Search PubMed⌕ Search

Biomedical subjects

A Ben-Nun

Publications and source records attributed to A Ben-Nun.

At least 37 records · Page 2Linked to original sources
PubMed1999

Elevated levels of antibody to myelin oligodendrocyte glycoprotein is not specific for patients with multiple sclerosis.

OBJECTIVE: To evaluate the presence and specificity of anti-myelin oligodendrocyte glycoprotein (MOG) antibody in the cerebrospinal fluid and plasma of patients with multiple sclerosis (MS). DESIGN: Case-control study of patients with clinically definite MS compared with patients with other neurologic diseases (ONDs) of the central nervous system and control subjects. SETTING: Referral center in the Department of Neurology of Hadassah University Hospital, greater Jerusalem area, Israel. PARTICIPANTS: Consecutive cerebrospinal fluid samples from 31 patients with MS, 31 patients with ONDs, and 28 healthy controls; and plasma samples from 33 patients with MS, 28 patients with ONDs, and 31 healthy controls were taken from the cerebrospinal fluid and plasma bank of the Department of Neurology, Hadassah University Hospital. MAIN OUTCOME MEASURES: Levels and frequencies of anti-MOG antibody in patients with MS, as defined by enzyme-linked immunosorbent assay. RESULTS: Cerebrospinal fluid levels of antibodies to MOG and to myelin basic protein were significantly higher in patients with MS (P<.001 and P = .001, respectively) and patients with ONDs (P = .005 and P = .03, respectively) compared with controls; frequency of antibodies to MOG, but not to myelin basic protein, was higher in patients with MS and patients with ONDs (P = .01 and P = .003, respectively, for the frequency of anti-MOG antibody, and P = .65 and P = .41, respectively, for the frequency of anti-myelin basic protein antibody). Plasma levels of antibodies to MOG and to myelin basic protein were higher in patients with MS compared with patients with ONDs (P = .003 for both comparisons) and with controls (P = .03 and P = .04, respectively); however, the frequency of antibodies to MOG and myelin basic protein was similar in patients with MS, patients with ONDs (P=.54 and P = .82, respectively), and controls (P = .50 and P = .14, respectively). CONCLUSIONS: The elevated presence of anti-MOG antibody is not specific for MS because a similar appearance was also demonstrated in patients with ONDs. Therefore, it is not clear whether this antibody is pathogenic in MS or, on the contrary, has a defensive role against further immune-mediated damage after myelin breakdown.

Adolescent↗
PubMed1999

Effect of the bm12 class II mutation on proliferative and cytokine responses of encephalitogenic T cells in myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis.

The bm12 mutation in the class II I-A(b)molecule can profoundly influence experimental autoimmune disease, enhancing the development of systemic lupus erythematosus-like syndromes in NZB.H-2(bm12)mice or, conversely, abolishing the susceptibility of C57BL/6J (H-2(b)) mice to the induction of experimental autoimmune myasthenia gravis. We have studied the effect of this mutation on experimental autoimmune encephalomyelitis (EAE), induced in H-2(b)mice by myelin oligodendrocyte glycoprotein (MOG), and recently showed that MOG 35-55 peptide (pMOG 35-55), which represents the immunodominant encephalitogenic region for H-2(b)mice, is also a strong encephalitogen for H-2(bm12)mice. Nevertheless, although the differences in fine epitope specificity and TCR-Vbeta gene usage between encephalitogenic pMOG 35-55-specific T cells from H-2(b)and H-2(bm12)mice were subtle, H-2(bm12)and H-2(b)antigen presenting cells failed to effectively cross-present pMOG 35-55 non-syngeneically to I-A(b)/pMOG 33-55- and I-A(bm12)/pMOG 35-55-specific T cells, respectively. In the present study, we show that the abrogation of the response to pMOG 35-55 by the Th1 encephalitogenic pMOG 35-55-specific T cells upon non-syngeneic cross-presentation is neither due to a cytokine shift to a Th2 pattern, nor a result of anergy induction. Therefore, we suggest that presentation of pMOG 35-55 to I-A(b)/pMOG 35-55-specific T cells via the bm12 class II MHC molecule resulted in ineffective stimulation, similar to a weak agonistic effect.

