Immune system, milk proteins, HLA, etc.

[Guest guest]

This is probably more geared towards those that have read the book, " The

Virus Within " or " Osler's Web " . The reason I say that is that there is alot

below on retroviruses.

I realize this is a somewhat " out there " type of post. If nothing else it

will make you wonder, LOL.

I'm reposting the info on autism because the other info relates to some of

their findings. There is also a few things on milk proteins, plus alot of

overlap between disorders. I think it's easy to see why most disorders are

a combination of genes and environmental triggers.

Some of the links to autism are the same 7q locations as MS. Another

location linked to MS (TALDO) on 11p is a location linked to ADHD. CFS has

alot in common with MS.

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The Etiology of Autism and NICHD Research- Immune Findings in Autism

The following is part of the slide presentation given by Marie

Bristol-Power, PhD, who serves as the Special Assistant for Autism, in the

Office of the Director at the NICHD, at the March 8, 2001, meeting of the

Institute of Medicine (IOM) Immunization Safety Review Committee.

Immune findings in autism

From Warren, et al. (See abstract below)

C4B " null allele " -25/50 subjects vs. 17/85 controls

Extended HLA haplotype B44-S30-DR4-14/50 subjects vs. 2/85 controls

HVR-3 sequence 1-17/50 subjects vs. 2/85 controls

Abstract for Warren et. al.

Autism results from several different etiologies or combination of

pathological mechanisms. Mounting evidence indicates that immune dysfunction

along with an environmental pathogen may be factors contributing to the

development of some cases of autism. One of the immune deficiencies observed

in autism is abnormal T-cell mediated immunity. Another is altered levels of

certain classes of antibodies (immunoglobulins), including decreased levels

of immunoglobulin A and deficient complement activity, based on the

inheritance of a null allele of the C4B gene. In addition to the C4B gene,

other genes on chromosome 6 also appear to be associated with autism. In the

developing child, genetically determined immune deficiencies might increase

the risk for autism in 2 ways: (1) A pathogen or its toxins might damage the

brain, and (2) the pathogen might trigger an autoimmune mechanism that would

interfere with brain functioning. In the mother, immune deficiency might

allow a pathogen to persist in utero, damaging the fetal brain directly or

triggering a maternal immune response that creates pathogenesis in the fetal

brain. © 2000 APA/PsycINFO, all rights reserved.

Some CPEA Research Findings

Genetic hotspots exist for autism (done with an international consortium),

especially on Chromosome 7

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Chronic Fatigue Syndrome (CFS) and Multiple Sclerosis (MS)

as Subsets of a Group of Cellular Immunity Disorders

P. Englebienne, M. Fr mont, V. Herst and K. De Meirleir

Free University of Brussels and RED Laboratories, Belgium.

Apoptosis (cell suicide) is a critical component of adaptative

cellular immunity. Upon infectious challenges, type I interferons

elicit apoptotic responses by inducing the expression of 2-5A

synthetase (2-5OAS), RNase L and the p68 RNA-dependent

kinase (PKR). Activated PKR induces apoptosis by inhibiting

translation (through eIF2? phosphorylation) and by a mechanism

involving the activation of caspase 8 mediated by the

Fas-associated death domain. Activation of 2-5OAS results in

the production of 2-5oligoadenylates which in turn activate

RNase L. Activated RNase L induces apoptosis by a

mechanism involving the caspases. Results from our

laboratories point to an improper activation of 2-5OAS both in

CFS and MS monocytes. This results in an inappropriate

activation of RNase L. This process ultimately leads to a

blockade of the RNase L-mediated apoptotic program. This

supports the involvement of environmental factors and cellular

stress capable of generating small RNA fragments and/or

inducing the transcription of endogenous retrovirus or repetitive

Alu sequences. These " abnormal " RNA sequences are

responsible for the inappropriate activation of 2-5OAS and have

been implied in the etiology of both disorders. These RNA

fragments, depending on their origin and structure, are

capable of either activating or down-regulating PKR. This results

in a differential effect not only on the PKR/RNase L-mediated

apoptotic programs but also on the activation by PKR of the

inducible NO synthetase (through NF-KB). A release of NO at

either high (CFS) or low rates (chronic MS) by lymphocytes has

corrolary consequences: triggering the skeletal and cardiac

muscle ryanodine receptors (calcium channels), NK cell function,

COX2 activation and glutamate release by activated T-cells in

the brain. Glutamate upregulation leads to oligodendrocyte

excitotoxicity in MS and downregulation in CFS impairs

hypothalamic CRH secretion. Our results suggest that

CFS and chronic MS are the extremes of an array of

dysfunctions in the 2-5A/RNase L/PKR pathways where other

autoimmune diseases might fit.

