Pasi, 2011 "A two?edged weapon in chronic fatigue syndrome" (NK cell related)

[WillowJ]

Pasi A, Bozzini S, Carlo-Stella N, Martinetti M, Bombardieri S, De Silvestri A, Salvaneschi L, Cuccia M. "Excess of activating killer cell immunoglobulin?like receptors and lack of HLA-Bw4 ligands: A two?edged weapon in chronic fatigue syndrome." Mol Med Report. 2011 May;4(3):535-40. doi: 10.3892/mmr.2011.447. Epub 2011 Mar 4. PMID: 21468604

HLA Laboratory, Immunohaematology and Transfusion Center, Pavia, Italy.

Abstract
Chronic fatigue syndrome (CFS) is an inflammatory disease of unknown aetiology. Researchers have proposed infectious, neurological and immunological causes of this syndrome. Recently, the xenotropic murine leukemia virus-related virus was detected in 67% of patients with CFS in a US study. This observation is in agreement with one ascertained aspect of the disease: a decreased efficiency in NK cell lytic activity in CFS patients.

Here, we analyzed the genomic polymorphism of killer cell immunoglobulin-like receptors (KIRs) and their HLA class I cognate ligands in patients with certified CFS. An excess of KIR3DS1 was found in CFS patients with respect to controls, as well as an increased frequency of the genotype missing KIR2DS5.

Forty-four CFS patients and 50 controls also underwent genomic typing for the HLA-ligands. In the patients, a great proportion of KIR3DL1 and KIR3DS1 receptors were found to be missing their HLA-Bw4Ile80 binding motif.

We hypothesize that an excess of KIR3DS1, combined with an excess of ligand-free KIR3DL1 and KIR3DS1 receptors, may hamper the clearance of a pathogen via NK cells, thus favouring the chronicity of the infection.

 

[WillowJ]

we've moved a step up. several steps, actually. not just any disease of unknown aeteology but an inflammatory disease of unknown aeteology. and the proposed aeteologies are all disease processes (no psychobabbling). :victory:

some additional specific reasons why NK cells might not work. without access to the full paper I can't try to understand (nor attempt to explain) what is going on.

About all I can do is explain a jargon word for those few that might be reading this forum and might not already know it: a ligand is something that binds to another molecule (an enzyme, or something else, in this case a white blood cell) in a specific location (like a dock or let's say a computer port; there might be several matched ones available--think of it like a memory stick loaded with a particular plug-n-play program which needs to find a matching USB port, only in on the cell's surface there are perhaps millions of variations of types of USB ports).

This act of binding might change the shape or the electrical charge of the enzyme to, say, allow something else to bind, cause some other ligand to disassociate from another part of the enzyme, open an ion channel, or otherwise transmit a cellular message, sometimes through a cell membrane.

I'd need to do some reading to figure out what the KIR's do, and the rest of the specific things said here, and don't have the energy for that right now (saving it for other projects).

 

[Mark]

Thanks very much for posting this WillowJ. I don't have time to follow this up in depth either, but I did a bit of digging around and found some interesting related links.

One of the paper's citations, also Italian, from 2009, looks like a useful review:

Immunological aspects of CFS (Ricevuti et al):
http://www.ncbi.nlm.nih.gov/pubmed/18801465

I then ran a quick search for KIR2DS5 - terms like that lend themselves well to googling by the way, so they are often a good way to get a handle on what a technical abstract like this one is all about.

http://www.genecards.org/cgi-bin/carddisp.pl?gene=KIR2DS5

Killer cell immunoglobulin-like receptors (KIRs) are transmembrane glycoproteins expressed by natural killer cells and subsets of T cells. The KIR genes are polymorphic and highly homologous and they are found in a cluster on chromosome 19q13.4 within the 1 Mb leukocyte receptor complex (LRC). The gene content of the KIR gene cluster varies among haplotypes, although several "framework" genes are found in all haplotypes (KIR3DL3, KIR3DP1, KIR3DL4, KIR3DL2). The KIR proteins are classified by the number of extracellular immunoglobulin domains (2D or 3D) and by whether they have a long (L) or short (S) cytoplasmic domain. KIR proteins with the long cytoplasmic domain transduce inhibitory signals upon ligand binding via an immune tyrosine-based inhibitory motif (ITIM), while KIR proteins with the short cytoplasmic domain lack the ITIM motif and instead associate with the TYRO protein tyrosine kinase binding protein to transduce activating signals. The ligands for several KIR proteins are subsets of HLA class I molecules; thus, KIR proteins are thought to play an important role in regulation of the immune response.

http://www.wikigenes.org/e/gene/e/3810.html

The first high-impact citation in the above link shows that a missing KIRDS5 gene is also associated with psoriasis; the other high-impact citations note that these novel variants of KIRDS5 are associated with the 'B' haplotype, which is associated with various autoimmune conditions (diabetes, rheumatoid arthritis, celiac disease...).

So the summary of all that seems to be: this finding, in CFS patients, of missing KIRD2S5, and of KIR3DL1 and KIR3DS1 receptors lacking their binding motif, suggests a genetic vulnerability in many CFS patients associated with the regulation of the immune response (due to missing binding mechanisms for NK cell regulation), and this specific vulnerability is already associated with a range of other 'autoimmune' conditions.

Sounds like a valuable fleshing-out of the detail of the NK-cell abnormalities in CFS, and of the genetic factors contributing to those problems.

Good stuff!