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Biomedical subjects

H Festenstein

Publications and source records attributed to H Festenstein.

At least 73 records · Page 4Linked to original sources
PubMed1987

HLA associations with multiple sclerosis in Sicily and Malta.

The islands of Sicily and Malta have very different prevalence rates for multiple sclerosis (MS): at least 44 per 100,000 in Sicily and only 4 per 100,000 in Malta. In Northern Europe, MS is associated with HLA-DR2/Dw2. The other components of the commonest DR2-containing haplotype of this region, HLA-A3-B7-DR2-Dw2, also tend to be present at higher frequency in MS patients. HLA Class I and II antigen frequencies and associations in controls and MS patients from Sicily and Malta were studied to discover whether they might account for the difference in MS prevalence. In Sicilian MS patients, DR2 is increased in frequency compared with controls and four out of five DR2-positive patients also type as Dw2. In the Maltese population, DR2 is present at high frequency but approximately half of the DR2 positive individuals do not type as Dw2 so that DR2 is probably most commonly present as part of Class II haplotypes other than those commonly associated with MS. Additional differences in HLA profile of the Sicilian and Maltese populations were found when HLA-A, -B, and B-DR antigen associations were examined. Therefore, some of the difference in MS prevalence might be explained by genetic factors.

Cross-Sectional Studies↗
PubMed1986

Bone-marrow transplantation has a limited role in prolonging second marrow remission in childhood lymphoblastic leukaemia.

Fifty-three children with acute lymphoblastic leukaemia whose first complete remission ended in bone-marrow relapse received similar reinduction and consolidation therapy. Thirteen had an HLA-compatible sibling donor and were eligible to receive a bone-marrow transplant (BMT); five survive, all off treatment in continuing remission. Forty had no donor and received further chemotherapy; sixteen survive, twelve in remission and six off treatment. After 1-5.5 years' follow-up from relapse, there is no significant difference in survival between the groups. The major obstacle to success is marrow relapse which occurred in two eligible patients before BMT could be carried out. The lengths of first and second remissions in both groups were significantly correlated. Morbidity in survivors was substantial. The scope of BMT as retrieval therapy for ALL is limited by the instability of second remissions; this difficulty will not be overcome by increasing the number of potential donors or the use of autologous marrow.

Adolescent↗
PubMed1986

Long-term follow-up in London Transplant Group recipients of cadaver renal allografts. The influence of HLA matching on transplant outcome.

The London Transplant Group followed 1341 patients with cadaver renal transplants, none of whom received cyclosporine, for six months to 14 years to determine the effect on graft survival of matching donor and recipient for HLA Class I antigens (HLA-A, -B, and -C) and Class II antigens (HLA-DR, -MT, and -DQ). Long-term graft survival was greatly improved by matching for HLA Class I antigens, especially HLA-B. Transplants that could not be matched for both B-locus antigens but were completely matched for Bw4/Bw6 also did very well. In addition, since 1978, excellent results have been obtained with HLA-DR and -DRw52/53 (HLA-MT) matching, but not with HLA-DQ matching. Multivariate analysis using the Cox regression model confirmed that combination Class I and Class II matching produced significant improvements in graft survival. Thus, transplants matched for HLA-DR plus HLA-B and those matched for HLA-MT plus HLA-B had excellent results--even better than those reported with cyclosporine treatment. Double HLA-MT incompatibilities yielded the poorest results. We conclude that this approach of combining the broad and narrow specificities of Class I and II is extremely practical and that appropriate matching of tissue types is clinically important.

Antibodies↗
PubMed1986

A DR3-related DX alpha gene polymorphism strongly associates with insulin-dependent diabetes mellitus.