Animals↗
PubMed1998

Differential recognition of MBP epitopes in BALB/c mice determines the site of inflammatory disease induction.

Although myelin basic protein (MBP)-recognizing T cells are not readily obtained after immunization of BALB/c mice with MBP (reflecting the BALB/c resistance to actively induced experimental autoimmune encephalomyelitis (EAE)), they can be expanded and cloned after several rounds of in vitro culture. The majority of BALB/c-derived clones recognize an epitope defined by MBP peptide 59-76. When transferred to naive BALB/c recipients, these clones cause classical EAE, with characteristic inflammation and demyelination of the central nervous system (CNS). We previously showed that two related clones recognizing a minor epitope, defined by MBP peptide 151-168, cause inflammation and demyelination preferentially of the peripheral nervous system (PNS). Because MBP has alternatively spliced isoforms, residues 151-168 are not present contiguously in all MBP isoforms. In order to determine whether induction of PNS disease is idiosyncratic to these sister clones, or related to their properties of epitope recognition, an independent T-cell line with similar recognition properties was studied. Clone 116F, derived from a BALB/c shiverer mouse, expresses a different T-cell receptor (TCR), with distinct TCR contact residues, but like the previously described T cells, this clone requires residues from both exons 6 and 7 for optimal stimulation. When adoptively transferred to BALB/c recipients, this clone preferentially induces disease of the PNS. A control BALB/c shiverer-derived MBP 59-76-recognizing clone, in contrast, induces CNS disease. These data strongly suggest that the site of disease initiation may correlate with epitope recognition, particularly when alternative isoforms are involved.

Alternative Splicing↗
PubMed1998

Interleukin-6 functions in autoimmune encephalomyelitis: a study in gene-targeted mice.

The encephalitogenic peptide pMOG 35-55 from the myelin oligodendrocyte glycoprotein was used to induce experimental autoimmune encephalomyelitis (EAE) in H-2b mice with the interleukin-6 (IL-6) gene intact or disrupted. The IL-6+/+ mice developed a chronic form of EAE ascending paralysis, whereas the IL-6-/- mice were resistant to the disease. Injections of recombinant IL-6 following pMOG immunization induced severe disease in the IL-6-/- mice. Histological examination of brain and spinal cord sections showed that the perivascular infiltration of inflammatory cells evident in IL-6+/+ mice was absent in the IL-6-/- animals and could be restored by exogenous IL-6 administration. Anti-MOG antibody levels were much lower in the IL-6-/- mice, but were not restored to high levels by IL-6 injections which elicited the development of pMOG 35-55-induced EAE. T lymphocytes reactive to the pMOG antigen were recovered from lymph nodes of both types of mice and Tcell lines could be established from both. Adoptive transfer of Tcell lines from IL-6+/+ mice induced EAE in the mice with the intact IL-6 gene but less in the IL-6-deficient mice, indicating that the resistant phenotype cannot be explained solely by lack of encephalitogenic Tcells. The absence of cell infiltrates in the brain and spinal cords of IL-6-/- mice upon adoptive transfer of the pathogenic Tcells from IL-6+/+ mice is consistent with a function of IL-6 in the local perivascular inflammatory process.

Adoptive Transfer↗
PubMed1998

T-cell responses to myelin antigens in multiple sclerosis; relevance of the predominant autoimmune reactivity to myelin oligodendrocyte glycoprotein.

