Ecoclimber
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Ok,Two Journal Articles Below:
Case Rep Hematol. 2014;2014:641483. doi: 10.1155/2014/641483. Epub 2014 Feb 10.
Epstein-barr virus infection in an elderly nonimmunocompromised adult successfully treated with rituximab.
Smeltzer JP1, Howard MT2, Gonsalves WI1, Witzig TE1.
Author information
Abstract
Epstein-Barr virus (EBV) is a ubiquitous virus that commonly affects children and adolescents. In addition to causing a viral illness, it is also associated with various malignancies in particular B cell lymphomas and lymphoproliferative disorders. Differentiating between the two processes can be a diagnostic challenge. Here, we present a case of an atypical EBV infection in an elderly patient with severe systemic symptoms, multiorgan involvement, lymphadenopathy, and negative EBV serology. Excisional lymph node biopsy demonstrated features of a lymphoproliferative process involving EBV.
Despite supportive care, she experienced continued clinical deterioration and was successfully treated with rituximab. This case illustrates the diagnostic challenges of these cases particularly in the elderly who may have age related immunosenescence, the utility of EBV PCR testing, and the clinical efficacy of rituximab in clearing the infected cells.
******************************************************************************************************
However
In this highly technical journal not all of the B-Cells were eradicated using Rituximab for another disease category.
We therefore hypothesize that intrathecal immune suppression should negate intrathecal IgG secretion by clearing CNS TLO (1). Clinical trials using intrathecal drugs offer a real hope to cure progressive MS. However, these trials were designed to use intrathecal rituximab. A pitfall of this treatment may be the resistance of CD20+ B-cells nested in TLO as observed in rheumatoid arthritis, and the persistence of local IgG secretion as observed in serum (1, 92). In fact, after intravenous
+
intrathecal rituximab treatment, a complete B-cell depletion is obtained in serum but depletion is still incomplete in CSF at 3
months: −85% for B-cells, −82% for T-cell (93).
Results for IgG secretion and clinical/radiological data are not yet available. Although incomplete, these results suggest that intrathecal rituximab is a first step, but that it may not be sufficient alone to eradicate CNS TLO.
Conclusion:
Although typical of MS, the non-specific intrathecal reaction has long been a theoretical issue. We propose to consider this non-specific reaction as a common physiological property of intrathecal inflammation, involving the general properties of TLO located in the CNS. We extend this concept to (non-MS) CNS autoimmune and infectious disorders associated with intrathecal synthesis. Moreover, we propose that the cortical lesions associated with TLO observed in MS are not specific for MS but for TLO. We therefore propose the concept of “TLO-pathy” to describe cortical lesions associated with the presence of TLO. The concept of non-specific secretion deserves further study to clarify the influence of immunization schedule.
Front Neurol. 2014; 5: 27.
Published online Mar 11, 2014. doi: 10.3389/fneur.2014.00027
PMCID: PMC3949135
Does Disease-Irrelevant Intrathecal Synthesis in Multiple Sclerosis Make Sense in the Light of Tertiary Lymphoid Organs?
Mickael Bonnan1,*
For those technically minded Click on the Full Free Article Above:
Introduction
The intrathecal synthesis of immunoglobulins (Ig) and oligoclonal bands (OCB) is an early occurring event in the course of multiple sclerosis (MS), and once acquired, persists essentially unchanged throughout life, whatever therapies are undertaken [see review in Ref. (1)].
As a consequence, intrathecal Ig secretion is still a major supportive diagnostic argument. However, the antigens targeted by these intrathecal Ig are often considered to be largely unknown and studies have yielded contradictory results (2).
The lack of specificity against the three major myelin proteins does not preclude any other specificity (3), either against other minor myelin proteins or brain antigens, or against foreign antigens (viral antigens for example).
Indeed, the failure to find a major antigen for an intrathecally synthesized Ig may not relate to a nonsense antibody production but instead may reflect the molecular complexity of the CNS and the presumed antigenic target.
Studies without any a priori, which are better suited to revealing unknown specificities, have confirmed the existence of an immense pool of targets against other brain membrane proteins, lipids, and glycolipids [see Ref. (3)].
Paradoxically and despite these huge efforts, the puzzling problem of non-brain targets directed against a virus in the absence of brain infection seems irreconcilably contradictory with an intrathecal antigen–antibody selection.
