Table of Contents

Science behind immunopathology

Related articles: Managing immunopathology, Immunopathology

When patients on the MP kill bacterial pathogens they experience a reaction called immunopathology. Immunopathology is an increase in one's present symptoms of Th1 inflammation, or a return of previous Th1 inflammatory symptoms, that is caused largely by cytokines generated by the immune response and endotoxins released from dying bacteria. Occasionally, immunopathology will result in a new symptom or abnormal laboratory value (e.g., elevated creatinine, elevated liver enzymes, low white blood count, etc.). The occurrence of subclinical bacterial inflammation is due to olmesartan's activation of the immune system. Immunopathology appears to be a necessary part of recovery. The amount of immunopathology a patient experiences on the Marshall Protocol (MP) tends to correlate with disease severity and bacterial load. Patients who are less sick will have comparatively less-strong immunopathology.

Immunopathology is sometimes used synonymously with the “Jarisch-Herxheimer reaction” or “herx.”

Many MP patients who have experienced prolonged periods of immunopathology have reached stages of significant improvement or remission. This supports the conclusion that immunopathology is a necessary result of chronic bacterial death, and a precursor to disease reversal. The MP is not unique in this regard. A number of other diseases and/or therapies generate immunopathological or immunopathological-like reactions.1) 2) 3)

Lab work and patient reports can be used to track clinical signs of immunopathology.

Competing models for immunopathology

According to a 2010 review by evolutionary biologist Paul Ewald, PhD, there are essentially three categories of explanations for immunopathology in chronic disease:4) - The immune system is exposed to environmental conditions to which the individual is not well adapted. One hypothesis within this category, often referred to as the hygiene hypothesis, proposes that new more hygienic environmental conditions have generated compositions of symbionts that differ from those to which humans have been adapted. - Infectious agents act as triggers of immunopathology by shifting the immune system into a self-destructive state. - Infectious agents cause collateral damage by virtue of persistent and ongoing infections.

Of the three , the third and final explanation is most consistent with the Marshall Pathogenesis.

Symptoms of infection are caused by the body's response to microbes

A 2011 study, using a novel mouse model, showed that mice that were engineered to have a reduced innate immune response to the common cold actually showed less – not more – airway inflammation and bronchoconstriction (airway spasm) following infection.5) According to the study's lead author:

In our study, we offer the first direct evidence that limiting the immune response reduces the manifestations of rhinovirus infection. In our model, cold-induced asthma flare-ups were caused by the body's immune response to the virus, not the virus itself. Chemicals produced by the immune system inflame cells and tissues, causing asthma symptoms such as cough and wheeze.

Marc B. Hershenson, M.D., ScienceDaily June 17, 2011

Even though it was conducted in a murine modelA model of disease which uses rats or mice to mimic human conditions., this work is relevant as it strongly suggests that symptoms of infection are due not so much to the infection but the body's response to it.

Molecular nature of immunopathology

In patients suffering from any of the Th1 diseasesThe chronic inflammatory diseases caused by bacterial pathogens., pulsed low-dose antibiotics and frequent administration of olmesartan (Benicar) kill intraphagocytic and other pathogenic forms of bacteria. When bacteria die, endotoxins and inflammatory cytokines (signaling molecules) are released at the site of infection. Cells with a significant bacterial load will be destroyed along with the microbiotaThe bacterial community which causes chronic diseases - one which almost certainly includes multiple species and bacterial forms., and this adds to the immunopathology.

Example of immunopathology – Members of the observational cohort tend to experience temporary increase in several antibody titers, and a decline in latter stages of treatment.6)

Cytokines

Related article: Innate immune response and Th1 inflammation

During immunopathology, cytokines, are elevated. Cytokines are released by the inflammatory process.

The release of cytokines appears to be essential for recovery after an infection. One study found that the cytokine TNF-alpha was essential for the proper expression of acquired specific resistance following infection with Mycobacterium tuberculosis.7) 8) 9) For this reason among others, TNF-alpha inhibitors, drugs which suppress the cytokine, are contraindicated for MP patients.

Endotoxins

Endotoxins, sometimes referred to as lipopolysaccharides, are proteins associated with bacteria and bacterial communities (microbiota). When these bacteria are destroyed by the innate immune system, as will happen during the MP, endotoxins are released causing a spike in symptoms known as an immunopathological reaction.