Until recently, the search for the 'culprit' autoantigen towards which deleterious autoimmunity is directed in multiple sclerosis (MS) centered mostly on myelin basic protein (MBP) and proteolipid (PLP), the two most abundant protein components of central nervous system (CNS) myelin, the target tissue for the autoimmune attack in MS. Although such research has yielded important data, furthering our understanding of the disease and opening avenues for possible immune-specific therapeutic approaches, attempts to unequivocally associate MS with MBP or PLP as primary target antigens in the disease have not been successful. This has led in recent years to a new perspective in MS research, whereby different CNS antigens are being investigated for their possible role in the initiation or progression of MS. Interesting studies in laboratory animals show that T-cells directed against certain non-myelin-specific CNS antigens are able to cause inflammation of the CNS, albeit without expression of clinical disease. However, reactivity to these antigens by MS T-cells has not been demonstrated. Conversely, reactivity by MS T-cells to non-myelin-specific antigens such as heat shock proteins, could be observed, but the pathogenic potential of such reactivity has not been corroborated with the encephalitogenicity of the antigen. More relevant to MS pathogenesis may be, as we outlined in this review, the autoimmune reactivity directed against minor myelin proteins, in particular the CNS-specific myelin oligodendrocyte glycoprotein (MOG). Here, we review the current knowledge gathered on T-cell reactivity to possible target antigens in MS in the context of their encephalitogenic potential, and underline the facets which make MOG a highly relevant contender as primary target antigen in MS, albeit not necessarily the only one.

Amino Acid Sequence↗
PubMed1997

T cell receptor expression and differential proliferative responses by T cells specific to a myasthenogenic peptide.

Myasthenia gravis (MG) is a T-cell-regulated autoimmune disease in which a pathological autoantibody response is mounted against the nicotinic acetylcholine receptor of the neuromuscular junction. Our laboratory previously identified a T cell epitope, p195-212, derived from the human acetylcholine receptor alpha subunit, which triggered PBL to proliferate from about 70% of MG patients tested. p195-212 was also found to be an immunodominant T cell epitope in SJL mice and a cryptic epitope in C3H.SW mice. Inoculation of naive SJL mice with cells from a p195-212-specific syngeneic T cell line caused MG-related autoimmune manifestations in those mice. In these studies we analyzed TCR alpha and beta chain sequences used by T cell lines and clones from both high- and low-responder mouse strains in response to p195-212. T cell lines generated from either strain expressed single TCR V beta gene segments (V beta 17 in SJL mice and V beta 8 in C3H.SW mice). By deleting V beta 17-expressing T cells in p195-212-immunized SJL mice we established a T cell line that expressed the V beta 6 gene product, suggesting that SJL mice are not limited to using a single V beta gene segment in response to p195-212. In addition, we found that N- and/or C-terminal-truncated peptides of p195-212, presented under the same culture conditions to different clones bearing the same TCR alpha beta chain, could elicit very different proliferative responses from the clones. Thus, even within a constrained system, factors other than TCR sequence contribute to the differential stimulation of T cell responses.

Amino Acid Sequence↗
PubMed1997

Predominance of the autoimmune response to myelin oligodendrocyte glycoprotein (MOG) in multiple sclerosis: reactivity to the extracellular domain of MOG is directed against three main regions.