Although the concept of molecular mimicry has long been debated [review in Ref. (4)], epidemiological data suggest that mimicry alone cannot explain the intrathecal synthesis that occurs against so many infectious agents [(5, 6), see below].
Here, we reassess the pathophysiological consequences of this non-specific (disease-irrelevant) intrathecal reaction in MS in the light of the most recent immunological data and develop a new concept with great explanatory potential by bringing together the apparently contradictory data in the literature.
First, we comprehensively review the non-specific intrathecal reaction in MS. While the classical “MRZ pattern” is the hallmark of this non-specific reaction, we argue that MRZ is simply part of a broader non-specific reaction involving many non-brain targets, such as most of the common infectious agents.
We then explore the conditions necessary to produce and maintain an intrathecal reaction. We first use the example of peripheral (non-brain) lymphoid organ physiology to demonstrate how a sustained antibody secretion may take place in a given lymphoid organ, even if the mature B-cells originate from a different immune compartment.
We posit that disease-irrelevant Ig secretion is a common feature of tertiary lymphoid organs (TLO) in various inflammatory disorders. We then link these observations to the fact that intrathecal synthesis needs the presence of cortical TLO, implying in turn a non-specific intrathecal synthesis.
We then explain why virtually all the CNS disorders associated with intrathecal synthesis may also harbor some non-specific synthesis, and provide evidence for this reaction and its extent in multiple CNS inflammatory disorders.
Since intrathecal synthesis involves CNS TLO and bearing in mind that TLO in progressive MS are associated with sub-pial lesions (7), we propose the pathological concept of “TLO-pathy” and provide examples from chronic CNS infections.
Finally, we return to the issue of MS. Since non-specific intrathecal synthesis is directed against many infectious agents, the question arises as to whether an immunization schedule could be used to accurately assess the time of MS onset? Secondly, although EBV infection precedes MS in virtually all patients, the intrathecal reaction against EBV is paradoxically very low. This might either illustrate the role of the immunization schedule or a specific relationship between EBV and MS.
In practice, intrathecal synthesis in MS informs the clinician mostly of the persistence of CNS TLO at the pathological level. Such information obtained from a simple lumbar puncture could help in the monitoring of future treatments targeting CNS TLO.
Case Rep Hematol. 2014;2014:641483. doi: 10.1155/2014/641483. Epub 2014 Feb 10.
Epstein-barr virus infection in an elderly nonimmunocompromised adult successfully treated with rituximab.
Smeltzer JP1, Howard MT2, Gonsalves WI1, Witzig TE1.
Author information
Abstract
Epstein-Barr virus (EBV) is a ubiquitous virus that commonly affects children and adolescents. In addition to causing a viral illness, it is also associated with various malignancies in particular B cell lymphomas and lymphoproliferative disorders. Differentiating between the two processes can be a diagnostic challenge. Here, we present a case of an atypical EBV infection in an elderly patient with severe systemic symptoms, multiorgan involvement, lymphadenopathy, and negative EBV serology. Excisional lymph node biopsy demonstrated features of a lymphoproliferative process involving EBV.
Despite supportive care, she experienced continued clinical deterioration and was successfully treated with rituximab. This case illustrates the diagnostic challenges of these cases particularly in the elderly who may have age related immunosenescence, the utility of EBV PCR testing, and the clinical efficacy of rituximab in clearing the infected cells.
******************************************************************************************************
However
In this highly technical journal not all of the B-Cells were eradicated using Rituximab for another disease category.
We therefore hypothesize that intrathecal immune suppression should negate intrathecal IgG secretion by clearing CNS TLO (1). Clinical trials using intrathecal drugs offer a real hope to cure progressive MS. However, these trials were designed to use intrathecal rituximab. A pitfall of this treatment may be the resistance of CD20+ B-cells nested in TLO as observed in rheumatoid arthritis, and the persistence of local IgG secretion as observed in serum (1, 92). In fact, after intravenous
Results for IgG secretion and clinical/radiological data are not yet available. Although incomplete, these results suggest that intrathecal rituximab is a first step, but that it may not be sufficient alone to eradicate CNS TLO.
