In contrast to conventional T lymphocytes and other Tregs, the NKT cell TCR does not interact with peptide antigen presented by classical MHC-encoded class I or II molecules, but instead it recognizes glycolipids presented by CD1d, a nonclassical antigen—presenting molecule reviewed in refs. Similar T cells are present in other mammalian species, including humans.
The evolutionary conservation of these cells is striking, as mouse NKT cells recognize human CD1d plus glycolipid antigen and vice versa 6.
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This alone is sufficient to suggest that these cells play a critical, and probably unique, role in the immune system. In reviewing immune regulation by NKT cells, it is first necessary to clarify the definition of the term. It is apparent that the simple classification of NKT cells as T lymphocytes that also express NK receptors is inadequate.
We have discussed this issue in greater detail elsewhere 1 , but the main problems with this definition are that many conventional T cells upregulate NK receptors, including NK1. It is reasonable to emphasize this subgroup not only because of its distinct characteristics, but because most of the literature on immune regulation by NK1.
The significance of species-specific differences in NKT cell frequencies is unknown. The recognition of glycolipid antigens in association with CD1d means that NKT cells recognize a class of antigens ignored by conventional T cells. Relatively few examples of these antigens are defined, although presentation of several mycobacterial cell wall antigens by the 3 other human CD1 molecules, CD1a, CD1b and CD1c, has been well characterized reviewed in ref. The compound most efficient for activating the majority of NKT cells is a synthetic glycolipid originally derived from a marine sponge known as —a-galactosylceramide a-GalCer reviewed in refs.
In fact, NKT cells in mice and humans can be best identified by binding of fluorochrome-conjugated, tetrameric complexes of CD1d loaded with a-GalCer 9 , 20 , Many other glycolipid molecules have been tested for NKT cell stimulatory capacity, with some, including ganglioside GD3 22 , glycophosphatidylinositol 23 , 24 , phosphoethanolamine 25 , and some forms of b-GalCer 26 , activating subsets of these cells 22 — When activated, NKT cells respond with vigorous cytokine production within 1—2 hours of TCR ligation reviewed in refs.
Moreover, individual NKT cells are able to make both Th1- and Th2-type cytokines simultaneously following stimulation in vivo 9 , 29 , 31 , an unusual characteristic that at face value seems paradoxical, as Th1 cytokines often antagonize the action of Th2 cytokines and vice versa. Adding to the unpredictability surrounding the functional consequences of NKT cell activation, these lymphocytes have been implicated as immunosuppressive cells in some systems, usually via their production of the Th2-type cytokines or IL, while in other systems, they appear to promote enhanced cell-mediated immunity via production of Th1-type cytokines reviewed in refs.
The mechanisms that determine the cytokine polarity of the NKT cell response, and the influence of the NKT cells response on the systemic immune system, are not well understood, and indeed, this problem represents a key challenge in the field of NKT cell research. Resolving this problem requires careful analysis of NKT cells at the single-cell level using intracellular cytokine staining or similar approaches to monitor the changes that occur in individual NKT cells over time and in response to different types of stimuli.
Why the followers of Engineer Ali: Mirza:
NKT cells influence and regulate a wide range of immune responses. We also find in mice that while CD25 is expressed at low levels by NKT cells, it is upregulated upon activation in vivo D. Godfrey and R. Keating, unpublished data.
It is therefore important to carefully distinguish these cells, and the table highlights their similarities and, more importantly, their differences. The potent production of immunosuppressive cytokines such as IL-4, IL, and IL by NKT cells prompted speculation that these cells might be able to suppress cell-mediated immune responses. Over the last few years, this has been demonstrated in several different models. The introduction of antigen into the anterior chamber of the eye in mice results in local and systemic inhibition of antigen-specific inflammatory T cell responses, known as anterior chamber—associated immune deviation ACAID.
This is thought to be one of several mechanisms responsible for the immune-privileged status of this organ. There is evidence that this may normally be a thymus-dependent step in which tolerogenic APCs traffic from the eye to the thymus, which leads to thymic NKT cell migration to the periphery 33 , This would explain how NKT cells, which themselves are unlikely to be protein antigen specific, can promote protein antigen—specific suppression.