Our previous analysis of the T cell reactivity to myelin antigens in a group of 24 patients with multiple sclerosis (MS) and 16 control individuals revealed that the autoimmune response to myelin oligodendrocyte glycoprotein (MOG) predominates in MS over that to myelin basic protein (MBP), proteolipid protein or myelin-associated glycoprotein, suggesting a prevalent role for the autoimmune response to MOG in the pathogenesis of MS. Using a recombinant human MOG (rhMOG) preparation corresponding to the extracellular immunoglobulin-like domain of the MOG molecule, we have now analyzed another group of 52 MS patients and 49 control individuals for reactivity of their peripheral blood lymphocytes (PBL) to rhMOG and to MBP concomitantly. Of the 52 MS patients tested 24 responded to MOG and 10 out of 49 responded to MBP, whereas only 5 MOG-reactive and 4 MBP-reactive control individuals were detected out of the 49 tested. These results are therefore highly confirmatory of the predominant reactivity to MOG in MS. The analysis of the primary proliferative response to 11 synthetic overlapping peptides (phMOG) spanning the extracellular domain of human MOG by PBL from 9 MS patients and 15 control individuals (9 healthy controls and 6 patients with neurological diseases other than MS) further supports a prevalent role for the autoimmune response to MOG in MS, as only 1 of the 15 controls tested showed reactivity to any of the phMOG, whilst 5 out of the 9 patients studied reacted to at least 1 of the phMOG. PBL from 10 MS patients, and from 4 controls, were selected in vitro with each of the phMOG. Of the 10 patients studied 7 reacted to at least 1 phMOG upon secondary stimulation and the reactivity was mostly directed to epitopes localized within three main regions (amino acids 1-22, 34-56 and 64-96), as was observed for the primary response of PBL. The predominant response to MOG of PBL from MS patients as demonstrated in two separate studies using native MOG and rhMOG as antigens, and the high incidence of reactivity of these PBL compared to the lack of response to phMOG by control PBL, emphasize the relevance of MOG in MS pathogenesis and support a primary role for the autoimmune T cell response to MOG in disease development.

Adult↗
PubMed1997

Immunomodulation of murine experimental autoimmune encephalomyelitis by pertussis toxin: the protective activity, but not the disease-enhancing activity, can be attributed to the nontoxic B-oligomer.

Bordetella pertussis and its major virulence component, pertussis toxin (PT), have been used routinely to promote the development of such murine experimental autoimmune diseases as experimental autoimmune encephalomyelitis (EAE). Recently, we reported that B. pertussis also can protect against EAE. The protective activity was assigned to PT, a complex holomer composed of an A-promoter, the toxic S1 subunit, and a B-oligomer comprised of subunits S2, S3, S4, and S5. Although some data are available to explain how PT can enhance the development of EAE, nothing is known about the mechanism by which it protects against the disease. Toward understanding how PT can have such conflicting effects on EAE, we investigated the immunomodulatory activity of the various components of PT. Herein we show that the enhancing and protective activities reside within different regions of the PT holomer. Thus, though S1 appeared essential in imparting enhancing activity to PT, it played no role of importance in disease protection, and the protective effects of PT could be assigned fully to the B-oligomer. Further investigation with gel-purified PT subunits revealed that B-oligomer subunits protected against EAE to varying extent, with S3 being the most protective. These data suggest a potential therapeutic application for the B-oligomer or some of its subunits, which appear to be potent protective agents, without the toxicity or disease-promoting activity associated with PT.

Adjuvants, Immunologic↗
PubMed1996

Delineation of the minimal encephalitogenic epitope within the immunodominant region of myelin oligodendrocyte glycoprotein: diverse V beta gene usage by T cells recognizing the core epitope encephalitogenic for T cell receptor V beta b and T cell receptor V beta a H-2b mice.

