Klimas London presentation, CD26/DPPIV impaired in CFS - retroviral involvement?

latest research, cd26 produced by the cell but does not enter bloodstream (at least they are not detecting any, levels lower than emitted by HIV infected cells)

this is not good news as cd26 cleaves neuropeptide Y, if it is not cleaved it is neurotoxic

(btw what about gluten??)


NPY levels correspond to severity of CFS, so could be a good diagnostic bio/marker. she is very excited about all this.



anyways results of a short search to see if there could be retroviral involvement in dp26 inhibition:


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Crystal structures of HIV-1 Tat-derived nonapeptides Tat-(1-9) and Trp2-Tat-(1-9) bound to the active site of dipeptidyl-peptidase IV (CD26).
http://www.jbc.org/content/280/15/14911.long

J Biol Chem. 2005 Apr 15;280(15):14911-7. Epub 2005 Jan 28.Weihofen WA, Liu J, Reutter W, Saenger W, Fan H.Institut fr Chemie/Kristallographie, Freie Universitt Berlin, Takustrasse 6, D-14195 Berlin, Germany.

CD26 or dipeptidyl-peptidase IV (DPPIV) is engaged in immune functions by co-stimulatory effects on activation and proliferation of T lymphocytes, binding to adenosine deaminase, and regulation of various chemokines and cytokines. DPPIV peptidase activity is inhibited by both Tat protein from human immunodeficiency virus (HIV)-1 and its N-terminal nonapeptide Tat-(1-9) with amino acid sequence MDPVDPNIE, suggesting that DPPIV mediates immunosuppressive effects of Tat protein. The 2.0- and 3.15-A resolution crystal structures of the binary complex between human DPPIV and nonapeptide Tat-(1-9) and the ternary complex between the variant MWPVDPNIE, called Trp(2)-Tat-(1-9), and DPPIV bound to adenosine deaminase show that Tat-(1-9) and Trp(2)-Tat-(1-9) are located in the active site of DPPIV. The interaction pattern of DPPIV with Trp(2)-Tat-(1-9) is tighter than that with Tat-(1-9), in agreement with inhibition constants (K(i)) of 2 x 10(-6) and 250 x 10(-6) m, respectively. Both peptides cannot be cleaved by DPPIV because the binding pockets of the N-terminal 2 residues are interchanged compared with natural substrates: the N-terminal methionine occupies the hydrophobic S1 pocket of DPPIV that normally accounts for substrate specificity by binding the penultimate residue. Because the N-terminal sequence of the thromboxane A2 receptor resembles the Trp(2)-Tat-(1-9) peptide, a possible interaction with DPPIV is postulated.
PMID: 15695814 [PubMed - indexed for MEDLINE]Free Article


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Decreased dipeptidyl peptidase IV enzyme activity of plasma soluble CD26 and its inverse correlation with HIV-1 RNA in HIV-1 infected individuals.

Clin Immunol. 1999 Jun;91(3):283-95. Hosono O, Homma T, Kobayashi H, Munakata Y, Nojima Y, Iwamoto A, Morimoto C. Department of Clinical Immunology, University of Tokyo, Japan.
Abstract

Human plasma contains soluble CD26/dipeptidyl peptidase IV (sCD26/DPPIV) although its physiological significance remains unclear. To determine whether the plasma sCD26 levels have clinical relevance in HIV-1 infected individuals, the concentration and DPPIV enzyme activity of plasma sCD26 were measured. While there is no significant difference between the plasma levels of sCD26 in 90 HIV-1 infected individuals and in 79 uninfected controls, specific DPPIV enzyme activity of sCD26 was significantly decreased HIV-1 infected individuals (P < 0.0001). Specific DPPIV enzyme activity was correlated with the levels of CD4+ T cells (r = 0.247; P < 0.02), CD8+ T cells (r = 0.236; P < 0.03), and adenosine deaminase (r = 0.227; P < 0.05) and had an inverse correlation with HIV-1 RNA (Spearman's r = 0.474; P = 0.0012). Furthermore, recombinant sCD26 enhanced the in vitro PPD-induced response of lymphocytes from HIV-1 infected individuals with decreased specific DPPIV enzyme activity. These results suggest that the specific DPPIV enzyme activity of plasma sCD26 may contribute to the immunopathogenesis of HIV infection. PMID: 10370373 [PubMed - indexed for MEDLINE]


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Role of CD26/dipeptidyl peptidase IV in human immunodeficiency virus type 1 infection and apoptosis.
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC44937/?tool=pubmed
Morimoto C, Lord CI, Zhang C, Duke-Cohan JS, Letvin NL, Schlossman SF. Division of Tumor Immunology, Dana-Farber Cancer Institute, Boston, MA.

