TGI Friday! Our weekly round-up of recently published research abstracts and other items | 5 June 2015

June 5, 2015

From Nature, Letter to the Editor, 1 June 2015.

Structural and functional features of central nervous system lymphatic vessels

Antoine Louveau (1,2), Igor Smirnov(1,2), Timothy J. Keyes(1,2), Jacob D. Eccles(3,4, 5),Sherin J. Rouhani(3,4,6), J. David Peske (3,4, 6), Noel C. Derecki(1,2), David Castle (7), James W. Mandell(8), Kevin S. Lee(1,2,9),Tajie H. Harris(1,2), Jonathan Kipnis (1,2,3).
1) Center for Brain Immunology and Glia, School of Medicine, University of Virginia, Charlottesville, Virginia 22908, USA
2) Department of Neuroscience, School of Medicine, University of Virginia, Charlottesville, Virginia 22908, USA
3) Medical Scientist Training Program, School of Medicine, University of Virginia, Charlottesville, Virginia 22908, USA
4) Beirne B. Carter Center for Immunology Research, School of Medicine, University of Virginia, Charlottesville, Virginia 22908, USA
5) Department of Medicine (Division of Allergy), School of Medicine, University of Virginia, Charlottesville, Virginia 22908, USA
6) Department of Microbiology, Immunology, and Cancer Biology, School of Medicine, University of Virginia, Charlottesville, Virginia 22908, USA
7) Department of Cell Biology, School of Medicine, University of Virginia, Charlottesville, Virginia 22908, USA
8) Department of Pathology (Neuropathology), School of Medicine, University of Virginia, Charlottesville, Virginia 22908, USA
9) Department of Neurosurgery, School of Medicine, University of Virginia, Charlottesville, Virginia 22908, USA


One of the characteristics of the central nervous system is the lack of a classical lymphatic drainage system.

Although it is now accepted that the central nervous system undergoes constant immune surveillance that takes place within the meningeal compartment, the mechanisms governing the entrance and exit of immune cells from the central nervous system remain poorly understood.

In searching for T-cell gateways into and out of the meninges, we discovered functional lymphatic vessels lining the dural sinuses. These structures express all of the molecular hallmarks of lymphatic endothelial cells, are able to carry both fluid and immune cells from the cerebrospinal fluid, and are connected to the deep cervical lymph nodes.

The unique location of these vessels may have impeded their discovery to date, thereby contributing to the long-held concept of the absence of lymphatic vasculature in the central nervous system.

The discovery of the central nervous system lymphatic system may call for a reassessment of basic assumptions in neuroimmunology and sheds new light on the aetiology of neuroinflammatory and neurodegenerative diseases associated with immune system dysfunction/

Missing link found between brain, immune system'| MedicalXpress News | 1 June 2015

From Mitochondrion, 26 May 2015 (e-published before print).

Hurt, tired and queasy: Specific variants in the ATPase domain of the TRAP1 mitochondrial chaperone are associated with common, chronic “functional” symptomatology including pain, fatigue and gastrointestinal dysmotility

Richard G. Boles(a), Holly A. Hornung(a), Alastair E. Moody(a), Thomas B. Ortiz(a), Stacey A. Wong(a), Julie M. Eggington(a), Christine M. Stanley(a), Mu Gao(b), Hongyi Zhou(b), Stephen McLaughlin(a), Amir S. Zare(a), Katherine M. Sheldon(a), Jeffrey Skolnick(b), Kevin J. McKernan(a)
a) Courtagen Life Sciences, 12 Gill St, Ste. 3700, Woburn, MA 01801
b) Center for the Study of Systems Biology, Georgia Institute of Technology, 250 14th St, Atlanta, GA 30318


• Functional symptoms are common and often associated with mitochondrial dysfunction.

• TRAP1 encodes a mitochondrial chaperone that is important inantioxidant defense.

• Herein, TRAP1 variants were correlated with chronic pain, fatigue and GI dysmotility.

• These conditions are strongly associated with 3 conserved variants in the TRAP1 gene.

• These variants predispose towards these common functional conditions.