Conclusion:
Although typical of MS, the non-specific intrathecal reaction has long been a theoretical issue. We propose to consider this non-specific reaction as a common physiological property of intrathecal inflammation, involving the general properties of TLO located in the CNS. We extend this concept to (non-MS) CNS autoimmune and infectious disorders associated with intrathecal synthesis. Moreover, we propose that the cortical lesions associated with TLO observed in MS are not specific for MS but for TLO. We therefore propose the concept of “TLO-pathy” to describe cortical lesions associated with the presence of TLO. The concept of non-specific secretion deserves further study to clarify the influence of immunization schedule.
Front Neurol. 2014; 5: 27.
Published online Mar 11, 2014. doi: 10.3389/fneur.2014.00027
PMCID: PMC3949135
Does Disease-Irrelevant Intrathecal Synthesis in Multiple Sclerosis Make Sense in the Light of Tertiary Lymphoid Organs?
Mickael Bonnan1,*
For those technically minded Click on the Full Free Article Above:
Introduction
The intrathecal synthesis of immunoglobulins (Ig) and oligoclonal bands (OCB) is an early occurring event in the course of multiple sclerosis (MS), and once acquired, persists essentially unchanged throughout life, whatever therapies are undertaken [see review in Ref. (1)].
As a consequence, intrathecal Ig secretion is still a major supportive diagnostic argument. However, the antigens targeted by these intrathecal Ig are often considered to be largely unknown and studies have yielded contradictory results (2).
The lack of specificity against the three major myelin proteins does not preclude any other specificity (3), either against other minor myelin proteins or brain antigens, or against foreign antigens (viral antigens for example).
Indeed, the failure to find a major antigen for an intrathecally synthesized Ig may not relate to a nonsense antibody production but instead may reflect the molecular complexity of the CNS and the presumed antigenic target.
Studies without any a priori, which are better suited to revealing unknown specificities, have confirmed the existence of an immense pool of targets against other brain membrane proteins, lipids, and glycolipids [see Ref. (3)].
Paradoxically and despite these huge efforts, the puzzling problem of non-brain targets directed against a virus in the absence of brain infection seems irreconcilably contradictory with an intrathecal antigen–antibody selection.
Although the concept of molecular mimicry has long been debated [review in Ref. (4)], epidemiological data suggest that mimicry alone cannot explain the intrathecal synthesis that occurs against so many infectious agents [(5, 6), see below].
Here, we reassess the pathophysiological consequences of this non-specific (disease-irrelevant) intrathecal reaction in MS in the light of the most recent immunological data and develop a new concept with great explanatory potential by bringing together the apparently contradictory data in the literature.
First, we comprehensively review the non-specific intrathecal reaction in MS. While the classical “MRZ pattern” is the hallmark of this non-specific reaction, we argue that MRZ is simply part of a broader non-specific reaction involving many non-brain targets, such as most of the common infectious agents.
We then explore the conditions necessary to produce and maintain an intrathecal reaction. We first use the example of peripheral (non-brain) lymphoid organ physiology to demonstrate how a sustained antibody secretion may take place in a given lymphoid organ, even if the mature B-cells originate from a different immune compartment.
We posit that disease-irrelevant Ig secretion is a common feature of tertiary lymphoid organs (TLO) in various inflammatory disorders. We then link these observations to the fact that intrathecal synthesis needs the presence of cortical TLO, implying in turn a non-specific intrathecal synthesis.
We then explain why virtually all the CNS disorders associated with intrathecal synthesis may also harbor some non-specific synthesis, and provide evidence for this reaction and its extent in multiple CNS inflammatory disorders.
Since intrathecal synthesis involves CNS TLO and bearing in mind that TLO in progressive MS are associated with sub-pial lesions (7), we propose the pathological concept of “TLO-pathy” and provide examples from chronic CNS infections.
Finally, we return to the issue of MS. Since non-specific intrathecal synthesis is directed against many infectious agents, the question arises as to whether an immunization schedule could be used to accurately assess the time of MS onset? Secondly, although EBV infection precedes MS in virtually all patients, the intrathecal reaction against EBV is paradoxically very low. This might either illustrate the role of the immunization schedule or a specific relationship between EBV and MS.
In practice, intrathecal synthesis in MS informs the clinician mostly of the persistence of CNS TLO at the pathological level. Such information obtained from a simple lumbar puncture could help in the monitoring of future treatments targeting CNS TLO.
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