The body responds to the presence of endotoxins by producing cholesterol10) and C-reactive protein,11) among other defense mechanisms.

In immunology, the term “LPS challenge” refers to the process of exposing a subject to a lipopolysaccharide that may act as a toxin. Injecting mice with LPS has been used as models for preterm labor,12) hyperactivity,13) lung injury,14) and periodontitis,15) to cite just a few examples.

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Symptom levels on the MP wax and wane over time due to immunopathology. In practice, the variation in symptoms tends to be more random than this illustration suggests, but there is a distinct downward trend.

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Exacerbation of symptoms

We need to change our paradigm from the existing one that symptoms are directly due to the pathogen or insult to the understanding that the symptoms and in fact clinical markers are due to the immune response. So instead of believing shingles erupts or herpes erupts or cystitis symptoms erupts when our immunity is depressed, we see these eruptions as an immune activation.

Of course, if there are factors suppressing immune function than these reactions will be ineffective long term. But our routine approach of suppressing symptoms when faced with an “acute illness” is likely promoting chronic problems.

Greg Blaney, M.D.

The increase in endotoxin and cytokines causes a corresponding increase in symptoms. Sometimes the symptoms are generalized and may include pain and fatigue. Other times symptoms occur at the site of infection. Patients with the lung disease sarcoidosis may notice that their coughing spells get worse. Those with psoriasis may notice a flare in their skin symptoms.

Cardiac, neurological, and respiratory immunopathologyA temporary exacerbation in symptoms of the lungs due to bacterial death. Requires careful management by physicians. should be of particular concern to healthcare providers as they can be life-threatening.

Occasionally, patients may notice new symptoms occurring in organs not known to be infected. The MP cannot create new infection, such symptoms are due to exacerbation of previous sub-clinical microbiota.

The strength of an immunopathological or herx reaction is associated with the severity of disease.16) 17)

Other examples of immunopathology

The Jarisch-Herxheimer reaction is similar if not identical to immunopathology. These reactions have been accepted as an indication of progress and, according to the literature, have been observed in at least ten different diseases and conditions:

Recovery from other infections and diseases also entails an immunopathological-like response:

Immune reconstitution inflammatory syndrome (IRIS)

During IRIS, HIV/AIDS patients experience the worsening or onset of systemic inflammatory clinical signs and symptoms following treatment with highly active antiretroviral therapy (HAART). This syndrome results when HAART allows for partial recovery of the immune response. This causes renewed and exuberant host immunological responses towards opportunistic infectious agents, agents that the host accumulated during prior periods of immunosuppression.35)

A number of well-known readily cultured pathogens have been conclusively linked to IRIS: the herpes viruses, cytomegalovirus, hepatitis B and C, M. tuberculosis, Mycobacterium avium complex and Cryptococcus neoformans.36) However, many more microbes likely contribute to the reaction since AIDS clinicians do not yet have access to the metagenomic tools. Certainly, the existence of IRIS in culture-negative HAART patients suggests that more microbes may be present than the few that have already been isolated.37)

Interestingly, patients experiencing IRIS often “develop” autoimmune conditions as a manifestation of immune restoration. These include sarcoidosis and other granulomatous reactions,38) 39) diabetes mellitus, rheumatoid arthritis,40) systemic lupus erythematosus,41) Guillain–Barre syndrome,42) Graves disease43) and autoimmuneA condition or disease thought to arise from an overactive immune response of the body against substances and tissues normally present in the body thyroid disease.44) 45) This suggests that these patients accumulated microbes that are directly involved in the pathogenesis of these disease states.

In a 2009 study, Sun and Singh reviewed the existence of IRIS in non-HIV immunocompromised patients including solid organ transplant recipients, women during the postpartum period, neutropenic patients, and tumor necrosis factor antagonist recipients.46)

Immunopathology reveals disease

Given its pervasiveness across diseases, immunopathology belies the common assumption that feeling well is the same as being healthy.