Interestingly, this also suggests that different Treg populations might sometimes work as part of an integrated system. Data from experimental mouse models suggest that NKT cells may mediate allograft tolerance. Corneal allografts represent one of the most readily accepted types of solid tissue grafts. NKT cells have been shown to participate in 2 different models of cardiac allograft tolerance following tolerogenic immunotherapy.
In both models, the suppressive influence of these cells was only observed in association with immunological conditioning regimens, which were effective in the presence but not the absence of NKT cells. Similar results were reported by the same group using a different model of GVHD suppression, involving nonmyeloblative, fractionated lymphoid irradiation and antibody-mediated T cell depletion In both studies, inhibition was critically dependent on the ability of the NKT cells to produce IL-4 44 , The IL-4 dependence not only indicates that other NKT cell—derived immunosuppressive cytokines, such as IL and IL, were insufficient for suppression of GVHD in these models, it also suggests that IL-4 production by NKT cells dominates the response, counteracting the potential Th1-like influence by these cells, at least in this model.
Indeed, a-GalCer treatment was unable to improve cardiac allograft survival in mice Furthermore, in a study of maternal-fetal tolerance, although NKT cells did not appear to play a decisive physiological role, treatment of the pregnant mice with a-GalCer almost invariably triggered abortion 46 , which indicates that intentional stimulation of NKT cells by this glycolipid that strongly activates NKT cells does not necessarily promote a tolerogenic effect, although a weaker stimulation by natural or endogenous glycolipids might do so.
While the above studies are all rodent based, and there are currently no comparable studies in human tissue graft recipients, the clear functional overlap between NKT cells in humans and mice makes this an important area of investigation with obvious clinical potential. There is evidence from some autoimmune disease models suggesting that NKT cells naturally influence autoimmunity, while in other models, intentional activation of NKT cells by a-GalCer is required to elicit their regulatory function.
Until we understand the factors that naturally lead to NKT cell activation, the basis for their involvement in some but not all autoimmune diseases will remain elusive. This highlights the unpredictable nature of the NKT cell influence on immune responses and the importance of being able to understand the basis for the regulation of their cytokine production as well as to harness their activity and drive them in the desired direction.
The greatest number of studies investigating the role of NKT cells in autoimmune disease pathogenesis has involved type 1 diabetes. Nonetheless, stimulation of these cells via repeated administration of a-GalCer has a therapeutic effect 53 , 55 — In a number of studies, protection from diabetes by NKT cells was associated with the induction of a Th2 response to islet autoantigens 53 , In a transfer model, however, activation of diabetogenic T cells given to NOD mice in the presence of NKT cells inhibited differentiation of the former into IFN-g producers by preventing their expansion and proliferation, but the NKT cells did not act through IL-4 production In another study, treatment with a-GalCer led to increased numbers of CD8a — myeloid DCs in the pancreatic lymph nodes, and transfer of myeloid DCs from the pancreatic lymph node of untreated mice prevented diabetes in recipients Albeit indirectly, these data implicate a role for regulatory DCs acting downstream of NKT cell activation.
These findings were supported by 1 study 60 , but contradicted by 2 others 61 , The discrepancy could be due to differences in the patient and control populations, different methods of detection of NKT cells in the different human studies, and problems related to the comparison of analyses of peripheral blood of humans to analyses of lymphoid tissues in mice.
The latter concern is highlighted by the fact that while NOD mice are deficient for NKT cells in thymus, liver, and spleen, NKT cells in peripheral blood are at normal or even higher levels than in other commonly used mouse strains Experimental autoimmune encephalomyelitis EAE is an animal model of MS caused by immunizing susceptible rodent strains with myelin-derived antigens. This could be due to differences in the models used or the timing 65 or dose and route 64 of a-GalCer. Whether this longer-term effect solely reflects an altered NKT cell response or, alternatively, reduced IFN-g production by bystander cells, known to occur following a-GalCer administration 71 , 72 , remains to be determined.
A decrease in V a J a 18 mRNA in the peripheral blood of MS patients has been found, and short-term lines of NKT cells from MS patients in remission had a Th2 cytokine bias compared with similar lines from relapsed patients, which suggests a regulatory role for these cells in this human disease An influence of NKT cells in prevention of lupus was suggested in 2 early reports using mouse models of lupus 75 , 76 , although NKT cells were not well defined in these studies.