The nature of the autoimmune T cell response to myelin oligodendrocyte glycoprotein (MOG), recently recognized as a potential target antigen in multiple sclerosis (MS), has not yet been characterized, in contrast to the T cell reactivity to other potential target antigens in MS such as myelin basic protein and proteolipid protein. Here, we show that the encephalitogenicity of the recombinant Ig-like domain of human MOG is associated, in H-2 b mice, with an immunodominant T cell reactivity against a single region of MOG spanning amino acids 35-55, accounting for the previously reported strong encephalitogenic activity of pMOG 35-55. A single injection of pMOG 35-55 with or without administration of pertussis toxin was sufficient to induce severe clinical experimental autoimmune encephalomyelitis (EAE) in H-2 b mice. Encephalitogenic pMOG 35-55-specific T cell lines derived from C3H.SW (V beta b) mice were diverse in their TCR V beta gene usage (V beta 1, V beta 6, V beta 8 and V beta 15), although V beta 8.2 was most predominantly expressed (48%). However, V beta 8 + T cells may only be part of the encephalitogenic MOG-specific T cell repertoire in H-2 b mice, as demonstrated by the susceptibility of C57L (V beta a) mice to disease induced by pMOG 35-55. Encephalitogenic T cell lines from V beta a mice were also diverse in their TCR V beta gene usage (V beta 1, V beta 2, V beta 6, V beta 14 and V beta 16). Such a heterogeneous TCT V beta gene expression by pMOG 35-55/I-A b-reactive T cells from both V beta a and V beta b H-2 b mice suggested multiple epitopes within pMOG 35-55. Analysis of the pattern of reactivity by pMOG 35-55-reactive T cells to a set of truncated peptides was not commensurate with independent nested epitopes, but revealed a requirement for recognition of a core sequence, YRSPFSRVV (pMOG 40-48). However, optimal stimulation was obtained with longer peptides, with each additional amino acid flanking either the N or the C terminus differentially increasing the stimulatory capacity of pMOG 40-48. Nonetheless, pMOG 40-48 was the minimal encephalitogenic epitope for both V beta a and V beta b mice. Thus, the T cell reactivity against the immunodominant encephalitogenic region of MOG is characterized by a diverse V beta gene usage and a requirement for the same core epitope. This pattern of reactivity may favor epitope-directed, rather than TCR-targeted, approaches to immunospecific therapy for MOG-related autoimmune disease.

Adoptive Transfer↗
PubMed1996

The autoimmune reactivity to myelin oligodendrocyte glycoprotein (MOG) in multiple sclerosis is potentially pathogenic: effect of copolymer 1 on MOG-induced disease.

Multiple sclerosis (MS), an autoimmune disease of the central nervous system (CNS) characterized by primary demyelination, is believed to result from an autoimmune attack against myelin components. In view of their ability to induce experimental autoimmune encephalomyelitis (EAE), an animal model for MS, the quantitatively major malign proteins--myelin basic protein (MBP) and proteolipid protein (PLP)--have been extensively studied as the relevant primary antigens in MS, and therapeutic approaches have been targeted to counteract autoimmune reactivity to MBP and PLP. Accordingly, copolymer 1, a random synthetic amino acid copolymer crossreactive with MBP and highly protective against the induction of EAE with MBP or PLP, is not being extensively tested in clinical studies as a therapeutic agent for MS. However, increasing evidence suggests that autoimmune reactivity against other CNS-specific myelin proteins could also be involved in the pathogenesis of MS. In this context, we have demonstrated that peripheral blood lymphocytes from patients with MS respond predominantly to myelin oligodendrocyte glycoprotein (MOG) rather than to MBP or PLP, suggesting an important role for cell reactivity against MOG in the pathogenesis of MS. We have demonstrated that T-cell reactivity in MOG can also be pathogenic by inducing neurological disease in H-2u and H-2b mice with the same peptide of MOG, pMOG 35-55. Most interestingly, the expression of the disease differed with the different MHC backgrounds. Induction of a differentially expressed disease in different strains of mice with the same myelin antigen makes this new model particularly relevant to MS, where different expression of the disease is seen in different patients. Therefore, notwithstanding the importance of the autoimmune reactivity to MBP and PLP in MS, the potentially pathogenic autoimmune reactivity to MOG must now also be taken into consideration in therapeutic approaches to MS. In this context, we have investigated the possible effect of copolymer 1 treatment on autoimmune reactivity to MOG and on the development of EAE induced by MOG. Copolymer 1 was found to inhibit the binding of MOG peptides to MHC molecules, as well as the proliferation of MOG-reactive T cells, in a dose-dependent manner. In parallel, injection of copolymer 1 concomitantly with the encephalitogenic MOG peptide exerted a strong protective effect against the development of EAE. These preliminary data on the effect of copolymer 1 on the autoimmune response to MOG in mice indicate that copolymer 1 may also be effective in cases of MS where the autoimmune response to MOG prevails, and should therefore be further investigated in this context.