In observing a set of worsening symptoms, patients and clinicians may be tempted to assume that the disease itself is worsening. Even a small number of researchers are mistakenly convinced that antibiotics cause or exacerbate chronic disease. The best example of this may be so-called “minocycline-induced lupus.”47) In fact, there is no reasonable mechanism, proven or theoretical, which explains how minocycline, the primary action of which is to block the 30s ribosome of bacteria, can cause lupus – or any other disease.48) Nor is there a mechanism by which olmesartan can cause porphyria cutanea tarda (a blood disorder) as was reported in a 2010 Journal of the European Academy of Dermatology and Venereology paper.49)

Edward L. Krawitt, M.D. has it right when he suggests the possibility that minocycline, “unmasks” autoimmune hepatitis.50)

In the same vein, an “allergic” reaction to minocycline or any of the other antibiotics formerly used with Olmesartan was invariably due to the immunopathological response generated by taking olmesartan (Benicar) and antibiotics.

Some Marshall Protocol patients have reported that the treatment appears to clinically reveal markers of latent infections.

My wife, Carol, who has been on the Marshall Protocol since 8/2003 with rheumatoid arthritis, suffered an eye condition over a year ago that doctors said looked very much like Trachoma. Trachoma is a third world eye infection caused by Chlamydia. The eye doctor asked her if she had travelled to a foreign country recently, and she had not. They were then forced to conclude that it was not Trachoma, although we strongly suspected that it was.

Phil, Bacteriality.com

Even olmesartan alone may reveal infection as a 2012 study by Mayo clinic researchers suggests.51) A study of 22 patients with diarrhea and taking standard doses of olmesartan showed that those symptoms improved upon discontinuation of the drug.

Immunopathology can be suppressed

One of the common instincts among researchers who study immunopathological type reactions is to suppress this reaction.52) Indeed, two German papers have noted that the Jarisch-Herxheimer reaction can be suppressed with the administration of different kinds of prednisolone, a powerful corticosteroidA first-line treatment for a number of diseases. Corticosteroids work by slowing the innate immune response. This provides some patients with temporary symptom palliation but exacerbates the disease over the long-term by allowing chronic pathogens to proliferate..53) 54)

However, one of the factors that may play a large role in the incidence and prevalence of chronic disease is that the immunopathological reaction is being systematically inhibited on a population-wide basis. There are a broad range of substances including prescription drugs, supplements, and foods that inactivate the innate immune response. These include, among many others:

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===== Notes and comments =====

Lots of explanations about molecular nature of IP: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC118062

Surg Neurol. 2003 Jun;59(6):509-11.Delirium in the elderly resulting from azithromycin therapy. Cone LA, Padilla L, Potts BE. Department of Medicine, Eisenhower Medical Center, Rancho Mirage, California, USA. Abstract BACKGROUND: Azithromycin, a semi-synthetic azalide antibiotic, is a macrolide that thus far has not shared the neuropsychiatric side effects of other macrolides such as erythromycin and clarithromycin. METHODS: We now report significant delirium associated with conventional dosing of azithromycin in two geriatric patients who were being treated for lower respiratory tract infection. RESULTS: The onset of delirium was apparent within 72 hours of initiating azithromycin therapy and lasted 48 to 72 hours after discontinuing treatment with the drug. CONCLUSIONS: In contrast to the adverse central nervous system symptoms associated with clarithromycin, those induced by azithromycin seem to take longer to resolve, perhaps based upon the longer elimination half-life of the latter antimicrobial, particularly in geriatric women. PMID: 12826358

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Include stuff on antibodies

A single intravenous dose of endotoxin rapidly alters serum lipoproteins and lipid transfer proteins in normal volunteers

Lisa C. Hudgins1,*,, Thomas S. Parker*,, Daniel M. Levine*,, Bruce R. Gordon*,, Stuart D. Saal*,, Xian-cheng Jiang, Cindy E. Seidman*, Jolanta D. Tremaroli*, Julie Lai* and Albert L. Rubin,*

* The Rockefeller University, 1230 York Avenue, New York, NY 10021 The Rogosin Institute, 505 East 70th Street, New York, NY 10021 SUNY Downstate Health Sciences Center, 450 Clarkson Avenue, Brooklyn, NY 11203