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NKT cells increased in number after the onset of disease, and their transfer from diseased mice to young recipients induced proteinuria and swelling of glomeruli. Furthermore, in vivo treatment with an anti-CD1d antibody had beneficial effects in this model Thus, the model seems to create an environment that favors the immune potentiating function, rather than suppressive function, of NKT cells, due to a mechanism that may involve IFN-g secretion and the promotion of the synthesis of pathogenic IgG2a isotype anti-DNA Igs.
In colitis induced by dextran sodium sulfate, activation of NKT cells was partially protective Interestingly, NKT cells were required, even in the absence of a-GalCer activation, for colitis induced by the hapten oxazalone 84 , and NKT cell—derived —IL was considered to be critical in this model.
Human NKT cells are reduced in the peripheral blood of patients with a variety of organ-specific and systemic autoimmune conditions but not in association with Graves disease, myasthenia gravis, and celiac disease Limitations of these studies, however, include the very low frequency and variability in the number of NKT cells in normal humans, assessment of the number of cells rather than their function in some cases, and the possibility that peripheral blood might not be representative of the site of disease. For example, in primary biliary cirrhosis, NKT cells were increased in patients in the liver, the target organ, but not in the peripheral blood Again, it is also relevant to point out that NKT cells are reduced in thymus, spleen, and liver of NOD mice but are present at similar levels to other strains in peripheral blood Clearly there is ample evidence that NKT cells may influence the outcome of autoimmunity, but this may be to the benefit or detriment of the host.
It is therefore important to develop a stronger understanding of the mechanisms leading to NKT cell activation in association with autoimmune disease, as well as the physiological factors that drive these cells to suppress or enhance the autoimmune response. Further studies into the behavior of these cells, and the influence of different exogenous stimuli, in the different mouse models of autoimmune disease are required before NKT cells can be safely targeted as an approach to autoimmune disease therapy in the clinic.
The potential importance of NKT cells in tumor rejection has been established NKT cells were found to be necessary for IL—mediated tumor therapy in mice 88 , and the earliest and best-documented effect of a-GalCer as an immunotherapeutic agent is its ability to promote NKT cell—dependent rejection of a broad range of experimental tumor lines, including melanoma, thymoma, carcinoma, and sarcoma 17 , 87 , Recent evidence has also shown that a-GalCer treatment can protect against spontaneous, carcinogen-, or oncogene-induced primary tumor formation in mice These studies suggest that NKT cells do not need to directly kill the tumor cells, and they are not acting primarily as effectors, but instead they recruit and promote a response by downstream effectors in an IFN-g—dependent manner.
It is important to emphasize that these studies support the concept that NKT cells can be induced to promote tumor rejection when using immunotherapeutic factors such as IL or —a-GalCer. Whether this reflects the physiological activity of these cells is an important question, particularly in light of the fact that NKT cells are often associated with immunosuppression rather than immune aggression. Another model where NKT cells are clearly required for tumor rejection, this time in the absence of exogenous stimulation, is the rejection of methylcholanthrene-induced sarcomas in mice.
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Sarcoma cell lines also grew preferentially in NKT cell—deficient mice, and rejection could be mediated by adoptive transfer of purified NKT cells from WT donors Similar findings were more recently reported for an experimental model of pulmonary sarcoma metastasis Compounding the paradox of the differential immune activity mediated by NKT cells, in other mouse tumor models, NKT cells appear to play a suppressive role. CD1d-dependent T cells have also been implicated in the UV-induced suppression of tumor rejection Furthermore, a-GalCer—stimulated human NKT cells can kill or inhibit the growth of tumor cells in vitro , , and they can activate human NK cells through an IL-2—dependent mechanism , which highlights the potential of NKT cell stimulation for immunotherapy.
They say that although Ah:mad was not the Noun of Mirza: Of Qa:diya:n, but when some followers used this noun for him he did not stop them, this means that he accepted it as his noun [Ism]. The answer is that such a way cannot prove a noun as a proper noun of any person whether he be Mirza: of Qa:diya:n or else. In this case the modifying is just choosing the second component of the compound proper noun instead of the third.
It is very subtle one. This can be generalized to a compound noun of any number of components what so ever, whether 4 of 5 and so on. With such powerful refutations , it has become very clear that the compound noun Ali: Bhai is not a proper noun of the Mirza: of Jhelum. This is not only Possible but also probable since the Mirza: of Jhelum is uses to coin new term using old words. So it is very likely that he has coined a Nick Name for him to be used as his proper noun in his circle of a small radius.