Animals↗
PubMed1996

[Carcinoma of the appendix--rare but important].

Villous adenoma of the vermiform appendix is very rare; the treatment of choice is appendectomy. We report a 72-year-old woman with a villous adenoma and a single focus of invasive, colonic adenocarcinoma. This finding required changes in diagnostic procedures and treatment, and altered the prognosis. The purpose of this report is to increase awareness of this phenomenon and to indicate correct management.

Adenocarcinoma↗
PubMed1995

A 12-kDa protein of Mycobacterium tuberculosis protects mice against experimental autoimmune encephalomyelitis. Protection in the absence of shared T cell epitopes with encephalitogenic proteins.

Mycobacterium tuberculosis (Mt), routinely used to promote the induction of autoimmune diseases, can also protect against their development. Recently, we demonstrated that purified protein derivative (PPD) is the major fraction of Mt that protects mice against the induction of experimental autoimmune encephalomyelitis (EAE). We have now ascribed the protective activity to a 12-kDa protein purified from PPD. Sequence identity between the first 17 amino acids of the 12-kDa PPD protein and the 10-kDa BCG-a protein of Mt suggested that these proteins are identical or closely related. However, in contrast to the 12-kDa PPD protein, the 10-kDa BCG-a protein did not protect against EAE, nor did it stimulate PPD-specific T cells, suggesting that the 12-kDa PPD protein and the 10-kDa BCG-a protein share some homology but are not identical. The protective activity of the 12-kDa PPD protein correlated with its ability to stimulate PPD-specific T cells. The significance of this correlation is not clear and the mechanism of protection was not fully elucidated. However, N-terminal sequence identity between the 12-kDa PPD protein and the 10-kDa BCG-a protein, which shares 43% homology with GroES stress protein, suggested that the 12-kDa PPD protein may also belong to the bacterial heat-shock protein (hsp) family. Thus, by analogy with protection against arthritis or diabetes by hsp65, the mechanism of protection could be based on shared T cell epitopes with the target self Ag. However, the 12-kDa PPD protein did not stimulate encephalitogenic T lymphocytes. Effective protection against EAE by the 12-kDa PPD protein, in the absence of a stimulatory effect on encephalitogenic T lymphocytes, suggests a potential use for this protein in the therapy of autoimmune diseases.

Amino Acid Sequence↗
PubMed1995

Chronic relapsing experimental autoimmune encephalomyelitis with a delayed onset and an atypical clinical course, induced in PL/J mice by myelin oligodendrocyte glycoprotein (MOG)-derived peptide: preliminary analysis of MOG T cell epitopes.

Myelin basic protein (MBP) and proteolipid protein (PLP), the most abundant proteins of central nervous system (CNS) myelin, have been extensively studied as possible primary target antigens in multiple sclerosis (MS), a primary demyelinating autoimmune disease of the CNS. However, there is increasing evidence to suggest that autoimmune reactivity against the quantitatively minor myelin component, myelin oligodendrocyte glycoprotein (MOG), can also play a role in the pathogenicity of MS. We recently demonstrated a predominant response to MOG by peripheral blood lymphocytes from patients with MS tested for their reactivity against various myelin antigens, including MBP and PLP. To ascertain whether or not T cell reactivity to MOG in MS is a potentially pathogenic response, we have tested the ability of synthetic MOG peptides (pMOG) representing potential T cell epitopes, to induce neurological disease in mice. Both strains of mice tested (SJL/J and PL/J mice) were able to mount a primary T cell response to some of the five MOG peptides synthesized, pMOG 1-21, 35-55, 67-87, 104-117 and 202-218. T cell lines could be raised in both strains to pMOG 35-55 and 67-87, but epitope definition revealed that each strain recognized a different minimal epitope within these two peptides. T cell lines to pMOG 1-21 and 202-218 could also be raised in SJL/J and PL/J mice, respectively. T cell reactivity to pMOG 104-117 was not observed in either mouse strain. None of the peptides tested induced detectable clinical signs in SJL/J mice. In contrast, an MS-like chronic relapsing-remitting disease could be induced in PL/J mice with pMOG 35-55. The disease presented with a delayed onset and with clinical signs which differed significantly in their progression and expression from the typical ascending paralysis of experimental autoimmune encephalomyelitis induced with other myelin components, such as MBP and PLP. Histological examination of CNS tissue from mice injected with pMOG 35-55 revealed only mild neuropathological signs with few inflammatory foci in brain and spinal cord. Some myelin splitting and edema were detected upon electron microscopic examination in the spinal cord and cerebellum. Transfer of pMOG 35-55 reactive T cells into naive PL/J mice resulted in pathological changes characterized by inflammatory foci in the brain and spinal cord. This passively induced disease was clinically silent, as was also reported for Lewis rats injected with T cells specific for the same MOG peptide.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acid Sequence↗
PubMed1995