HLA-DQ alpha and HLA-DX alpha gene polymorphisms were analyzed by Southern blot techniques in 78 Caucasoid insulin-dependent diabetes mellitus (IDDM) subjects and 55 control subjects. Five restriction fragment length polymorphisms of the HLA-DQ alpha gene correlated with HLA-DR typing. Two allelic DX alpha-related gene fragments, of 2.1 kb (U) and 1.9 kb (L) in size were identified. Genotype frequencies in the IDDM group for UU, UL, and LL were 54%, 38.5%, and 7.5%, respectively, whereas the corresponding frequencies in the control group were 24%, 40%, and 36% (P less than 0.00005 for differences in genotype frequencies). The U allele was associated particularly with IDDM patients who were DR3, with healthy controls who were DR3, as well as with IDDM patients who were not DR3. Thus, if this DX alpha U allele is not the DR3-associated IDDM susceptibility gene, it is the closest marker hitherto studied.

Chromosome Mapping↗
PubMed1986

Ontogenic and functional implications of the differential expression of HLA-DQ antigens on leukemic cells.

We have examined the HLA class II antigenic profiles on different types of leukemic cells and have attempted to relate these findings to the normal differentiation pathways of the cells from which they have arisen. Monoclonal antibodies reacting with the different HLA class II determinants, HLA-DR, DRw52(MT), and DQ, were used to study the expression of these antigens on Epstein-Barr virus transformed cell lines, chronic lymphocytic leukemic cells, acute lymphoblastic leukemic blasts, acute myeloblastic leukemic blasts, and established leukemic cell lines by indirect immunofluorescence binding and immunoprecipitations. The results showed that whereas the HLA-DR and HLA-DRw52(MT2) antigens are normally expressed on the majority of the cells tested, there is a different expression of the HLA-DQ antigens on acute leukemic blasts, chronic lymphocytic leukemic cells, and leukemic cell lines indicating that the DQ molecules may be differentiation antigens preferentially expressed on mature cells. Furthermore, when the pre-B cell leukemic line NALM 6 was induced to differentiate with phorbol ester (TPA), normal expression of the HLA-DQ antigen was obtained after 5 days of culture. The absence of HLA-DQ antigens from the acute leukemic blasts suggests that these immature cells "froze" in the early stages of cell differentiation. We discuss these findings in relation to the role of these HLA class II antigens in cell differentiation and the immune response.

Antibodies, Monoclonal↗
PubMed1986

HLA-Dw specificity assignments are independent of HLA-DQ, HLA-DR, and other class II specificities and define a biologically important segregant series which strongly activates a functionally distinct T cell subset.

Several lines of evidence indicate that HLA-Dw, as defined by HTC typing, is not the result of the combined stimulatory effect of HLA-DR and DQ. Therefore, responder cells do not have to share HLA-DQ antigens with the stimulator HTCs to give a typing response. The common HLA-DR-DQ associations observed in HTCs correspond to different patterns of linkage disequilibrium in different populations. HLA-DQ and HLA-Dw are functionally heterogeneous. Although HLA-DQ molecules may play a role in primary stimulation, this role is distinct from that of Dw determinants which have strong lymphocyte activating properties. The role of the HLA-DQ determinants on the other hand, is one of modulating the total T cell response by controlling the proliferation of suppressor and cytotoxic cells. The primary MLC response is the result of the proliferative effect of HLA-Dw, DR, DP, and other associated determinants, in conjunction with a modulatory effect of DQ molecules. However, HLA-Dw (as detected by HTC typing) are DR associated determinants which are immunodominant in primary MLR. The genes of the HLA-DR subregion have been named DR by the WHO nomenclature committee. This subregion encodes the HLA-DR specificities and the DRw52 and DRw53 determinants. Unfortunately this nomenclature does not take into account the need to define the genetic basis of the HLA-Dw determinants--whether they are encoded by separate genes within the HLA-DR subregion or whether they are encoded by as yet unspecified genes in the HLA class II region in linkage disequilibrium with HLA-DR DRw52/53. There are at least three and possibly four beta chain genes in the HLA-DR subregion, all in strong linkage disequilibrium with each other. Some of these are expressed in most haplotypes while others are not; some behave as pseudogenes in some haplotypes and in others, all the genes are expressed. All the genes of the class II region have not been fully characterized. HLA-Dw determinants may be specified by one or more of these genes. When more information becomes available, the genetic and molecular basis of the HLA-Dw series as well as the functional heterogeneity and antigenic strength of the various class II determinants will be better understood.