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In Vivo 2001 Nov-Dec;15(6):461-5 Related Articles, Books, LinkOut

Dynamics of chronic active herpesvirus-6 infection in patients with chronic

fatigue syndrome: data acquisition for computer modeling.

Krueger GR, Koch B, Hoffmann A, Rojo J, Brandt ME, Wang G, Buja LM.

Department of Pathology & Laboratory Medicine, University of Texas-Houston

Medical School, 6431 Fannin St, MSB 2.246, Houston, Texas 77030, USA.

Gerhard.Krueger@uthtmcedu

Ten adult patients with persistent active HHV-6 variant A infection and

clinical chronic fatigue syndrome (CFS) were studied over a period of 24

months after initial clinical diagnosis. CFS was diagnosed according to

IIIP-revised CDC-criteria as defined by the CFS Expert Advisory Group to the

German Federal Ministry of Health in 1994. Changes in HHV-6 antibody titer,

viral DNA load, peripheral blood T lymphocytes and subpopulations, as well

as CD4/CD8 cell ratio and cell death (apoptosis) were monitored. Data were

collected for comparison with respective changes in acute HHV-6 infection

and as a basis for future computer simulation studies. The results showed

variable but slightly elevated numbers of HHV-6 DNA copies in the blood of

patients with CFS, while PBL (peripheral blood lymphocyte) apoptosis rates

were clearly increased. CD4/CD8 cell ratios varied from below 1 up to values

as seen in autoimmune disorders. Contrary to acute HHV-6 infection, T

lymphocytes do not exhibit the usual response to HHV-6, that is elevation of

mature and immature populations suggesting a certain degree of

unresponsiveness. The data suggest that persistent low-dose stimulation by

HHV-6 may favor imbalanced immune response rather than overt immune

deficiency. This hypothesis requires confirmation through additional

functional studies.

PMID: 11887330 [PubMed - in process]

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Immunogenetics 2001 Feb;53(1):1-9 Related Articles, OMIM, Books, LinkOut

The endogenous retroviral insertion in the human complement C4 gene

modulates the expression of homologous genes by antisense inhibition.

Schneider PM, Witzel-Schlomp K, Rittner C, Zhang L.

Institute of Legal Medicine, Johannes Gutenberg University, Mainz, Germany.

pschneid@...

Intron 9 contains the complete endogenous retrovirus HERV-K(C4) as a 6.4-kb

insertion in 60% of human C4 genes. The retroviral insertion is in reverse

orientation to the C4 coding sequence. Therefore, expression of C4 could

lead to the transcription of an antisense RNA, which might protect against

exogenous retroviral infections. To test this hypothesis, open reading

frames from the HERV sequence were subcloned in sense orientiation into a

vector allowing expression of a beta-galactosidase fusion protein. Mouse L

cells which had been stably transfected with either the human C4A or C4B

gene both carrying the HERV insertion (LC4 cells), and L(Tk-) cells without

the C4 gene were transiently transfected either with a retroviral construct

or with the wild-type vector. Expression was monitored using an enzymatic

assay. We demonstrated that (1) HERV-K(C4) antisense mRNA transcripts are

present in cells constitutively expressing C4, (2) expression of

retroviral-like constructs is significantly downregulated in cells

expressing C4, and (3) this downregulation is further modulated in a

dose-dependent fashion following interferon-gamma stimulation of C4

expression. These results support the hypothesis of a genomic antisense

strategy mediated by the HERV-K(C4) insertion as a possible defense

mechanism against exogenous retroviral infections.

PMID: 11261924 [PubMed - indexed for MEDLINE]

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Front Biosci 2001 Aug 1;6:D986-91 Related Articles, Books, LinkOut

Ethnic diversity of class III genes in autoimmune disease.

Moulds JM.

Department of Microbiology and Immunology, MCP Hahnemann University School

of Medicine, Philadelphia, PA 19129-1096, USA. jmm56@...

One may wonder why the genes for the class III region are even situated in

the human Major Histocompatibility Locus (MHC). However, on closer

inspection we find that the genes for the complement components, tumor

necrosis factor (TNF) and others may play an important role in host immune

defenses. Thus, this region on chromosome six may be more appropriately

thought of as an immune response area. Accordingly, there is a high degree

of polymorphism in many genes within the MHC, the most notable being the HLA

genes. In the class III region C2, factor B (Bf) and C4 are polymorphic in

as many populations studied to date. The purpose of this review will be to

briefly describe the class III region, identify the genetic polymorphism

found in various ethnic groups and define their roles in autoimmune

diseases.

Publication Types:

Review

Review, Tutorial

PMID: 11502490 [PubMed - indexed for MEDLINE]

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J Immunol 2001 Dec 15;167(12):7119-25 Related Articles, Books, LinkOut

T cell epitopes of human myelin oligodendrocyte glycoprotein identified in

HLA-DR4 (DRB1*0401) transgenic mice are encephalitogenic and are presented

by human B cells.

