scholar’s Guide to Academic Writing and Publishing. Westport, CT: Praeger.
Myers, J.L., and Well, D., 2003. Research Design and Statistical Analysis. Mahwah, N.J: Lawrence Erlbaum Associates.
Williams, M., and Ahmed, R., 1999. B cell memory and the long-lived plasma cell. Current Opinion in Immunology, 11 (2) 172-177.
Variela, I., 2001. Design, Analysis and Communication of Scientific Research. New York: Oxford University Press.

Multiple Sclerosis (MS): Pathophysiology and Management

Multiple sclerosis (MS) is an autoimmune inflammatory disease, in which multiple lesions or plaques are formed within the brain and spinal cord. It can be characterised as a demyelinative disease of the central nervous system that is associated with relative loss of the myelin sheath and axon. The hallmark feature of the disease is the loss of this myelin sheath which leads to scarring and various other symptoms including muscle weakness and visual disturbances. The myelin sheath is a vital component of the axon as it provides protection and insulation (figure 1). Demyelinization of the sheath exposes the underlying axon and can lead to defects in synaptic transmission. In healthy individuals, myelin repair is spontaneous however in patients with MS this repair process occurs slowly or not at all. The integrity and functioning of the nervous system relies on myelinated neurons which allow fast and efficient transfer of electrical impulses and when this function is impaired it can contribute to complete or partial loss of central nervous system (CNS) functions. MS can be a potentially debilitating disease with unpredictable results and sadly there is no cure, however there are some treatments available that assist in the management of the disease. There has been noted beneficial effects with either immunosuppressive or immunomodulatory therapies, though these effects are somewhat reserved as patients responses to treatment are variable (lassmann, 2002). There have been many investigations into the use of novel immunomodulatory therapies, in particular, those using sex hormones such as oestrogen and testosterone. It is thought by many (Voskuhl 2002, Eikelenboom et al 2009, Nicot 2009) that gender is a contributing factor to the initiation and course of MS and that underlying mechanisms of the disease can be linked to sex hormones. The contribution of sex hormones and their actions in the management of the disease will be further discussed.
The immune system plays fundamental role in Multiple Sclerosis The immune system can be linked to the gender differences in MS, as sex hormones are thought to affect the immune systems cytokine response (Eikelenboom 2009). It has been perceived that cytokines play an important, however complex, role in the pathogenesis of multiple sclerosis, as well as many other inflammatory diseases (Imitola et al, 2005). The disease is thought to be initiated by the release of Th1 cells which have a pro-inflammatory affect (Figure 2). Subsequent to this is an anti-inflammatory response that is mediated by the Th2 cytokines. MS is thought to occur in genetically susceptible individuals in whom Th1 autoimmunity is activated, thus multiple sclerosis is seen primarily as a Th1- mediated auto-immune disese (Gold et al, 2009). One of the more recent theories on MS pathology is that the establishment of the disease is thought to be triggered by an imbalance between Th1 and Th2 cytokine responses (Van den Broek et al 2005). It has been known for some time that gender and gonadal hormones can influence and modulate the immune cytokine response (Schuurs et al 1990, Van den Broek et al 2005). The differences between males and females are first seen during teenage years when testosterone levels in males and oestrogen levels in females start to increase. Furthermore, multiple sclerosis is more common in those who have reached sexual maturity and the disease can be influenced by other changes in hormone levels such as menopause and menstruation (Smith et al 1992). Thus, factors such as gender, that contribute to sex hormone levels, and cytokine regulation and secretion are fundamental in understanding MS pathogenesis.
Gender issues in Multiple Sclerosis There have been several studies that have linked gender to the clinical course of MS (Voskuhl 2002 , Reipert 2004). Females have been found to be most frequently affected by MS and this is the case in many other auto-immune diseases (McCarthy 2000). Also, there is higher disease prevalence and better prognosis amongst women with the disease (Whitacre et al 1999). The severity of the disease may often be greater in men, as both sexes follow a different course of the disease. The onset of MS in males is linked with the beginning of the decline in bioavailability of testosterone in healthy men (Reipert 2004). Therefore, susceptibility and severity of the disease between men and women are frequently contrasting. The causes of gender specificity remain unclear; however current interpretations may push towards identifying factors that lead to female bias in MS. Due to the fact that females are dominated by the the disease, it can be proposed that differences in sex hormones may offer protection to males against the disease.