Epitopes↗
PubMed1986

HLA antigens in the pathogenesis of Menière's disease.

In the Department of Otolaryngology of the London Hospital many clinical and laboratory investigations have been conducted over the past fifteen years in an attempt to unravel some of the mysteries of Menière's disease. Many of these have been directed towards diagnosis, prognosis or therapy. Some have had a bearing on the aetiology of the idiopathic disease--these were summarised by Morrison (1981), including the finding of an hereditary predisposition, of an association with migraine in a significant proportion, also familial, of a 'personality type' of patient with Menière's disease and of typical radiological changes in the skull base in the majority of sufferers. More recently Brookes (1985), writing from this department, drew attention to both the occasional finding of an association between endolymphatic hydrops and elevated levels of circulating immune complexes, and also to the immunological studies in progress in patients with Menière's disease. These latter early results were reported by Morrison (1984) and are summarised in Table I. There was a highly significant difference between the levels of circulating complement and of immune complexes in patients with Menière's disease compared with control patients. There was, however, no difference in the results of autoantibody screening nor in the levels of serum immunoglobulins between the groups.

Adolescent↗
PubMed1986

HLA antigens in palindromic rheumatism and palindromic onset rheumatoid arthritis.

Fifty patients who presented with typical palindromic rheumatism of at least 6 months' duration were tissue-typed for HLA A, B, C antigens. DR typing was also performed but was not possible for technical reasons in three patients. Twenty-three patients who had progressed to definite or classical rheumatoid arthritis (RA) after a mean interval of 5 years were compared with 20 patients whose palindromic attacks had persisted over a similar period. Both groups showed a significantly higher frequency of DR4 antigen than a control population. The RA group also showed an increased frequency of DR1. There was no significant difference in the frequency of DR4 or any other DR antigen between the two patient groups. The frequency of B27 antigen was significantly higher in the palindromic group compared with the controls. It is suggested that although DR4 may be associated with a tendency to inflammatory joint problems, environmental or other unrelated genetic factors may be more important in determining the progression of palindromic rheumatism to RA.

Arthritis, Rheumatoid↗
PubMed1986

Serological biochemical and functional characterisation of three different HLA-DR monoclonal antibodies derived from C57BL6 mice.

C57BL6 mice which do not express I-E gene products were immunised with EBV transformed human B cell lines to generate MoAbs. Three hybridoma supernatants which initially reacted with the immunising donor cell but not a T cell line lacking Class II antigens were further investigated. I-D SDS-PAGE patterns of molecules precipitated by the three supernatants from a cell membrane lysate were characteristic of HLA-Class II alpha and beta chains. Two-dimensional analysis established the specificity of the supernatants as HLA-DR specific. This was confirmed by the reaction patterns with Class II mutant deletant cell lines. In both ELISA and cytotoxicity one reacted with all lymphoblastoid cell lines tested, one reacted with all except two that were DR7 homozygous and the third reacted strongly only with cells that were DR3. All three antibodies were cytotoxic to both peripheral blood lymphocytes and EBV transformed B cell lines. The DR3 specific MoAb (IgG2a) was suitable as a typing reagent. The DR3 reactive MoAb specifically inhibited stimulation by a Dw3 HTC and the other two MoAbs inhibited all HTCs tested. These findings are consistent with the view that certain determinants responsible for the Dw specificities are carried on the DR molecules.

Animals↗
PubMed1986

Different HLA associated gene combinations contribute to susceptibility for coeliac disease and dermatitis herpetiformis.

Forty two white patients of British or Irish descent with coeliac disease and 28 with dermatitis herpetiformis were typed for class I HLA-A, B, and C, and class II DR and DQ antigens. In coeliac disease there was a significant increase in the frequencies of A1, B8, DR3, DR7, and DQw2 compared with controls but no increase of DR2. In dermatitis herpetiformis there were similarly increased frequencies of A1, B8, DR3, and DQw2. In contrast with coeliac disease, however, the frequency of DR7 (18%) was no different from the control group but there was an increased frequency of DR2.

Adolescent↗
PubMed1986

New HLA DNA polymorphisms associated with rheumatoid arthritis.