Forsthuber TG, Shive CL, Wienhold W, de Graaf K, Spack EG, Sublett R, Melms

A, Kort J, Racke MK, Weissert R.

Institute of Pathology, School of Medicine, Case Western Reserve University,

Cleveland, OH 44106, USA. tgf2@...

Myelin oligodendrocyte glycoprotein (MOG) is an Ag present in the myelin

sheath of the CNS thought to be targeted by the autoimmune T cell response

in multiple sclerosis (MS). In this study, we have for the first time

characterized the T cell epitopes of human MOG restricted by HLA-DR4

(DRB1*0401), an MHC class II allele associated with MS in a subpopulation of

patients. Using MHC binding algorithms, we have predicted MOG peptide

binding to HLA-DR4 (DRB1*0401) and subsequently defined the in vivo T cell

reactivity to overlapping MOG peptides by testing HLA-DR4 (DRB1*0401)

transgenic mice immunized with recombinant human (rh)MOG. The data indicated

that MOG peptide 97-108 (core 99-107, FFRDHSYQE) was the immunodominant

HLA-DR4-restricted T cell epitope in vivo. This peptide has a high in vitro

binding affinity for HLA-DR4 (DRB1*0401) and upon immunization induced

severe experimental autoimmune encephalomyelitis in the HLA-DR4 transgenic

mice. Interestingly, the same peptide was presented by human B cells

expressing HLA-DR4 (DRB1*0401), suggesting a role for the identified MOG

epitopes in the pathogenesis of human MS.

PMID: 11739534 [PubMed - indexed for MEDLINE]

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J Immunol 2001 Apr 1;166(7):4751-6 Related Articles, Books, LinkOut

T cells of multiple sclerosis patients target a common environmental peptide

that causes encephalitis in mice.

Winer S, Astsaturov I, Cheung RK, Schrade K, Gunaratnam L, Wood DD,

Moscarello MA, O'Connor P, McKerlie C, Becker DJ, Dosch HM.

The Hospital For Sick Children, Research Institute, Toronto, Ontario,

Canada.

Multiple sclerosis (MS) is a chronic autoimmune disease triggered by unknown

environmental factors in genetically susceptible hosts. MS risk was linked

to high rates of cow milk protein (CMP) consumption, reminiscent of a

similar association in autoimmune diabetes. A recent rodent study showed

that immune responses to the CMP, butyrophilin, can lead to encephalitis

through antigenic mimicry with myelin oligodendrocyte glycoprotein. In this

study, we show abnormal T cell immunity to several other CMPs in MS patients

comparable to that in diabetics. Limited epitope mapping with the milk

protein BSA identified one specific epitope, BSA(193), which was targeted by

most MS but not diabetes patients. BSA(193) was encephalitogenic in SJL/J

mice subjected to a standard protocol for the induction of experimental

autoimmune encephalitis. These data extend the possible, immunological basis

for the association of MS risk, CMP, and CNS autoimmunity. To pinpoint the

same peptide, BSA(193), in encephalitis-prone humans and rodents may imply a

common endogenous ligand, targeted through antigenic mimicry.

PMID: 11254737 [PubMed - indexed for MEDLINE]

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Proteomics 2001 May;1(5):721-5 Related Articles, Books, LinkOut

Analysis of antibody to milk proteins in HIV positive/negative sera using

two-dimensional electrophoresis, western blot and immunoassay.

Goldfarb M.

Anatek-EP, 17 Bishop Street, Portland, ME 04103, USA. anatekep@...

Homology between the 120 envelope glycoprotein of HIV-1 virus and

alpha-lactalbumin (a milk protein) stimulated interest in analysis of

antibody in HIV-1 positive plasma to cow's milk. Western blots of a

two-dimensional (2-D) separation of milk were assayed with nine HIV-1

positive plasmas and nine control sera. The control sera from reference labs

represented various disease problems. All nine HIV-1 positive plasma had

antibody to between two and five milk proteins. All nine HIV-1 positive

plasma had antibody to albumin and immunoglobulin (IgG); in addition, seven

reacted with butyrophilin, five with alpha-lactalbumin, six with casein.

Four of the control sera had no antibody to milk proteins; three had minor

reactivity to casein and two, one diagnosed as an IgM Lyme positive, one

diagnosed with Helicobacter pylori detected three and four milk proteins.

None of the control sera had antibody to albumin or alpha-lactalbumin.

Bovine and human albumin have almost identical sequence, and antibody

generated to bovine serum albumin could react with human serum albumin. To

look at this, three of the HIV-1 positive plasmas were assayed with 2-D

Western blots of human milk and did have reactivity with albumin and IgG.