Published, JLR Papers in Press, May 16, 2003. DOI 10.1194/jlr.M200440-JLR200

1 To whom correspondence should be addressed. e-mail: hudgins@mail.rockefeller.edu

Endotoxemia is associated with rapid and marked declines in serum levels of LDL and HDL by unknown mechanisms. Six normal volunteers received a single, small intravenous (iv) dose of endotoxin (Escherichia coli 0113, 2 ng/kg) or saline in a random order, cross-over design. After endotoxin treatment, volunteers had mild, transient flu-like symptoms and markedly increased serum levels of tumor necrosis factor and its soluble receptors, interleukin-6, cortisol, serum amyloid A, and C-reactive protein. Triglyceride (TG), VLDL-TG, and nonesterified fatty acid increased (peak at 3–4 h), then TG declined (nadir at 9 h), and then cholesterol, LDL cholesterol, apolipoprotein B (apoB), and phospholipid declined (nadirs at 12–24 h). HDL cholesterol and apoA-I levels were not affected, but half of the decrease in phospholipid was HDL phospholipid. Lipopolysaccharide binding protein (LBP) rose 3-fold (peak at 12 h), with smaller and later decreases in the activities of phospholipid transfer protein and cholesteryl ester transfer protein.

In conclusion, a decline in LDL was rapidly induced in normal volunteers with a single iv dose of endotoxin. The selective loss of phospholipid from HDL may have been mediated by LBP and, after more intense or prolonged inflammation, could result in increased HDL clearance and reduced HDL levels.

The release of endotoxin or lipopolysaccharide (LPS) from the cell walls of gram-negative bacteria into the circulation precipitates an acute inflammatory response that often leads to shock and death (1, 2). A less-recognized component of the acute-phase response to endotoxemia and a variety of inflammatory states in humans is a rapid and marked decline in serum levels of cholesterol, phospholipid, apolipoprotein B (apoB), and apoA-I carried in LDL and HDL (3–5). Low levels of cholesterol, in turn, predict a poor prognosis in hospitalized (3) and chronically ill patients (6, 7). It has been proposed that the lipoproteins protect against the lethal effects of endotoxin by binding it and reducing the secretion of proinflammatory cytokines by monocytes and macrophages (8–11). Thus, a better understanding of the mechanism(s) of the decrease in plasma lipoproteins by circulating endotoxin may result in new therapeutic approaches to increase lipoproteins in patients who have, or are at high risk for, endotoxemia and inflammation. This may include treatment of low HDL levels that may result from and contribute to the inflammation of atherosclerotic cardiovascular disease (12).

The injection of a single dose of endotoxin into experimental animals or humans has been used for decades as a model to study the interrelationships between infection and the host response (13–15). In humans, there is a well-characterized dose-related response to intravenous (iv) endotoxin consisting of mild fever, flu-like symptoms, marked increases in tumor necrosis factor (TNF), interleukin-6 (IL-6), cortisol, epinephrine, serum amyloid A (SAA), and C-reactive protein (CRP), and changes in other cytokines, hormones, and inflammatory markers.

J Am Acad Dermatol. 2004 Nov;51(5 Suppl):S161-5. Tumid lupus erythematosus occurring following highly active antiretroviral therapy for HIV infection: a manifestation of immune restoration. Chamberlain AJ, Hollowood K, Turner RJ, Byren I. Department of Dermatology, Oxford Radcliffe Hospitals, Oxford, United Kingdom. richard.turner@orh.nhs.uk Erratum in: J Am Acad Dermatol. 2004 Dec;51(6):1040. Abstract Tumid lupus erythematosus (LE) is a relatively rare and only recently recognized subset of chronic cutaneous lupus. We report a case occurring in a male with HIV infection whereby his rash was only unmasked by immune restoration following highly active antiretroviral therapy (HAART). The phenomenon of latent inflammatory or autoimmune disease appearing following HAART is now recognized as the “immune restoration syndrome” and tumid LE has not been reported in this setting previously. Fortunately this variant of lupus does not result in scarring and is responsive to anti-malarials, allowing continuation of HAART in this patient. PMID: 15577760

The immune reconstitution inflammatory syndrome (IRIS) is characterized by clinical deterioration occurring after the initiation of effective antiretroviral therapy (ART) and results from a disordered and exuberant immune response.(19857389)

J Eur Acad Dermatol Venereol. 2010 Aug;24(8):977-8. Epub 2009 Dec 15. Porphyria cutanea tarda induced by olmesartan.55)

Mas-Vidal A, Coto-Segura P, García-Varona A, Santos-Juanes J. PMID: 20015057

  • need to distinguish between lipopolysaccharide and endotoxins?
  • alternate terms for immunopathology?
  • examples of uses of the word immunopathology

J Clin Immunol. 2008 May;28 Suppl 1:S20-8. Epub 2008 Jan 12.Disorders of apoptosis: mechanisms for autoimmunity in primary immunodeficiency diseases. Oliveira JB, Gupta S.