Studies of restriction enzyme fragment length polymorphisms (RFLP) have further clarified two DNA polymorphisms detected in DR4 positive individuals with a DQ beta probe. These patterns have been designated DQ beta omega, characterized in the Dw4 homozygous typing cell (HTC) BM14 and DQ beta phi, characterized in the Dw4 HTC MCF, and so do not correspond with different Dw types. These patterns clearly segregate in families with HLA haplotypes. We suggest that omega and phi may be polymorphisms of the DX beta gene. The previously reported DX alpha polymorphisms U and L were found with all DR types and in association with DQ beta omega (U) and DQ beta phi(L). In addition DQ beta phi was found to be strongly associated with TA10 positively (a subdivision of DQw3) although this association was not absolute. Associations between RFLP and other HLA Class II and I antigens seen in DR4 patients and DR4 controls suggest the existence of at least two preferential allelic associations (PAA), one containing omega/U and the other phi/L. PAA1: DX alpha U-DQ beta omega-TA10 negative-DQw3-Dw4-DR4----Bw62-Bw6-Cw3-A2 PAA2: DX alpha L-DQ beta phi-TA10 positive-DQw3-Dw4-DR4----B44-Bw4-Cw3-A2 The frequency of the omega pattern was higher, although not significantly in the RA patients compared with controls. However, a significantly higher frequency of omega was found in RA patients with extra-articular manifestations (EA) compared (a) with controls (p less than 0.04) and (h) with those patients without EA (p less than 0.05). In addition the frequency of phi was significantly higher in RA patients with nodules and/or erosions (N/ER) compared with patients without these features (p less than 0.008). When cumulative scores were assigned to patients after assessing the number of components fulfilled for each PAA, PAA1 appeared to be pronounced in patients with EA and PAA2 in patients with N/ER. The frequency of a previously reported DQ beta T6 band found with the enzyme Taq 1 and DQ-beta probe was found at a higher frequency in RA patients compared with controls. In addition a significantly higher frequency of this band was found in female RA patients compared to males.

Arthritis, Rheumatoid↗
PubMed1986

HLA and rheumatoid arthritis: an analysis of multicase families.

In a study of multicase RA families, significantly raised frequencies of the HLA antigens DR4, DR1, Bw62, Cw3, A2, A31 and significantly lower frequencies of DR2, DR3, and B8 were found in probands compared to normal controls. When haplotype frequencies were compared between probands and controls, two haplotypes A2-B44-DR4 and A2-Bw62-DR4 were at higher frequency in probands. These differences no longer reached significance when only DR4-containing haplotypes were compared between probands and controls. A significantly lower haplotype frequency of A1-B8-DR3 was observed in probands compared to controls. This difference did not remain significant when only non-DR4 haplotypes were compared. Using an affected sibling pair ratio method, significant linkage between HLA and RA was found (P less than 0.01). Significant linkage was also observed between HLA and seropositivity. Analysis of Hardy-Weinberg equilibrium for the DR locus did not support the suggestion that DR4-associated RA susceptibility was inherited as a dominant trait. In addition it did not support the notion of an additive effect of DR4 and DR1 in RA susceptibility as these antigens were not found together more frequently than predicted by their individual gene frequencies.

Arthritis, Rheumatoid↗
PubMed1986

HLA and rheumatoid arthritis: susceptibility or severity?

An analysis of data collected on 440 British Caucasoid rheumatoid arthritis patients has confirmed positive association with HLA-DR4, Dw4, DRw53, and A2 and negative associations with HLA-DR2, 3, and 7. HLA-DR4 is more associated with RA 'severity' than with RA 'susceptibility', when measured by the parameters of ARA classification, seropositivity, severity of erosions and extra-articular manifestations. The association between HLA-A2, Cw3, Bw62, DR4, DRw53, and Dw4 and extra-articular disease has been confirmed in this study. The analysis of HLA and RA severity with respect to sex showed high frequencies of DR4, Dw4, and DRw53 in females, which increased in those with severe erosions, seropositivity or extra-articular disease. In males with RA, the disease appears to be associated not only with DR4, Dw4 and DRw53, but also with A2, Cw3 and Bw62. However, no significant differences in these antigen frequencies were found between male patients with severe RA and those without. Despite a significant decrease in the frequencies of DR3, B8 and A1 in most RA patient subsets, RA patients with Sjogren's syndrome showed a marked increase of A1 and B8 and patients with auto-antibodies had a significant increase in HLA-DR3 frequency when compared with patients without these features.