Also, the protein butyrophilin is highly immunogenic and has significant

homology with human neural and cellular proteins. Whether these antibodies

can be causing allergy or autoimmune disease is speculative, but they

indicate an immune system which is highly activated.

PMID: 11678041 [PubMed - indexed for MEDLINE]

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Adv Exp Med Biol 2001;490:99-107 Related Articles, Books, LinkOut

Functional role of epitope spreading in the chronic pathogenesis of

autoimmune and virus-induced demyelinating diseases.

SD, Eagar TN.

Department of Microbiology-Immunology and Interdepartmental Immunobiology

Center, Northwestern University Medical School, Chicago, IL 60611, USA.

These results support a model of epitope spreading (Figure 4) wherein

localized virus-specific T cell-mediated inflammatory processes lead to the

recruitment/activation of CNS-resident APCs which can serve both as effector

cells for myelin destruction and as APCs which efficiently process/present

endogenous self epitopes to autoreactive T cells. Thus, inflammatory

responses induced by viruses which trigger pro-inflammatory Th1 responses

and have the ability to persist in genetically susceptible hosts, may lead

to chronic organ-specific autoimmune disease via epitope spreading.

Regardless of the specificity of the T cells (myelin peptides in R-EAE or

TMEV epitopes in TMEV-IDD) responsible for initiating myelin destruction,

epitope spreading plays an important contributory role in the chronic

disease process in genetically susceptible SJL mice. Epitope spreading has

obvious important implications to the design of antigen-specific therapies

for the potential treatment of MS and other autoimmune diseases. This

process indicates that autoimmune diseases are evolving pathologies and that

the specificity of the effector autoantigen-specific T cells varies during

the chronic disease process.

Publication Types:

Review

Review, Tutorial

PMID: 11505979 [PubMed - indexed for MEDLINE]

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Clin Immunol 1999 Oct;93(1):75-80 Related Articles, Books, LinkOut

Cytokine regulation of env gene expression of human endogenous retrovirus-R

in human vascular endothelial cells.

Katsumata K, Ikeda H, Sato M, Ishizu A, Kawarada Y, Kato H, Wakisaka A,

Koike T, Yoshiki T.

School of Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-ku, Sapporo,

060-8638, Japan.

To determine whether human endogenous retroviruses are implicated in the

pathogenesis of inflammatory vascular diseases of unknown etiology, we

examined mRNA expression of a human endogenous retrovirus, HERV-R, which has

a long open reading frame in the env region, in cultured human vascular

endothelial and smooth muscle cells stimulated in the presence of various

cytokines. mRNA of HERV-R was always evident in these cells but not in

fibroblastic cells. Levels of expression in vascular endothelial cells were

significantly regulated by treatment with tumor necrosis factor-alpha,

interleukin (IL)-1alpha, and IL-1beta as up-regulators and interferon-gamma

as a down-regulator. These observations are interpreted to mean that HERV-R

expression may be up- or down-regulated at sites of inflammation in vessels

in vivo and hence may play a pathogenetic role in inflammatory vascular

diseases in humans, perhaps similar to endogenous retroviruses in mouse

models of polyarteritis nodosa in humans. Copyright 1999 Academic Press.

PMID: 10497013 [PubMed - indexed for MEDLINE]

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J Neuroimmunol 2002 Apr;125(1-2):141-8 Related Articles, Books, LinkOut

Chromosome 7q21-22 and multiple sclerosis: evidence for a genetic

susceptibility effect in vicinity to the protachykinin-1 gene.

Vandenbroeck K, Fiten P, Heggarty S, Goris A, Cocco E, Hawkins SA, Graham

CA, Marrosu MG, Opdenakker G.

Rega Institute for Medical Research, University of Leuven, B-3000, Louvain,

Belgium

Chromosome 7q21-22 and, in particular, the region surrounding D7S554 emerged

from the recent American genome screen in multiple sclerosis (MS) as the

most promising region genome-wide for harboring a disease susceptibility

gene. We tested association between D7S554 and MS in 217 Sardinian trio MS

families by the transmission disequilibrium test (TDT), and in a Northern

Irish case-control study comprising 542 individuals. In both populations, we

found evidence for significant allelic association (P©=0.04 and

P©=0.0002, respectively). In a second stage, we analysed five

microsatellite markers in a 4 megabase interval on chromosome 7q21-22 in the

same set of Sardinian families. Parental transmission of a single allele of

one of these markers, i.e. D7S3126, was significantly distorted

(P©=0.008). D7S554 and D7S3126 are located at distances of, respectively,

40 and 81 kb 5' from the startcodon of the protachykinin-1 gene (TAC1), and

occur in strong linkage disequilibrium (P<10(-7)). Our study indicates that

the previous finding of linkage with D7S554 refers possibly to the presence

of an MS susceptibility effect in vicinity to TAC1. In addition, a second

independent association was uncovered between a microsatellite polymorphism

in the plasminogen activator inhibitor-1 gene, i.e. D7S477, and MS. Overall,

the analysis presented here may contribute to the increasingly refined

genomic map of MS and underscores the requirement for a further

high-resolution screening of chromosome 7q21-22.