A number of primary immunodeficiency diseases represent a paradox of immunodeficiency and autoimmunity. In this minireview, we present basic concepts of apoptosis and disorder of apoptosis as one of the mechanisms to explain such a paradox between immunodeficiency and autoimmunity, which is exemplified by autoimmune lymphoproliferative syndrome (ALPS).(18193340)

  • HIV Infection and Rheumatic Diseases: The Changing Spectrum of Clinical Enigma
  • “Therapeutic paradox, which is clinical worsening despite cure of infection, is said to result from scar formation after rapid treponemal destruction by therapeutic agents…. The therapeutic paradox does not appear of great significance.”(1010785)
  • letter to the journal Eye, “Jarisch-Herxheimer reaction: paradoxical worsening of tuberculosis chorioretinitis following initiation of antituberculous therapy.”(18600241)
  • “However, evidence that this phenomenon is of clinical importance is scant. With the Jarisch-Herxheimer reaction (JHR), there is clear evidence for an acute deterioration with the initiation of antibiotic therapy and yet uncertainty as to the nature of the bacterial mediator(s) of this reaction.”(7619330)
  • Antibiotic-induced release of endotoxin. A therapeutic paradox.
  • Therapeutic paradox in CNS tuberculosis - The development of tuberculomas in cases of tuberculous meningitis whilst on anti-tubercular therapy, and in spite of satisfactory compliance is designated as paradoxical response or therapeutic paradox.

https://www.pediatricneurosciences.com/text.asp?2009/4/2/133/57331

Ironically, over the years, Herxheimer and IRIS, the word paradoxical But it’s not a paradox!

Science. 2005 Jul 29;309(5735):774-7.

Recognition of host immune activation by Pseudomonas aeruginosa.

Wu L, Estrada O, Zaborina O, Bains M, Shen L, Kohler JE, Patel N, Musch MW, Chang EB, Fu YX, Jacobs MA, Nishimura MI, Hancock RE, Turner JR, Alverdy JC.

Department of Surgery, University of Chicago, Pritzker School of Medicine, Chicago, IL 60637, USA.

Abstract

It is generally reasoned that lethal infections caused by opportunistic pathogens develop permissively by invading a host that is both physiologically stressed and immunologically compromised. However, an alternative hypothesis might be that opportunistic pathogens actively sense alterations in host immune function and respond by enhancing their virulence phenotype. We demonstrate that interferon-gammaAn inflammatory cytokine which causes extra mast cells to differentiate to monocytes and then to further differentiate into macrophages and dendritic cells. These phagocytes are the most active cells of the immune system and are charged with digesting bacterial pathogens. binds to an outer membrane protein in Pseudomonas aeruginosa, OprF, resulting in the expression of a quorum-sensing dependent virulence determinant, the PA-I lectin. These observations provide details of the mechanisms by which prokaryotic organisms are directly signaled by immune activation in their eukaryotic host.

PMID: 16051797

Cytotherapy. 2010 Sep;12(5):574-5. Immunosuppression or immunostimulation for aplastic anemia? A blast from the past.

Scheinberg P. Hematology Branch, National Heart, Lung and Blood Institute, 10 Center Drive, Building 10 CRC, Room 3-5140, MSC 1202, Bethesda, MD 20892-1202, USA. Scheinbp@nhlbi.nih.gov PMID: 20735161