To examine the role of CD26/dipeptidyl peptidase IV (DPPIV; EC 3.4.14.5) in infection by human immunodeficiency virus type 1 (HIV-1), we utilized CD26 cDNA-transfected Jurkat T-cell lines. Both CD26- parental Jurkat cells and mutant CD26+ (DPPIV-) transfected Jurkat cells were readily infected with HIV-1, whereas wild-type CD26+ (DPPIV+) transfected Jurkat cells were more resistant to HIV-1 infection. Our results suggest that CD26 is not essential for HIV-1 infectivity as suggested by others but that DPPIV enzyme activity may decrease the efficiency of HIV-1 infection. Of great interest, we found that mutant CD26+ (DPPIV-) transfectants and CD26- parental Jurkat cells strongly expressed CD95 (Fas/Apo-1) and were more sensitive than wild-type CD26+ (DPPIV+) transfectants to the induction of apoptosis by anti-CD95 monoclonal antibody. These results suggest that CD26 may play a role in HIV-1-associated loss of -CD4+ cells through the process of programmed cell death.

HTLV-I also lowers DPPIV levels

Leuk Res. 1996 Apr;20(4):357-63.
Expression of CD26/dipeptidyl peptidase IV in adult T cell leukemia/lymphoma (ATLL).

Kondo S, Kotani T, Tamura K, Aratake Y, Uno H, Tsubouchi H, Inoue S, Niho Y, Ohtaki S.

Blood Transfusion Division, Miyazaki Medical College, Japan.
Abstract

The association of CD26/dipeptidyl peptidase IV (DPPIV) and human T lymphotropic virus type I (HTLV-I) was studied by two approaches. First, we examined the expression of CD26 in peripheral blood mononuclear cells (PBMC) from the patients with adult T cell leukemia/lymphoma (ATLL), an HTLV-I-related malignancy. The expression of CD26 on the surface of PBMC was decreased in all 20 patients with ATLL compared with those from normal individuals (P < 0.01) and the expression of the CD26 gene transcript was not detectable in seven out of eight patients with ATLL. Then we compared the quantity of viral DNA in CD26-negative (CD26-) and CD26-positive (CD26+) cells obtained from 17 HTLV-I healthy carries by using a polymerase chain reaction method. The CD26-cells had a higher copy number of viral DNA than CD26+ cells. These findings indicate that HTLV-I has in vivo tropism to CD26- cells, suggesting that some phenotypes of ATLL cells reflect the in vivo cellular tropism of HTLV-I.
PMID: 8642848

Interesting! I don't have a reference handy, but DPPIV is believed to be impaired in autism. This makes the finding that 6/11 of autistic patients tested by WPI were XMRV+ all the more interesting.

yes Dipeptidyl peptidase IV or DDP-IV, appears to be absent or reduced in autistic children.

http://www.healing-arts.org/children/autism-overview.htm#Dipeptidyl Peptidase Deficiency

Is this what causes me to just get that "empty brain" or "staring into space" thing? I am not daydreaming. I literally have no thoughts...just empty. I would think opiods might cause this.

Hi Frank,

For your interest... Here is some further information explaining Friedman's research on DPP-IV deficiency in autism

The Neurobiology of Lipids In Autistic Spectrum Disorder

http://articles.mercola.com/sites/articles/archive/2008/01/02/lipids-in-autism.aspx

The concept of opiate-like peptides affecting children with ASD was led by Shattock29-30, Reichelt31-32, and others33-34 through examination of urinary metabolites containing peptides from gluten and casein. The opiate antagonist naltrexone proved unsuccessful in controlled trials35-39 with dietary removal of gluten and casein yielding anecdotal positive results. Association with ASD and serotonin was scrutinized in intricate detail40-43 but not clarified until Matson44 (1996,unpublished data) isolated bufotinines, methylated serotonin compounds, in the serum of children with ASD.

Matson found that these compounds literally are created by the patient evoking hallucinogenic symptoms finding that children with ASD overmethylate. Friedman45 (stated in public forum) noted through tandem mass spec analysis in 1998 that aberrant peptides originally derived from casein/gluten as well as Clostridium created hallucinogenic effects initially linking casein ingestion to cellular surface immune response, specifically CD26, which is crucial to clearing of beta-casomorphin. Friedman continued his research (study submitted for publication) linking the effect of opiates from gluten, casein, and particular species of Clostridium upon the suppression the enzyme Dipeptidyl Peptidase-DPP4 or CD26 ultimately impacting the liver, kidney, small intestine and blood brain barrier where this enzyme predominates.