PMID: 11960650 [PubMed - in process]

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J Neurovirol 2000 May;6 Suppl 2:S67-75 Related Articles, Books, LinkOut

Particle-associated retroviral RNA and tandem RGH/HERV-W copies on human

chromosome 7q: possible components of a 'chain-reaction' triggered by

infectious agents in multiple sclerosis?

Perron H, Perin JP, Rieger F, Alliel PM.

BioMerieux STELHYS, Chemin de l'Orme, 69280 Marcy l'Etoile, France.

Different groups have observed retrovirus particle (RVP) production in cell

cultures from patients with multiple sclerosis (MS). This in vitro

production appeared relatively specific for MS versus healthy controls, but

was likely to be enhanced or activated by infectious triggers such as

Herpesviruses (e.g. HSV, EBV). Independent molecular analysis of retroviral

RNA associated with RVP revealed two different genetic families of

endogenous retroviral elements (HERV): MSRV/HERV-W and RGH/HERV-H.

Interestingly, these sequences were detected by mutually exclusive primers

in RT - PCR amplifications. Surprisingly, these two HERV families both

contain an ancestral proviral copy inserted in chromosome 7q21-22 region at

about 1 kb of distance of each other. Another HERV-W proviral sequence is

located within a T-cell alpha-delta receptor (TCR) gene in chromosome

14q11.2 region. Interestingly, these two regions correspond to genetic loci

previously identified as potentially associated with 'multigenic'

susceptibility to MS and TCR alpha chain genetic determinants have been

reported to be statistically associated with MS. A plausible role for

infectious agents triggering a co-activation of the chromosome 7q HERV

tandem (replicative retrovirus and/or other virus and/or intracellular

bacteria) and, eventually, other HERV copies, is discussed. The role of

particular HERV polymorphism and the production of pathogenic molecules

(gliotoxin and superantigen) possibly associated with retroviral expression

are also evoked. An integrative concept of pathogenic 'chain-reaction' in MS

involving several step-specific pathogenic 'agents' and 'products' somewhat

interacting with particular genetic elements would federate most partial

data obtained on MS, including retroviral expression.

Publication Types:

Review

Review Literature

PMID: 10871789 [PubMed - indexed for MEDLINE]

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Virology 2001 Sep 1;287(2):321-32 Related Articles, Nucleotide, Protein,

Books, LinkOut

Multiple sclerosis retrovirus particles and recombinant envelope trigger an

abnormal immune response in vitro, by inducing polyclonal Vbeta16

T-lymphocyte activation.

Perron H, Jouvin-Marche E, Michel M, Ounanian-Paraz A, Camelo S, Dumon A,

Jolivet-Reynaud C, Marcel F, Souillet Y, Borel E, Gebuhrer L, Santoro L,

Marcel S, Seigneurin JM, Marche PN, Lafon M.

BioMerieux-Pierre Fabre, R & D, Chemin de L'Orme, Marcy L'Etoile, 69280,

France. herve_perron@...

A retroviral element (MSRV) defining a family of genetically inherited

endogenous retroviruses (HERV-W) has recently been characterized in cell

cultures from patients with multiple sclerosis (MS). To address the possible

relationship with MS, direct detection of circulating virion RNA was

proposed but revealed technically difficult to perform in standardized

conditions, in the face of multiple endogenous HERV-W copies. A parallel

approach has evaluated MSRV potential pathogenicity in relation to

characteristic features of multiple sclerosis, in particular,

T-lymphocyte-mediated immunopathology. We report here that MSRV particles

induce T-lymphocyte response with a bias in the Vbeta16 chain usage in

surface receptor, whatever the HLA DR of the donor. A recombinant MSRV

envelope-but not core-protein reproduced similar nonconventional activation.

Molecular analysis of Vbeta CDR3 showed that Vbeta16 expansions are

polyclonal. Our results thus provide evidence that MSRV envelope protein can

trigger an abnormal immune response with similar characteristics to that of

superantigens. Copyright 2001 Academic Press.

PMID: 11531410 [PubMed - indexed for MEDLINE]

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Mol Evol 1999 Jun;48(6):675-83 Related Articles, Books, LinkOut

Comparison between two human endogenous retrovirus (HERV)-rich regions

within the major histocompatibility complex.

Kulski JK, Gaudieri S, Inoko H, Dawkins RL.

Centre for Molecular Immunology and Instrumentation, University of Western

Australia, Faculty of Medicine and Dentistry, P.O. Box 5100, Canning Vale,

6155, Western Australia, Australia. jkulski@....