Arthritis, Rheumatoid↗
PubMed1986

HLA antigen associations with radiological changes in the hands, feet, and cervical spines in early rheumatoid arthritis.

Clinical, laboratory, and genetic features measured at the onset of rheumatoid arthritis in 100 patients were compared with the severity of radiological changes in the hands and feet and in the cervical spines at a mean of 7.7 years. HLA-Dw4 was associated with more severe (p = 0.009) and HLA-Dw2 with less severe (p = 0.02)radiological changes in the hands and feet but the single strongest correlation with the severity of peripheral erosions was rheumatoid factor (p = less than 0.0001). Although none of the standard clinical or laboratory parameters correlated with severity of cervical spine changes, the presence of HLA-Dw2 and/or HLA B7 cross-reactive group were associated with more severe radiological changes in the cervical spine (p less than 0.02). Discriminant analysis selected certain standard laboratory parameters which in combination provided the most powerful prognostic index of radiological outcome in the hands and feet which was correct in 82 per cent. The addition of HLA data did not improve this figure. Conversely, the combination of the presence of HLA-Dw2, B27, and older age of onset of disease was found to be the most powerful predictor of the development of cervical spine changes and successfully predicted this complication of RA in 73 per cent.

Adult↗
PubMed1986

HLA-DQ molecular heterogeneity in HLA-DR4-Dw4 consanguineous cell lines.

Two-dimensional gel analysis (NEPHGE) of the molecules precipitated by the HLA-DR monomorphic antibody L243 showed a single and identical alpha chain spot from two consanguineous cell lines, BM14 and MCF. The latter was derived from a rheumatoid arthritis patient. No apparent structural polymorphism of the HLA-DR beta chains was detected. The data suggests that the HLA-DR4 haplotype expresses one alpha chain and up to four beta chains. The electrophoretic pattern of the HLA-DQ molecules precipitated with the monomorphic antibody TU22 revealed clear differences between BM14 and MCF. These differences were mainly in the beta chain profiles. Four acidic beta chains were found with the MCF cell line wheras only three beta chains at different isoelectric points were found with the BM14 cell line. The data obtained in this study argue for a considerable heterogeneity of the HLA-DQ antigens detected at the molecular level.

Arthritis, Rheumatoid↗
PubMed1986

HLA frequency and haplotype analysis in a family study of adult onset rheumatoid arthritis.

Twenty-five families with probands who have rheumatoid arthritis (RA) were studied for clinical evidence of disease and for HLA status. This confirmed an association between RA and DR4 in 19/25 probands (76 per cent, p = 0.008). These 19 probands carried 24 haplotypes which contained DR4. There was no significant increase of DR4 haplotypes bearing B15(Bw62) or B44 when compared with published control haplotype data. The rare complement allele C4 B3 was detected as part of the extended haplotype A2 Cw3 B15(Bw62) DR4 C4 A*3B*3 in three probands with severe RA. Further studies to examine disease severity and autoantibody expression are in progress.

Arthritis, Rheumatoid↗
PubMed1985

HLA-DR genotyping by restriction fragment length polymorphism analyses.

We have established unique restriction fragment length polymorphism (RFLP) patterns characteristic of homozygous typing cells (HTCs) for HLA-DR-1 through HLA-DR-8 haplotypes. These RFLP patterns were found to segregate in family members and correlate 100% with HLA-DR antibody phenotyping. The RFLP patterns were used to type chronic myelocytic leukemic cells which have a Philadelphia translocation from 23 randomly selected Caucasoid patients. The results show an alternative method for the determination of the HLA-DR types without using live cells and to study disease association with the HLA-DR region.

Cell Line↗