The role of CD26 is primarily one of T cell activation and the cleavage of peptides at the location of proline and alanine thereby breaking down aberrant peptides or inactivation of neuropeptides. Friedman has noted the amino acid sequencing of peptides in the urine of children containing alanine and proline in the D- rather than the L- position whereby CD26 cleavage of these isomers would be 1000 fold over peptides containing alanine and proline in the L-position. The research of Friedman and Matson link endogenous polypeptides to autistic behaviors (hallucinogenic in nature), with Matson's research oriented to serum rather than urinary metabolites, and indicating that the endogenous creation of bufotinines are related to bizarre behavior patterns.

Treatment protocols have not yet been established, but clinicians must consider that of tremendous concern in children with ASD is the very passage of peptides through the blood brain barrier, electrolyte instability, allergic manifestation, GI disturbance and intestinal permeability46 as all are indicative of a loss of cell membrane integrity. Bauman47 and Minshew48-49 have clearly identified aberrations in neurons and membrane phospholipids in ASD patients. Certainly the removal of casein and gluten may be of tremendous benefit, but the very mechanism of metabolic entropy, immune dysregulation and loss of cell membrane integrity must be addressed to sustain the health of multiple body systems.

Frank I think this is the brand new study that klimas presented for the first time, have you tried pubmed?

Hi, this is my first post. I don't have a CFS diagnosis, just depression for the past 15 years, but I have some of the typical CFS issues, though not (yet) debilitating. I have a 5 year old son with autism.

You might want to try a 100% gluten-free casein-free diet, cold turkey. I did, three years ago, with the initial intent of trying just 30 days, out of curiosity, after my child with autism had an incredible dramatic response to this diet within 2 weeks, when he was 2 years old.

Wow, was I up for a wild ride. First 3-4 days, I did not notice anything different. Fourth day, I had major pain in my lower back, insomnia, pressure in my head on my temples, MAJOR mood swings and anger outbursts, feeling of being disconnected from my body. It just lasted a few days, then these 'widthdrawal' symptoms left me. In the next weeks I noticed the following things: my overractive physical response to stress and extreme anxiety had disappeared (diarrhea, abdominal cramping, sweating, increased urination when under stress). Big changes in stool appearance. Much less thirst and urination (huge difference). Resolution of some sensory issues, for example I had never been able to swing with my son at the playground because the butterflies in my stomach were unbearable. This disappeared on GFCF.

Three years later, I am still GFCF...

Hi Karin,

Thanks for posting here. It always pleases me when parents of autistic children join the forum because they give us such good information.

Advocate

O.K. I don't want to put a damper on things here but I want to make sure that all of our i's and t's are crossed. I googled the opioid peptides thing with autism and found a study out of Johns Hopkins back in 2002 that did NOT find the opioid connection but did find a lower cell production of CD3 and CD26. Here is the link:

http://www.ncbi.nlm.nih.gov/pubmed/12578238

Now I am confused because 1. They compared urine samples of children vs plasma from adults (would that make a difference?). 2. They did show that ASD children did have a significantly lower percentage of cells expressing CD3 AND CD26. Am I missing something here? Does not the lower expression of CD26 cells show that there is a dipeptidyl peptidase IV (DPPIV/CD26) defiency in ASD children?

This is very important because my kids are on a NIDS diet, not a GFCF diet.

@ advocate
That is so true!!
I wish I had some "parents of autistic children" of my own...

The Klimas article is now published, I have added a new thread under "Latest research" to discuss methodology, results and related issues.

Link to the new thread

Previously published research from Nancy Klimas on CD26/DPPIV

Clin Exp Immunol. 2005 December; 142(3): 505511.
Chronic fatigue syndrome is associated with diminished intracellular perforin
K J Maher,* N G Klimas,* and M A Fletcher*

From the Discussion Section:

Many of the symptoms of CFS are inflammatory in nature (myalgia, arthralgia, sore throat, tender lymphadenopathy), and have prompted a theory of infection induced illness. CFS often presents with acute onset of illness (reported in 6080% of published samples) with systemic symptoms similar to influenza infection that do not subside [13]. However, reports of associated microbial infection or of latent virus reactivation have been inconsistent. Whether associated with a known antigen (e.g. a specific infection) or not, there is a considerable literature describing immune activation in CFS. These reports have described the elevation of lymphocyte surface activation markers [6,14], the expression of proinflammatory cytokines and evidence of Th2 cytokine increase [1517]. In order to determine if the cohort of CFS patients in this study had evidence of immune activation we elected to analyse the surface marker, CD26 (dipeptidyl peptidase IV). This ectoenzyme is known to increase upon cell activation [18]. DPPIV/CD26 is a multifunctional molecule that is a proteolytic enzyme, receptor, co-stimulatory protein, and is involved in adhesion and apoptosis. CD26 is associated on T cells with adenosine deaminase (ADA), and plays a major role in immune response. Abnormal expression is found in autoimmune diseases, HIV-related diseases and cancer [19]. Compared to controls, the CFS patients we studied had a significantly elevated percentage and absolute count of CD26+ lymphocytes.