Sixteen human endogenous retrovirus (HERV) sequences were detected within

656 kb of genomic sequence obtained from the alpha- and beta-block of the

class I region of the major histocompatibility complex (MHC). The HERVs were

identified and characterized as family members of HERV-16 (11 copies),

HERV-L (1 copy), HERV-I (2 copies), HERV-K91 (1 copy), and HARLEQUIN (1

copy) by sequence comparison using CENSOR or Repeat Masker, BLAST searches,

and dot plots. The 11 copies of HERV-16 arose as products of duplication of

genomic segments containing HLA class I (HLAcI) and PERB11 (MIC) genes inter

alia, whereas the other five HERVs arose after duplication probably as a

consequence of single insertion events or translocations. HERV-L and HERV-I

are located between the duplicated genes PERB11.2 (MICB) and PERB11.1

(MICA), and HLA-B and HLA-C, respectively, whereas HERV-K91 and HARLEQUIN

are located telomeric of HLA-C. A highly fragmented copy of HERV-I was also

found telomeric of PERB11. 4. Structural analysis of open reading frames

(ORFs) revealed the absence of intact coding sequence within the putative

gag, pol, and env gene regions of all the HERVs with the exception of

HERV-K91, which had two large ORFs within the region of the putative

protease and pol genes. In addition, the 5'-LTR of HERV-L contained a 2.5-kb

element that was AT-rich and large ORFs with putative amino acid sequences

rich in tyrosines and isoleucines. HERV-I, HARLEQUIN, and at least four

copies of HERV-16 appear to have been receptors for the insertion of other

retrotransposons including Alu elements and fragments of L1 and THE1.

Examination of flanking sequences suggests that HERV-I and HERV-L had

occurred by insertion into ancient L1 fragments. This study has revealed

that the alpha- and beta-block region within the MHC is rich in HERV

sequences occurring at a much higher ratio (10 to 1) than normally observed

in the human genome. These HERV sequences will therefore enhance further

studies on disease associations and differences between human haplotypes and

primates and their role in the evolution of class I genes in the MHC.

PMID: 10229571 [PubMed - indexed for MEDLINE]

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J---------------------------------------------------------------------

Genomics 2001 Feb 1;71(3):351-62 Related Articles, Nucleotide, Protein,

Books, LinkOut

The cluster of BTN genes in the extended major histocompatibility complex.

DA, Stammers M, Malcherek G, Beck S, Trowsdale J.

Department of Immunology, University of Cambridge, Tennis Court Road,

Cambridge, CB2 1QP, United Kingdom. dar32@...

We sequenced the 170-kb cluster of BTN genes in the extended major

histocompatibility complex region, 4 Mb telomeric of human leukocyte antigen

class I genes, at 6p22.1. The cluster consists of seven genes belonging to

the expanding B7/butyrophilin-like group, a subset of the immunoglobulin

gene superfamily. The main complex is composed of six genes, from two

subfamilies, BTN2 and BTN3, arranged in pairs. This alternating pattern must

have evolved by duplications of an original block of two genes, one from

each subfamily. The sequences from the two subfamilies share approximately

50% amino acid identity. By analysis of repeat elements within each block,

these duplications may be dated to approximately 100 million years ago, at

about the time of the branching of the Rodentia and Primate lineages. The

single BTN1A1 (butyrophilin) gene was positioned approximately 25 kb

centromeric to the cluster. Each gene covers approximately 12 kb and

consists of seven (BTN2 subfamily) or nine (BTN3 subfamily) coding exons.

The predicted leader sequence, immunoglobulin-like IgV (variable)/IgC

(constant) ectodomains, and the predicted transmembrane domain are encoded

on separate exons and are separated from a B30.2 domain by a variable number

of very short exons, 21 and 27 nucleotides in length. BTN transcripts were

detected in all tissues examined. Alternative splicing, involving

particularly the carboxyl-terminal B30.2 domain, was a notable feature. Most

transcripts of BTN2 subfamily genes contained this domain, whereas BTN3

genes did not. Using immunofluorescence, we showed surface expression of

BTN-green fluorescent protein fusions in mammalian cell transfectants.

Copyright 2001 Academic Press.

PMID: 11170752 [PubMed - indexed for MEDLINE]

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Summary: Transaldolase 1 is a key enzyme of the nonoxidative pentose

phosphate pathway providing ribose-5-phosphate for nucleic acid synthesis

and NADPH for lipid biosynthesis. This pathway can also maintain glutathione

at a reduced state and thus protect sulfhydryl groups and cellular integrity

from oxygen radicals. The functional gene of transaldolase 1 is located on

chromosome 11 and a pseudogene is identified on chromosome 1 but there are

conflicting map locations. The second and third exon of this gene were

developed by insertion of a retrotransposable element. This gene is thought

to be involved in multiple sclerosis.