A myelin oligodendrocyte glycoprotein peptide induces typical chronic experimental autoimmune encephalomyelitis in H-2b mice: fine specificity and T cell receptor V beta expression of encephalitogenic T cells.

A predominant response to myelin oligodendrocyte glycoprotein (MOG) was recently observed in patients with multiple sclerosis (MS). To study the possible pathogenic role of T cell response to MOG in MS, we have investigated the encephalitogenic potential of MOG. Synthetic MOG peptides, pMOG 1-21, 35-55, 67-87, 104-117 and 202-218, representing predicted T cell epitopes, were injected into C57BL/6J and C3H.SW (H-2b) mice. The mice developed significant specific T cell responses to pMOG 1-21, pMOG 35-55 and pMOG 104-117. However, pMOG 35-55 was the only MOG peptide which could induce neurological impairment. The highly reproducible disease was chronic, with ascending paralysis and neuropathology comparable with those observed in experimental autoimmune encephalomyelitis (EAE) induced by myelin basic protein or proteolipid protein, except that in H-2b mice the disease was consistently non-remitting. These features differ markedly from those which we recently observed in PL (H-2u) mice with pMOG 35-55-induced disease. In PL mice, pMOG 35-55-induces atypical chronic relapsing EAE, the expression and progression of which are unpredictable. Hence, in different mouse strains, the same MOG peptide can induce typical EAE characterized by ascending paralysis, or atypical EAE with unpredictable clinical signs. pMOG 35-55-specific T cells from H-2b mice recognized an epitope within amino acids 40-55 of the MOG molecule, and pMOG 40-55-reactive T cell lines were encephalitogenic upon transfer into syngeneic recipients. The encephalitogenic pMOG 35-55-reactive C57BL/6J T cell lines expressed V beta 1, V beta 6, V beta 8, V beta 14 and V beta 15 gene segments, and the pMOG 35-55-reactive C3H.SW T cell lines expressed V beta 1, V beta 2, V beta 6, V beta 8, V beta 10, V beta 14, and V beta 15 gene segments. However, in both mouse strains, the utilization of the V beta 8 gene product was predominant (40-43%). The highly reproducible encephalitogenic activity of pMOG 35-55 strongly suggests a pathogenic role for T cell reactivity to MOG in MS and supports the possibility that MOG may also be a primary target antigen in the disease.

Amino Acid Sequence↗
PubMed1995

T cell receptor repertoire in the peripheral blood and intestinal mucosa of coeliac patients.

The alpha beta and gamma delta T cell receptor (TCR) repertoire in the peripheral blood and intestinal mucosa of six coeliac and six age-matched controls was analysed by reverse transcription and polymerase chain reaction (PCR). No TCR alpha and gamma delta restriction was observed in coeliacs and controls. However, V gamma 3 was expressed only in coeliac peripheral and intestinal T cells. V delta 2 was strongly expressed in coeliacs and scarcely transcribed in control cells. The unique expression of these gamma delta TCR in coeliac patients suggests that V gamma 3 and perhaps V delta 2 TCR-bearing lymphocytes may play a role in the pathogenesis of coeliac disease.