The influence of sex hormones in Multiple Sclerosis It has already been established that gender plays a role in MS susceptibility. These differences can be explained by differences in sex hormones and their affect on the brain i.e. roles in damage and repair. Female to male ratios are seen to be approximately 2:1. MS susceptibility has been tested in EAE mice models (Figure 3) and the outcome has been that female mice are most susceptible when compared to male mice (Voskuhl et al, 2001). Sex hormones, oestrogen and testosterone may offer neuroprotection. For many years, it has been known that the prevalence of multiple sclerosis is higher in females than it is in males. This is often the case in many auto-immune diseases. Therefore, it is fair to say that sex hormones play specific roles in the immune responses of these auto-immune diseases such as Multiple sclerosis and Rheumatoid Arthritis (Cutolo 1997). Research into the roles of sex hormones in the immune system has been of topic sincethe 1950’s and 60s (Kappas et al 1963). It is differences in production and secretion patterns of cytokines that seems to vary between males and females with MS and each sex hormone is associated with different clinical manifestations of multiple Sclerosis. Therefore, the concentrations of sex hormones within the body during a certain period can influence the production of cytokines, which in turn affects disease severity and recovery.
Oestrogens Oestrogen can been described as an immunomodulator and its concentrations can vary within the body and can rise or fall, for example pregnancy, menstruation and menopause. The effects of oestrogen on the immune response have been studied in both In vivo and In vitro environments. In particular its effects on cytokine production have been noted. Also, it is thought that oestrogens have two effects on the immune system; one involving the suppression T cell development and the other stimulation of antibody production (Van den Broek). Oestrogen is one of the most researched sex hormones, which is thought to have a protective and favourable affects against the progression and clinical course of MS (Eikelenboom et al 2009). This effect is shown in pregnancy, particularly during the third trimester, where the levels of Oestrogen (and progesterone) are high (Figure 4) . The urine of nonpregant and pregnant women was tested for levels of oestrogen. In non pregnant women, the ratio of estriol to estron plus estradiol was approximately 1:1 compared to 10:1 in pregnant women (Drača et al 2006). These increased levels of oestrogens are thought to delay MS progression, which is beneficial. It was found that MS patients experienced clinical improvement during pregnancy (VOSKUHL ,2007) and decreased relapse rates. However, these effects are not permanent and subside post-partum. There may be periods of disease exacerbation post partum, where there is an increase in relapses (Sandyk 1996). Although pregnancy offers favourable disease conditions, these effects have not been conclusively shown to have long term effects. This theory has been supported in EAE, where a reduction in EAE was most prominent during late pregnancy. In addition, Van den Broek has shown that castrated female mice experience a delay in the onset of the disease, when supplemented with oestrogens. This may be indicative of disease modification by hormones. Furthermore, oral contraceptives, containing oestrogen may have similar effects in altering the course of the disease (Jama and archives journals 2005), however long term effects have not been extensively confirmed. Thus, the beneficial effects must outweigh the side effects of long term use for sufficient justification.
As previously mentioned Th1 and Th2 cells are involved in the mediation of the disease. Using the EAE animal model, it has been demonstrated that oestrogens promote a Th2 phenotype, which is considered to have anti-inflammatory affects (offner et al 2006). These protective effects seen in EAE, propose the use of oestrogen as a possible therapy for multiple sclerosis. During periods of high oestrogen levels, there is seen to be a decrease in pro-inflammatory cytokines such as TNF-α and an increase in suppressor cytokines such as IL-10, which are known to be beneficial on the clinical manifestations of Multiple Sclerosis. Furthermore, oestrogens have been shown to inhibit the production of nitric oxide and TNF-α, which are both toxic to myelin producing oligodendrocytes (Bruce-keller et al 2000). Past findings suggest that oestrogens used as hormonal supplementation may be beneficial in menopausal and post menopausal MS patients (Sandyk 1996). It was found that the risks hormonal replacement therapy outweighed the benefits in healthy menopausal women; however the risk/benefit ratio was thought to be more tolerable in women with autoimmune disease (Soldan et al 2003).
Testosterone Testosterone has many functions; however one of the less recognized is its role in nervous system development. Testosterone, as well as oestrogen, is seen as an immunomodulator, however each sex hormone has differing roles in MS. It has been suggested by clinical studies that testosterone could offer neuroprotection that could be useful in the management of MS (Gold et al 2008). Testosterone can offer direct or indirect neuroprotection. Free testosterone may pass the blood brain barrier to directly modulate neuronal cells or it may be converted into oestrogen in the brain, acting indirectly (Bialek et al 2004). The possible protective effects of testosterone have mainly been investigated by studying the effects of castration of male animals. It has been demonstrated that testosterone can decrease the production of inflammatory cytokines that appear to contribute to the pathogenesis of MS (D’Agostino et al 1999). Moreover, a shift towards Th2 immunity has been noted in testosterone treated EAE mice, suggesting the potential use of testosterone in treatment of auto- immune diseases such as multiple sclerosis. Gold et al explored the immune-modulatory effects of testosterone on a group of males, clinically defined for MS. An anti-inflammatory effect was seen due to a decrease in IL-2 and DTH (delayed type hypersensitivity) responses and an increase in TGFβ-1. Also, testosterone was shown to increase the production of BDNF (brain derived neurotrophic factor) and has a suggestive neuroprotective effect in MS. BDNFs were the first neurotrophin to be detected in inflammatory lesions (Hohlfeld 2008). BDNFs may have a role in limiting the damage caused by inflammation. Furthermore, there has been a link between MS severity and production of BDNFs (Bialek et al 2004). More damage to the white matter was associated with decreased levels of BDNF.