Proteome Summary: Protein related to transaldolase; catalyzes formation of

fructose-6-P and erythrose-4-P from sedoheptulose-7-P and glyceraldehyde-3-P

in the pentose phosphate pathway, may transfer aldol unit from

sedoheptulose-7-P to glyceraldehyde-3-P

Locus Type: gene with protein product, function known or inferred

Product: transaldolase 1

Alternate Symbols: TAL, TAL-H, TALDOR

Alias: glycerone transferase

dihydroxyacetone transferase

J Biol Chem 1994 Jan 28;269(4):2847-51 Related Articles, Nucleotide, OMIM,

Protein, Books, LinkOut

Cloning and expression of the human gene for transaldolase. A novel highly

repetitive element constitutes an integral part of the coding sequence.

Banki K, Halladay D, Perl A.

Department of Medicine, State University of New York Health Science Center,

College of Medicine, Syracuse 13210.

A novel highly repetitive retrotransposable element was cloned based on a

limited sequence homology to the human T-cell leukemia virus and a related

endogenous retroviral sequence, HRES-1. This repetitive element was found to

constitute an integral part of the coding sequence of the human gene for

transaldolase. In comparison with the intronless yeast gene, structural

analysis of the human transaldolase genomic locus revealed that the human

gene is comprised of five exons, second and third of which uniquely

developed by insertion of a retrotransposable element. The 1329-base pair

full-length cDNA, clone 4/2-4/1, contains an open reading frame coding for a

protein of 336 amino acids with a predicted molecular mass of 38 kDa. This

protein shows a 58% overall sequence homology with the 37-kDa yeast

transaldolase. Antibodies raised against a 22-kDa recombinant polypeptide

expressed from a 474-base pair 5' fragment of clone 4/2-4/1, containing

repetitive exons 2 and 3, cross-reacted with yeast transaldolase and

recognized the 38-kDa native human protein. Detection of a retrotransposon

in the coding sequence of the human transaldolase gene demonstrates the

importance of these repetitive elements in evolution of the eukaryotic

genome.

PMID: 8300619 [PubMed - indexed for MEDLINE]

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J Exp Med 1994 Nov 1;180(5):1649-63 Related Articles, Nucleotide, Protein,

Books, LinkOut

Oligodendrocyte-specific expression and autoantigenicity of transaldolase in

multiple sclerosis.

Banki K, Colombo E, Sia F, Halladay D, Mattson DH, Tatum AH, Massa PT,

PE, Perl A.

Department of Pathology, State University of New York College of Medicine,

Syracuse 13210.

Although the etiology of multiple sclerosis (MS) is unknown, there is

compelling evidence that its pathogenesis is mediated through the immune

system. Molecular mimicry, i.e., crossreactivity between self-antigens and

viral proteins, has been implicated in the initiation of autoimmunity and

MS. Based on homology to human T cell lymphotropic virus type I (HTLV-I) a

novel human retrotransposon was cloned and found to constitute an integral

part of the coding sequence of the human transaldolase gene (TAL-H). TAL-H

is a key enzyme of the nonoxidative pentose phosphate pathway (PPP)

providing ribose-5-phosphate for nucleic acid synthesis and NADPH for lipid

biosynthesis. Another fundamental function of the PPP is to maintain

glutathione at a reduced state and, consequently, to protect sulfhydryl

groups and cellular integrity from oxygen radicals. Immunohistochemical

analyses of human brain sections and primary murine brain cell cultures

demonstrated that TAL is expressed selectively in oligodendrocytes at high

levels, possibly linked to production of large amounts of lipids as a major

component of myelin, and to the protection of the vast network of myelin

sheaths from oxygen radicals. High-affinity autoantibodies to recombinant

TAL-H were detected in serum (25/87) and cerebrospinal fluid (15/20) of

patients with MS. By contrast, TAL-H antibodies were absent in 145 normal

individuals and patients with other autoimmune and neurological diseases. In

addition, recombinant TAL-H stimulated proliferation and caused aggregate

formation of peripheral blood lymphocytes from patients with MS. Remarkable

amino acid sequence homologies were noted between TAL-H and core proteins of

human retroviruses. Presence of crossreactive antigenic epitopes between

recombinant TAL-H and HTLV-I/human immunodeficiency virus type 1 (HIV-1) gas

proteins was demonstrated by Western blot analysis. The results suggest that

molecular mimicry between viral core proteins and TAL-H may play a role in

breaking immunological tolerance and leading to a selective destruction of

oligodendrocytes in MS.

PMID: 7964452 [PubMed - indexed for MEDLINE]

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Clin Immunol 2002 Feb;102(2):107-16 Related Articles, Books, LinkOut

Endogenous retroviruses in systemic lupus erythematosus: candidate lupus

viruses.