It has been nearly 50 years since Humble described the benefit of intravenous phytohemagglutinin (PHA) in patients with aplastic anemia (AA) (1). In this small series, activated lymphocytes were noted in the peripheral blood (PHA blasts) days after the infu- sion of PHA, and improvement in blood counts was observed in some cases soon thereafter. The notion at the time was that circulating lymphocytes entered the bone marrow and transformed into myeloid precursors, giving rise to erythrocytes, neutrophils and platelets (2). In those days, treatment for AA was limited to androgens and transfusion support, and the prospect of PHA ameliorating cytopenias in AA and other forms of marrow failure was of inter- est. However, between 1963 and 1967, trials of a small number of patients using PHA in AA yielded conflicting results (3–6). In total, 44 patients with AA were treated with PHA, of which 24 showed evidence of blood count improvement (6). These early studies were limited by patient heterogene- ity, which included those with direct toxicity to the marrow from chemotherapy or radiation, exposure to drugs, pregnancy-associated and immune-medi- ated single and multilineage cytopenias; concomi- tant use of androgens and/or corticosteroids with PHA was common, and the optimal regimen for PHA administration was never defined (6). In the late 1960s efforts to develop PHA as a therapeutic agent were abandoned by Burroughs Wellcome Ltd (6). In subsequent decades, improved survival in AA was achieved with immunosuppressive therapy (IST) and hematopoietic stem cell transplantation (HSCT), which markedly changed the natural his- tory of this disease. The majority of patients with severe aplastic ane- mia (SAA) are not suitable candidates for HSCT because of a lack of histocompatible sibling donor, age, co-morbidities or inaccessibility to transplan- tation; therefore IST is often employed as a first treatment. The standard IST regimen is with horse anti-thymocyte globulin (h-ATG) plus cyclosporine (CsA), which produces hematologic recovery in 60–70% of cases and very favorable long-term sur- vival among responders (7). However, relapses occur in one-third of responders and clonal evolution in 10–15% of cases, limiting the success of this treatment modality in SAA. In order to overcome these limita- tions, several immunosuppressive regimens have been developed in the past 10–15 years, but the results to date have been disappointing and h-ATG/CsA remains the standard IST in SAA (7). In this issue of Cytotherapy, Chen et al. (8) have taken an approach reminiscent of that proposed by Humble in the 1960s (1). As a follow-up to this group’s experience using ex vivo-activated periph- eral blood mononuclear cells (PBMC) in promot- ing multilineage hematopoiesis in a myelosuppressed murine model and in patients with benzene-induced AA (9,10), Chen et al. (8) now report on a similar approach in idiopathic acquired AA. In total, 31 AA patients received ex vivo-activated autologous or allogeneic PBMC, which were stimulated in culture with interleukin (IL)-2, granulocyte–macrophage (GM) colony-stimulating factor (CSF) and calcium ionophore for 48 h prior to infusion. The number of cells infused varied between 6 􏰀 105 and 1 􏰀 108 (depending on age) per day for 4 days, and infusions were repeated weekly until the neutrophil count was greater than 0.5 􏰀 109/L. Nineteen patients had SAA and 12 non-SAA, of which four had received prior ATG/CsA, 13 CsA monotherapy and 14 no immu- nosuppression. Overall 25 (80%) patients responded to the infusions, of which 15 were in the SAA and 12 in the non-SAA groups. The authors report sig- nificant variability regarding the time to response, with hematologic improvement seen in SAA cases between 6 and 12 months, and in non-SAA between 3 and 6 months after infusion. Complete responses were only observed late, usually after 2–3 years. Over- all, the infusions were well tolerated, with the most common side-effects being infusion-related, which were manageable.The authors report no late events, such as relapse, clonal evolution or appearance of a paroxysmal nocturnal hemoglobinuria clone. The report by Chen et al. (8) is intriguing and, if confirmed, could be an alternative for improv- ing cytopenias in AA. However, several important points should be considered. First, the mechanism by which activated PBMC improve hematopoiesis in AA remains elusive.The authors have proposed, based on a murine model, that cytokines produced by activated PBMC can stimulate hematopoiesis in AA (9). How- ever, especially in SAA, growth factors are usually ineffective and not perceived as definitive therapy. In addition, multiple studies have not shown a benefit of adding G-CSF to IST in SAA (7). It is possible that an unknown cytokine produced by stimulated PBMC has potent stimulatory effects on the bone marrow, but