Full article here: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1440524/

@JillBohr: I saw that, too, and it's a good question. I expect that this research is riddled with technical issues every bit as complicated as WPI vs. UK/Netherlands XRMV research (note that "this study failed to replicate the findings of others" replicate? validate?). A few of-the-cuff observations: 1) their sample size was extremely small (cohort? what about subsets of ASD kids?), 2) I thought that DPP-IV was supposed to be active/deficient in the gut (is the blood the right place to measure DPP-IV?), and 3) is the urine the right place to look opioid for peptides?

I'm not at all asserting that they're wrong -- this study may be the summit of scientific quality and objectivity for all I know. I am just wary of accepting any of this sort of thing at face value now, given a) what we have witnessed with WPI and b) knowing that autism research, like CFS research, has at least two bitterly opposing factions.

what subtr4ct said. but adding yes, opiods in urines is where they usually look, the whole theory evolved around that... but YES to what you said about quality of studies and what agenda it is serving (you would not believe some studies out there that serve to 'disprove' findings... sadly those are the ones that get reported widely. the ones like groundbreaking jons hopkins and italian postmortem studies go completely unreported...)

gluten/casein on the side, I am more concerned here with neuropeptide Y, the one that nancy klimas said is cleaved by dppiv, ,and if not cleaved will accumulate in the blood and act as a neurotoxin!! which is what happens in CFS.

not sure if oral dppiv enzymes would help there??? worth trying, probably.

this also reminds me of Virastop/CDX enzymes - they are sometimes used in autism, not sure about CFS?? wonder if those would cleave npy? http://www.mandimart.co.uk/cdx-by-thermedix-42-capsules-scd-legal-432-p.asp
http://www.enzymedica.com/products/Virastop#tabsection

btw a friend of mine with CFS (probably around 6.lev at the time) went gluten free and that resolved her bad bloating and diarheas overnight. greatly reduced buzzing in ears (not completely though) and helped a little bit with cognitive symptoms. didn't do much for her energy levels.

Mrs. subtr4ct has been using digestive enzymes with DPP-IV (Kirkman's brand) for 1.5 or 2 years now. Our impression is that they help a little; they certainly do not work miracles, though. Note that her illness seems predominantly neurological rather than predominantly immune-related. She has been gluten-free for more than one year.

DPPIV and neuroblastoma

Suppression of neuroblastoma growth by dipeptidyl peptidase IV: Relevance of chemokine regulation and caspase activation http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2633428/?tool=pubmed
Imbalanced protease expression and activities may contribute to the development of cancers including neuroblastoma. Neuroblastoma is a fatal childhood cancer of the sympathetic nervous system that frequently overexpresses mitogenic peptides, chemokines and their receptors. Dipeptidyl peptidase IV (DPPIV), a cell surface serine protease, inactivates or degrades some of these bioactive peptides and chemokines, thereby regulating cell proliferation and survival. Our studies show that DPPIV is expressed in normal neural crest-derived structures, including superior cervical and dorsal root ganglion cells, sciatic nerve, and in adrenal glands, but its expression is greatly decreased or lost in cells derived from neuroblastoma, their malignant counterpart. Restoration of DPPIV expression in neuroblastoma cells led to their differentiation in association with increased expression of the neural marker MAP2 and decreased expression of chemokines including stromal-derived factor 1 (SDF1) and its receptor CXCR4. Furthermore, DPPIV promoted apoptosis, and inhibited SDF1 mediated in vitro cell migration and angiogenic potential. These changes were accompanied by caspase activation, and decreased levels of phospho-AKT and MMP9 activity, down stream effectors of SDF1-CXCR4 signaling. Importantly, DPPIV suppressed the tumorigenic potential of neuroblastoma cells in a xenotransplantation mouse model. These data support a potential role for DPPIV in inhibiting neuroblastoma growth and progression.


this is also quite interesting, in survivors where cancer gone BUT "chronic health conditions, such as neurological, endocrine, sensory, and musculoskeletal complications." remained long afterwards

http://www.medicalnewstoday.com/articles/159607.php