Adelman MK, Marchalonis JJ.

Microbiology and Immunology, The University of Arizona, Tucson, Arizona

85724, USA.

Although the etiology of systemic lupus erythematosus (SLE) remains unclear,

there is substantial circumstantial evidence that the development of SLE is

dependent on environmental, genetic, and retroviral factors. SLE patients

produce high titer antibodies to various retroviral proteins, including Gag,

Env, and Nef of HIV and HTLV, in the absence of overt retroviral infection.

We review the factors linking HERVs to SLE and consider the various

processes utilized by endogenous retroviruses in the etiopathogenesis of

SLE. In particular, we consider the role of HTLV-1-related endogenous

sequence (HRES-1) in SLE. We propose that molecular mimicry between HRES-1

and the small ribonucleoprotein complex initiates the production of

autoantibodies, leading to immune complex formation, complement fixation,

and pathological tissue deposition. Copyright 2001 Elsevier Science (USA).

Publication Types:

Review

Review, Tutorial

PMID: 11846452 [PubMed - indexed for MEDLINE]

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Genomics 1999 Oct 15;61(2):133-44 Related Articles, Nucleotide, Books,

LinkOut

Molecular characterization of a MSRV-like sequence identified by RDA from

monozygotic twin pairs discordant for schizophrenia.

Deb-Rinker P, Klempan TA, O'Reilly RL, Torrey EF, Singh SM.

Department of Zoology, and Division of Medical Genetics, The University of

Western Ontario, London, Ontario, N6A 5B7, Canada.

Retroviral-related amplicons were used in modified RDA to identify four

sequences from affected members of three pairs of monozygotic twins

discordant for schizophrenia. One sequence (schizophrenia associated

retrovirus, SZRV-1, GenBank Accession No. AF135487) is characterized here.

It is similar to two known sequences of retroviral origin: multiple

sclerosis-associated retrovirus, MSRV (GenBank Accession No. AF009668), and

ERV-9 (GenBank Accession No. S77575). It is present in multiple copies in

the human genome and has been localized to six different chromosomal sites.

A zooblot shows that this multicopy sequence is predominant in the primate

lineage and present in rhesus monkeys and humans. SZRV-1 is expressed as a

9-kb RNA band in the placenta. This could offer support to the hypothesis

that retroviral sequences transposing during fetal growth may alter

neurodevelopmental genes and cause diseases, although its direct involvement

in the causation of schizophrenia remains to be established. Copyright 1999

Academic Press.

Publication Types:

Twin Study

PMID: 10534399 [PubMed - indexed for MEDLINE]

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Pathobiology 2001;69(1):11-8 Related Articles, Books, LinkOut

Immunological hyperresponsiveness in HTLV-I LTR-env-pX transgenic rats: a

prototype animal model for collagen vascular and HTLV-I-related inflammatory

diseases.

Nakamaru Y, Ishizu A, Ikeda H, Sugaya T, Fugo K, Higuchi M, Yamazaki H,

Yoshiki T.

Department of Pathology/Pathophysiology, Division of Pathophysiological

Science, Hokkaido University Graduate School of Medicine, Sapporo, Japan.

We have earlier reported that diverse collagen vascular diseases, including

arthritis, arteritis, thrombosis, myocarditis, myositis,

sialo-/dacryoadenitis and dermatitis develop with the advent of

autoantibodies in transgenic rats carrying the LTR-env-pX gene of human T

lymphocyte virus type I (LTR-env-pX rats). To clarify the pathogenesis of

these collagen vascular diseases, immunological features of LTR-env-pX rats

were examined. In LTR-env-pX rats affected with these diseases, expression

of CD80/86 on both tissue-infiltrating and peripheral T cells increased,

compared with findings in non-transgenic rats with experimental inflammatory

diseases. CD80/86 was also upregulated on peripheral T cells in LTR-env-pX

rats prior to the development of diseases. Lymphocytes from LTR-env-pX rats

showed an increase in autologous proliferation and were hyperreactive

against several mitogens, including concanavalin A, immobilized anti-CD3

antibodies, and superantigens in vitro. Antigen-specific immune response was

also enhanced in LTR-env-pX rats. The collective evidence indicates that

lymphocytes of LTR-env-pX rats constitutively express surface molecules

related to T cell activation and are immunologically hyperresponsive. Bone

marrow cell transfer from LTR-env-pX rats to lethally irradiated

non-transgenic rats revealed that these immunologically pre-activated and

hyperresponsive lymphocytes play a critical role in the pathogenesis of

several collagen vascular diseases, especially of dermatitis in LTR-env-pX

rats. Copyright 2001 S. Karger AG, Basel

PMID: 11641612 [PubMed - indexed for MEDLINE]

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