Oestrogen and testosterone in the management of MS Oestrogens
The current observation that oestrogens produced during pregnancy subdue clinical manifestations of MS and other auto-immune diseases, has lead to the use of oestrogen therapy in patients whom are not pregnant and suffer severely from MS . There has been suggestion that this type of therapy will be able to mimic the Th1 to Th2 shift that is seen during pregnancy and is correlated with improved clinical symptoms. Oestrogen treatments such as oestriol and oestradiol may offer protection against the clinical severity of MS, as its effects have been shown in EAE (Gold et al 2009). The mechanism of protection that is offered by oestrogens is thought to exert anti-inflammatory processes, by affecting the cytokine response. Treatment with oestrogen has been shown to protect oligodendrocytes from cytotoxic attack (Sur et al 2003). This can be seen as beneficial as oligodendrocytes are responsible for producing myelin proteins that are need for nerve insulation and conductivity. The loss of myelin integrity and function can leave the individual vulnerable to MS. Many clinical studies have been carried out that have aimed to determine the effects of oestrogens for the management of MS. One particular study performed by Soldan et al involved the treatment with oral oestriol. The study intended to showcase the immunological effects of oestriol and the results showed significant decreases in CD4 and CD8 T cells. As well as these results, significant increases in anti-inflammatory cytokines, IL-5 and IL-10 and decreases in pro-inflammatory cytokines, TNFα were observed. The alterations in cytokine secretions were linked to reductions in lesions seen in monthly MRIs. Overall, it can be suggested that oestriols can influence the course of MS.
Oestrogens can regulate gene transcription, acting via oestrogen receptors, ER α and ER β. It has further been assessed whether or not oestrogen treatment was gender specific (Palaszynski et al 2004). It was found that the expression of ER α and ER β were equal in both genders and the disease severity was found to decrease in both males and females with oestriol treatment. Moreover, a decrease in proinflammatory cytokines resulted after oestriol treatment in both males and females. This reveals that therapies need not be gender specific and also a potential use of oestrogen treatment for men, as well as women.
Recent studies and clinical trials have been able to highlight the roles of testosterone in the management of multiple sclerosis. It is well known that testosterone offers protection to males which may be why they are less susceptible to MS and other auto-immune diseases, compared to females. One recent pilot study conducted by Sicotte et al treated 10 male MS patients with gel testosterone. The results concluded an improvement in spatial and working memory performance; however no changes in inflammatory immune responses were noted in MRI. Overall, the study indicated that testosterone was a safe potential treatment and it was well tolerated. Although the treatments have shown success, more investigations are required to further evaluate the neuroprotective roles of testosterone in the management of MS. Overall, it can be said that testosterone can be protective in MS. The cytokine responses vary between males and females which may explain why men are less affected by MS. These cytokine differences could be due to testosterone (Liva at al 2004).
Conclusion From the numerous studies that have been undertaken to further understand and explore the roles of Oestrogens and testosterones in disease initiation and progression, it can be concluded that sex hormones may have powerful anti-inflammatory and neuroprotective functions. In spite of there being no specific treatments that are able to offer improvements to the long term prognosis of the disease, there has been increasing evidence to suggest that gender and hormonal profile can affect therapy and that these factors should be taken into account (Nicot 2009). Using a gender based approach in the management of Multiple Sclerosis may be beneficial as many studies have pointed towards the importance of sex hormones in the pathogenesis of the disease. It has been acknowledged that sex hormones have roles in MS pathology therefore can be utilised in potential therapeutic measures for the treatment of the disease. It is known that immune mechanisms that promote the release of pro-inflammatory cytokines lead to a more severe and progressive disease and the mechanisms that promote the release of anti- inflammatory cytokines have shown to be protective (Palaszynski 2003). Sex hormones such as oestrogen and testosterone have been shown to encourage a shift towards an anti-inflammatory immune response which is favoured in multiple sclerosis. Therefore, oestrogen and testosterone are promising candidates for the treatment and management of multiple sclerosis as they posses anti-inflammatory and neuroprotective traits.