- Last Updated: 23 November 2015 23 November 2015
Eight professional workshops were then held throughout the first day. I attended the immunology workshop outlined below:
Dr Dan Peterson chaired this and introduced the session with a brief discussion about our body defences, such as the skin, mucus membranes, stomach enzymes, bacterial toxins in GI tract, phagocytes and natural killer (NK) cells. He explained the innate and adaptive immune systems which interact via the cytokines. A number of presentations by immunology experts then followed.
1. Sonya Marshall-Gradisnik (Gold Coast, Australia) who gave an overview of her work and the establishment of the $150million building attached to Griffith University—the National Centre for Neuro-immunology and Emerging Diseases. She discussed the role of NK-cells, residing in the immune system. They influence the adaptive immune response and kill abnormal cells. An envelope in the cell contains granzymes, which pass through a protein via perforin pores. The abnormal cell is lysed through a cell-death pathway. LAMP (membrane proteins) encapsulate granzymes and perforin. NK-cells bind to target cells. Chemokine receptors (KIRs) sneak out infected cells. There are 2 types of KIRs (killer immunoglobulin-like receptors): inhibitory and activating. MicroRNAs control the function of the NK-cells. There are two NK phenotypes—“ dim” and “bright”.
The current status of CFS/ME is that there is no diagnostic test, pathology is unknown but there is consistency of NK-cell lysis. A snapshot analysis of moderately ill CFS/ME patients was done looking at lytic proteins, to see if lysis and phenotypes are consistent over time. NK-cells are found to be down in function over time, and there is a significant reduction in “bright” over time. The question was asked “Do lytic proteins play a role in CFS/ME?” Granzyme B decreases over time. Impaired degranulation is suggested. There was significant reduction in lysis in the severely ill groups. There were significant differences between severely ill and controls in NK phenotypes (CD158b+ and CD158a/h+) with reduced activation. A number of microRNAs were significantly reduced on NK cells, which influence efficiency.
2. Sharni Hardcastle (Gold Coast, Australia) looked at their severe cohort. And the adaptive immune system. There were alterations in T-regulatory cells and increased B-cell activation. There were some cytotoxic cross-over cells. In the severely ill patients there was an increase in plasma dendritic cells, increased naïve and plasma B-cells, decrease in transitory and regulating B-cells and a decrease in ɣɗ1 phenotypes. Regulatory NKT-cells were increased in the severe patients. CD8a and CD4 were changed in the severely ill.
3. Nancy Klimas talked about cytotoxic T-cells and the immune system in CFS/ME. This is part of the acquired system. NK-cells evolve first and the acquired immune system develops over time. 5% of the immune system is in the blood, the rest is everywhere else, particularly in the gut. The cells need to be close together (e.g., in lymph nodes) to be efficient. There are more glial cells (white blood cells) than neurons in the brain. There is duality of the immune system: a) humoral (NK-cells) and b) cell-mediated (T-cells). T cells only recognize antigen associated with MHC (major histocompatibility complex ) molecules on the cell. This is very specific. Perforin and granzymes poke holes in the cells leading to death. Networks of communication may get severed. Ways to reconnect need to be modelled. Perforin has been found to be down in T-cells.
Biomarkers can be treatment targets. E.g., Neuropeptide-Y connects the immune system and the nervous system. IN CFS/ME there is high NPY and low CD-26.
4. Paula Waziry (Miami, USA) discussed gene regulation. There are variable symptoms in CFS/ME. Viral reactivation may occur due to genetic, environmental and epigenetic effects on gene expression. PBMCs are involved (B and T). Mononuclear cells have a nucleus! And everything is regulated at many levels by gene expression. Data shows decreased levels of human microRNAs in CFS/ME. In EBV there may be impaired NPC function, but interferon will “undo” the reaction.
5. Konstance Knox (Wisconsin, USA) had looked at B-cell function and the pathogenesis of CFS/ME. B-cells are produced in the marrow and travel to lymphoid organs. They are part of the adaptive immune system. 2-5% of serum IgM/IgG is not directed at specific pathogens. They are naturally occurring antibodies. Work has been done on mice (Jay Levy).
Regulatory B-cells (0.5% of B-cells): a) secrete IL-10 (anti-inflammatory) which restores TH-1/TH-2 balance and b) secrete TGF-β1 which induces apoptosis. B-cells receive and present the antigen. She mentioned the rituxin studies. The drug is directed at CD20. She questioned whether there may be an increased risk of lymphoma in CFS/ME. The B-cell may be a very important component of CFS/ME.
6. David Baewer (Wisconsin, USA) Talked about the role of serology in the diagnosis of the herpes virus, and how to order diagnostic studies. There are limitations in serology in CFS/ME, but there is a body of literature and a need to rule out a herpes diagnosis in CFS/ME. There are billions of herpes viruses in our systems, and we will all have viral antibodies. Positive IgM equates to active infection leading to latency for life. Reactivation to IgM response is rare. Therefore IgM will be of little use. Immune dysregulation means tests are unreliable. Molecular testing for herpes is more reliable. Qualitative tests for virus DNA is 85% positive in the population. Virus replication needs to be tested using reverse transcriptase PCR. Late transcript viral RNA is more reliable. The virus actively transcribes active gene products. There may be a smouldering herpes infection going on.
7. Troy Querec (Atlanta, USA) discussed cytotoxicity in a multicenter trial looking at impaired NK-cells. e.g. CD107a functional assay. He stressed the point that shipping time decreases cell viability, and discussed methods of shipping. Impaired NK function is a promising biomarker. Functional assays are not always available. A pilot study is planned to assess design variables.
8. Isabel Barao-Sylvestre (Nevada, USA) had looked at NK-cells and cytokines. Cytokines are LMW proteins. There is no single organ source. Lymphokines come from lymphocytes, chemokines are functional, interleukins are messengers between leucocytes. There are chains of cytokine action. They are potentially useful markers. She talked about therapeutic antibodies being used in autoimmune diseases, and IgG subclasses, with deficiencies in some patients in CFS/ME.
9. Mary Ann Fletcher (Miami, USA) – was described as having much wisdom after 35 years of research into this illness. In 1990 she found reduced NK function with elevated pro-inflammatory cytokines. These findings have been confirmed around the world and are potential biomarkers. Age of sample, technique used, and identified diagnosis of the patient are all important factors. Their team is ready to go ahead.
10. Dennis Mangan (California, USA) is a communications expert, which seems apt in the field of immunology . He describes communication as having a sender and receiver with a message flowing between them. Modification and sensitization is possible.
11. Beth Unger (Atlanta, USA) describing herself as a “non-immunologist” summed up the workshop. She described it as a very complex situation. There needs to be very good laboratories. With a focus on methods, there are excellent prospects. A lab has the potential to do almost “anything” if it is deemed important enough. The immune system seems crucial to understanding this illness.
89 posters were displayed and will be summarized later.