But this cannot falsify our research. Since Mirza:is of Qa:dian often use the full compound noun instead of a component of noun of Mirza: of Qa:diy:an. But still the use the component [short name] for their heretic aim. The Pseudo Noun Ali: Bhai is used for him in his circle for some specific reasons. These reasons are apparently multiple , but the technique to invent a Pseudo Noun is borrowed on as investigated above.
We have seen that this technique was developed in Subcontinent United India by Mirza: Mah:mu:d son of Mirza: Qa:diya:ni for an apostate purpose. The Mirza: of Jhelum who is a great borrower of such Anti Isla:mic techniques , and uses such Anti Isla:mic Techniques with slight modification engineered by him once again did the very same thing, this time indirectly. It is possible that some deeply hidden purposes are yet to be discovered, yet the technique is identified and once it is identified his hidden purposes which are not identified yet may not useful to him and cease to be productive.
This enucleate and elucidate the hidden and buried fact that what the Mirza: of Jhelum does do with the Ah:adi:th: Ass:ah:i:yah is similar to what Mirza:s of Qa:diyan did with the A:ya:t of Holy Qura:n. One may just see the distorted meanings of A:ya:t in their different works and almost a similar things are done by Mirza: of Jhelum with Ah:a:di:th: when he requires distortions.
Only those followers who have become Akhva:n Al Mubtadi: may like to continue to call him as Ali: Bhai , other wise no sensible person after studying the source of his technique is supposed to use this Pseudo Noun for him. If you are still not convinced then we request you to consult great scholars of Isla:m. You shall now the truth. The Mirza: of Jhelum purports to represent Isla:m free of sects , and purports that he is the correct representative of Islam.
But it may be seen that any one who comment on him or accuse him is declared as a False speaker and his allegation as false. If all the Muslim Scholars throughout the glob consider him as heretic inspite of all their diference this is a proof that a single person who oppose all others is a heretic, innovator, deviant and heterodox.
If you still need any evidence then you may see that Engineer Ali: Mirza: is opposed by every Scholar who comes to know some how about him and thus it implies an Ijma: of Muslims against him. The validity of Ijma: is recognized even be the Mirza: of Jhelum. As this establishes an Ijma: of Muslims against the Mirza: of Jhelum , this implies that he is a Heretic beyond the shadow of doubts.
If you are still cot convinced then the final request in this regard is to study yourself and then critically analyze the lectures of the heretic lecturer of Jhelum. I am the Messenger [Rasu:l]of Allah unto you, confirming that which was revealed before me in the Torah, and bringing Good Tidings of a Messenger who cometh after me, whose Proper Noun is the Ah:mad. Yet when He hath come unto them with clear proofs, they say: This is mere sorcery. Although Maulana Maudu:di: supported this book but he some times commit great mistake in regard to the matter of history.
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For Later. Related titles. Phrases and Philosophies for the Use of the Young. Jump to Page. Search inside document. He was excommunicated from Baha:sim by Abdul Baha:. His followers may not know the fact but it I very likely that the Engineer Ali: Mirza: knows it. An other part of the Noun is Mirza: which needs special discussion. It is as deep as the centre of the earth. The third Part was Ah:mad. See :Anva:rululu:m, a collection of works of Bahi:ruddi:n Mah:mu:d ,Vol-iii He was constantly refuted by scholars that if a compound Nouns consisting of several parts is a Proper Noun of a Person then No component of the Noun can be the Proper Noun of the person.
But he did not listen. Aims and Objectives may be Different. Although the scheme is the same but the aim and objectives may not be the same. But in this case the aim is different. One Technique and different aims. Do you still need some proofs on the heresy of Mirza: of Jhelum. Mirza:s throughout the world has a long history of heresies and we have witness one of them. Mir Ahmad Feroz. Abdullah Ibn Muhammad. Azmain Amin.
Nur Aida Joe. Pondok Moden Saadah Addaarain. Twiggy Pink. Ahmad Al-Hafidz Salahuddin. Mateen Yousuf. Shahzad Shameem. Tyler Franklin. Nikhil Parekh. Religion Compass Volume 1 issue 6 [doi Ebrahim Shahid. Mirza: Of Jhelum cannot refute Mahmudites based on his own standard. Crucifixion or Impalement , Historians and Muslim Perspective.
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