Functional disorders are common conditions with a substantial impact on a patients’ wellbeing, and can be diagnostically elusive. There are bidirectional associations between functional disorders and mitochondrial dysfunction.

In this study, provided clinical information and the exon sequence of the TRAP1 mitochondrial chaperone were retrospectively reviewed with a focus on the functional categories of chronic pain, fatigue and gastrointestinal dysmotility.

Very-highly conserved TRAP1 variants were identified in 73 of 930 unrelated patients.

Functional symptomatology is strongly associated with specific variants in the ATPase binding pocket. In particular, the combined presence of all three functional categories is strongly associated with p.Ile253Val (OR 7.5, P = 0.0001) and with two other interacting variants (OR 18, P = 0.0005).

Considering a 1-2% combined variant prevalence and high odds ratios, these variants may be an important factor in the etiology of functional symptomatology.

From BMC Immunology, 2 June 2015 (open access).

Characterisation of cell functions and receptors in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME)

Sharni Lee Hardcastle*, Ekua Weba Brenu, Samantha Johnston, Thao Nguyen, Teilah Huth, Naomi Wong, Sandra Ramos, Donald Staines and Sonya Marshall-Gradisnik
National Centre for Neuroimmunology and Emerging Diseases, Griffith Health Centre, School of Medical Science, Griffith University, Gold Coast, QLD, Australia
Corresponding author: Sharni L Hardcastle



Abnormal immune function is often an underlying component of illness pathophysiology and symptom presentation. Functional and phenotypic immune-related alterations may play a role in the obscure pathomechanism of Chronic Fatigue Syndrome/Myalgic Encephalomyelitis (CFS/ME).

The objective of this study was to investigate the functional ability of innate and adaptive immune cells in moderate and severe CFS/ME patients. The 1994 Fukuda criteria for CFS/ME were used to define CFS/ME patients. CFS/ME participants were grouped based on illness severity with 15 moderately affected (moderate) and 12 severely affected (severe) CFS/ME patients who were age and sex matched with 18 healthy controls.

Flow cytometric protocols were used for immunological analysis of dendritic cells, monocytes and neutrophil function as well as measures of lytic proteins and T, natural killer (NK) and B cell receptors.


CFS/ME patients exhibited alterations in NK receptors and adhesion markers and receptors on CD4+T and CD8+T cells.

Moderate CFS/ME patients had increased CD8+ CD45RA effector memory T cells, SLAM expression on NK cells, KIR2DL5+ on CD4+T cells and BTLA4+ on CD4+T central memory cells.

Moderate CFS/ME patients also had reduced CD8+T central memory LFA-1, total CD8+T KLRG1, naïve CD4+T KLRG1 and CD56dimCD16− NK cell CD2+ and CD18+CD2+.

Severe CFS/ME patients had increased CD18+CD11c− in the CD56dimCD16− NK cell phenotype and reduced NKp46 in CD56brightCD16dim NK cells.


This research accentuated the presence of immunological abnormalities in CFS/ME and highlighted the importance of assessing functional parameters of both innate and adaptive immune systems in the illness.

From The American Journal of Medicine, 30 May 2015 (e-published before print).

Somatic symptom disorders without known physical causes: One disease with many names?

Morton E. Tavel, MD, FACP, FACC,
Indiana University School of Medicine, St. Vincent Hospital, Indianapolis, IN.


Patients complaining of pain and/or fatigue in the absence of known physical diseases constitute a high percentage of those seeking general medical care. Depending upon the type of physician/specialist consulted, those individuals may receive disease labels that range from an implied psychological origin such as somatoform or psychosomatic disease, or to a presumed physical disease such as fibromyalgia.

Although all these conditions are regularly associated with fatigue, we are now provided with a new label suggesting another disease category, ‘systemic exertion intolerance disease', which replaces the previous ‘chronic fatigue syndrome.' All these conditions have common, overlapping features that usually consist of both fatigue and pain, and, in the absence of definitive objective confirmation, might be best classified under one heading such as somatic symptom

Management of these disorders is challenging, but suggestions for proper identification and treatment are presented.

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