Celiac Disease↗
PubMed1995

Immunomodulation of autoimmunity in MRL/lpr mice with syngeneic bone marrow transplantation (SBMT).

MRL-lpr/lpr mice spontaneously develop a severe autoimmune syndrome, characterized by massive generalized lymphadenopathy, arthritis, arteritis, dermatitis and immune complex-mediated glomerulonephritis. Bone marrow transplantation (BMT) from MHC-matched systemic lupus erythematosus (SLE)-resistant donors to susceptible recipients has proved effective in correcting autoimmune manifestations in autoimmune-prone mice. We investigated the effect of syngeneic BMT from MRL/lpr (donor) to immunocompromised MRL/lpr (recipient), after purging the bone marrow inoculum with MoAbs against mature T cells (anti-Thy 1.2). All the untreated mice developed lymphadenopathy and by the age of 36 weeks five of the eight were dead; in contrast, all the mice which underwent syngeneic BMT following acute immunosuppression with total body irradiation (900 cGy) (TBI) remained disease-free. In an additional experiment, it was found that conditioning with cyclophosphamide (CY) before BMT was more effective than TBI in inhibiting delayed-onset autoimmune manifestations (mean survival 350 days in the CY group and 305 days in the TBI group, versus 197 days in untreated controls). Under both immunosuppressive regimens T cell-depleted bone marrow grafts produced far better results than did unmanipulated BMT. Following syngeneic BMT the incidence of proteinuria and the level of serum anti-DNA (dd) antibodies were significantly reduced, compared with that of the age-matched untreated controls. CY was more effective than TBI in reducing the anti-DNA titres. Likewise, T depletion of bone marrow inocula before BMT induced a more drastic drop in autoantibodies, following both CY and TBI conditioning protocols. After syngeneic BMT (either CY or TBI) no signs of lymphadenopathy were observed even at an advanced age. Upon histopathological examination, the BMT-treated mice displayed normal glomeruli with occasional minimal signs of glomerulonephritis. Syngeneic T cell-depleted BMT following acute cytoreduction of anti-self immune lymphocytes may represent a new therapeutic approach for drug-resistant autoimmune diseases.

Animals↗
PubMed1994

Thyroglobulin-induced murine thyroiditis assessed by intrathyroidal T cell receptor sequencing.

Thyroid glands from CBA/J (H-2k) mice, with human thyroglobulin (Tg)-induced thyroiditis, were removed and total cellular RNA was prepared and reverse transcribed as target cDNA for PCRs to detect 17 murine T cell receptor (mTCR) V beta families. Southern analysis of the resulting PCR fragments showed a marked bias in the intrathyroidal expression of mTCR V beta gene families with only 10 detectable V beta gene families of the 17 tested. Four Tg-specific CBA/J T cell lines also showed a biased use of mTCR V beta gene families with only 7 V beta gene families detected of the 17 tested. Sequence analysis showed evidence of oligoclonal expansion of the intrathyroidal T cell populations, and some of the CDR3 sequences found in the thyroid infiltrates were identical, or similar, to examples of the patterns of CDR3 sequences seen in the Tg-specific lines. Overall, however, there was marked N-D-N sequence variation in both the lines and thyroid infiltrates. These data indicated that 1) mTcR V gene analysis of intact thyroid tissue reflected the thyroid Ag-specific T cells infiltrating the thyroid gland; 2) confirmed the phenomenon of oligoclonal expansion in early thyroiditis; 3) showed that certain V beta gene families may be overemployed in the T cell recognition of Tg in the context of H-2k; and 4) revealed, by the varied patterns of the CDR3 sequences, that the V gene itself may be more important in thyroid Ag recognition than N-D-N region motifs.

Amino Acid Sequence↗