this has yet to be demonstrated. Second, the cohort studied was heterogeneous with regard to disease severity, prior therapies, inclusion of patients in the non-SAA group and prior administra- tion of standard ATG/CsA in the SAA group, making it difficult to define its efficacy.Third, it is unclear how this intervention addresses the autoimmune insult to the marrow in AA. Could infusion of activated PBMC be immunosuppressive? Could they compete for homeostatic cytokines and act as a ‘cytokine sink’, dampening endogenous autoreactive T cells? Fourth, it remains unclear how the number of residual stem cells could limit the efficacy of this intervention if stimulatory cytokines are invoked as contributing to improved hematopoiesis. It is surprising that all but four SAA patients (where progenitor cell destruction is more pronounced) responded to this intervention. Fifth, it is unclear why an average of 75 infusions was required before a response was observed and that complete responses were only observed late. Sixth, it is likely that the host readily rejected unrelated allogeneic PBMC, with their contribution in improv- ing hematopoiesis doubtful. Finally, the absence of any late events is striking but a longer follow-up with repeated bone marrow evaluations will be important to confirm these initial findings. Notwithstanding these caveats, the results reported by Chen et al. (8) are provocative and further elucidation of the mechanisms by which hematopoi- esis is restored in AA after the infusion of ex vivo- stimulated PBMC will be important to define. Despite the shortcomings of the study, this pilot experience does appear to be impressive and we look forward to future work from this group characterizing the role of these cells in reversing marrow failure in AA. After all, it is possible that Humble could eventually be vindicated and advances in this line of work could take care of unfinished business started by him nearly five decades ago. Declaration of interest: The author report no con- flicts of interest. The author alone is responsible for the content and writing of the paper. References 1. Humble JG. In vivoA type of scientific study that analyzes an organism in its natural living environment. action of phytohaemagglutinin in severe human aplastic anemia. Nature. 1963;198:1313–4. 2. Cudkowicz G, Bennett M, Shearer GM. Pluripotent stem cell function of the mouse marrow ‘lymphocyte’. Science. 1964;144:866–8. 3. Fleming AF. Phytohaemagglutinin. Lancet. 1964;284:647–8. 4. Scott DB, Taylor SH. Phytohaemagglutinin in aplastic anae- mia. Lancet. 1967;290:991–2. 5. Retief FP,Wassermann HP, Hofmeyer NG. Phytohaemagglu- tinin in aplastic anaemia. Lancet. 1964;284:1343–4. 6. Wimer BM. PHA for aplastic anemias: the alpha but not the omega of mitogen therapies. Cancer Biother Radiopharm. 1998;13:109–20. 7. Young NS, Calado RT, Scheinberg P. Current concepts in the pathophysiology and treatment of aplastic anemia. Blood. 2006;108:2509–19. 8. Chen J, Liu W, Yu W, Chen L, Wu J, Zhan Y, et al. A novel cell-based therapy for patients with aplastic anemia. Cytotherapy. 2010;12:678–83. 9. Li G,Wang X,Wu L, ZhangW, Chen H, XieY, et al. Ex vivo activated immune cells promote survival and stimulate mul- tilineage hematopoietic recovery in myelosuppressed mice. J Immunother. 2005;28:420–5. 10. Chen J, LiuW,Wang X, Chen H,Wu J,YangY, et al. Ex vivo immunotherapy for patients with benzene-induced aplastic anemia. J Hematother Stem Cell Res. 2003;12:505–14.

How so? I don’t think there is any way to avoid being infected with a contagious cold virus when exposed. A healthy innate immune system will mount a defense resulting in the cold symptoms. However, the adaptive immune system will “remember” those specific viral antigens it has been previously exposed to and quickly eliminate them. This is the idea behind vaccination.

The problem with the common cold is that there are some 200+ different viral genomes that are constantly mutating forming new strains beyond recognition of the adaptive immune system. It is worrisome to think about these viral infections going unchecked by a suppressed immune system.

Gene

Liquid Crystal Droplets Discovered to Be Exquisitely Sensitive to an Important Bacterial Lipid ScienceDaily (May 19, 2011) — In the computer displays of medical equipment in hospitals and clinics, liquid crystal technologies have already found a major role. But a discovery reported from the University of Wisconsin-Madison suggests that micrometer-sized droplets of liquid crystal, which have been found to change their ordering and optical appearance in response to the presence of very low concentrations of a particular bacterial lipid, might find new uses in a range of biological contexts.

https://www.sciencedaily.com/releases/2011/05/110519141615.htm

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