Complete nucleotide sequence of HLA-B*0703, a B7 variant (BPOT).

HLA-B703 (BPOT) is a B7-like antigen segregating within families. To determine the complete B*0703 nucleotide sequence, HLA-ABC-cDNAs derived from the EBV cell line POT71 have been cloned. Four B*0703-positive clones were sequenced to obtain an accurate consensus sequence. With respect to the isoelectric focusing-identical HLA-B*0702 allelic product, HLA-B*0703 differed only in a cluster of four nucleotide substitutions in exon 2 and a single (silent) nucleotide substitution in exon 3. The resulting amino acid substitutions in the alpha 1 domain of B703 at residues 69 (Ala-->Thr), 70 (Gln-->Asn), and 71 (Ala-->Thr) probably have their origin in a segmental exchange between B7 and other B alleles.

Immunogenetic heterogeneity of seronegative rheumatoid arthritis and the antiperinuclear factor.

HLA typing was carried out in 132 patients with rheumatoid arthritis (RA) with long term follow up, and special attention was focused on rheumatoid factor negative patients. The patients were divided into four groups: 55 patients with a seropositive RA and a positive antiperinuclear factor (group A); 39 seropositive patients but a negative antiperinuclear factor (group B); 14 patients consistently seronegative for 3-28 years (mean 11.8 years) but positive for antiperinuclear factor (group C); patients consistently negative for 3-28 years (mean 11.8) and also negative for antiperinuclear factor (group D). The prevalence of HLA-DR4 was 31/55 (56%), 29/39 (74%), 10/14 (71%), and 9/24 (37%) for groups A, B, C, and D respectively, and in all groups was significantly higher than in 277 healthy controls (55/277, 20%). No significant difference was found between seropositive (groups A and B) and seronegative (groups C and D) patients, but groups A, B, and C had higher prevalences than group D. It is concluded that in seronegative RA HLA-DR4 is preferentially associated with the antiperinuclear factor positive group.

HLA-B SNA antigen: a BW6 associated B locus antigen belonging to the B5 CREG.

A new B locus antigen has been found in members of two unrelated families and in a patient originating from Morocco belonging to the Berber population. A complete analysis has been performed with antisera from the 9th and 10th IHWS defining the B5 CREG antigens. Serology, absorption experiments and family studies indicate that SNA antigen is a Bw6 associated subtype of B5 antigen closely related to but clearly distinct from each of the B5 CREG antigens. One-dimensional isoelectric focusing study (1D-IEF) confirms that the SNA antigen precipitates as a B locus gene product and has an isoelectric point identical to that of Bw52 and one of the charge variants of B51.

Transplantation of highly sensitized patients on the basis of acceptable HLA-A and B mismatches.

We think that the determination of acceptable mismatches is an efficient approach to increase the chance of finding a crossmatch-negative donor for highly sensitized patients. This approach has several advantages (4,5) namely: 1. There is no need for distribution of patient sera to other tissue typing centers. 2. Rather than performing crossmatches with all donors, most of which will be positive, selection is based on a predictable negative crossmatch. 3. Selection of potential donors is based on data obtained by the recipient centers, which has all the information concerning the patient's immunological background (transfusion, specific alloantibodies, autoantibodies) rather than on a negative crossmatch at another tissue typing center. 4. Selection is based on HLA-DR compatibility between donor and recipient, which is, both in our and other analyses (6), important for an optimal prognosis of graft survival in highly immunized patients. Of course, there are still patients for whom this protocol is not very helpful (rare HLA-types, hardly any or no acceptable mismatches). For these patients it might be that other approaches, including removal of circulating antibodies (7), may be the only solution.

HLA-DP in rheumatoid arthritis.

Frequencies of HLA-DR, Dw and DPw specificities were compared between rheumatoid arthritis (RA) patients, Felty's syndrome (FS) patients and normal controls. It was confirmed that the frequency of DR4 was increased in RA patients (54% (n = 111) vs 23% (n = 272), relative risk (RR) = 3.98, P less than 0.001). Cellular typing showed a highly significant increase in HLA-Dw14 in the entire RA population (17% (n = 32) vs 2% (n = 242), RR = 11.90, P less than 0.001), and a tendency towards an increase of HLA-Dw14 in DR4+ RA patients compared to DR4+ controls (28% (n = 32) vs 11% (n = 47), RR = 3.29, P less than 0.05). Regarding DPw specificities, the only significance was for a negative association with DPw3 (13% vs 22% (n = 254), RR = 0.51, P less than 0.05), with an additional tendential decrease of DPw1 (11% vs 19%, RR = 0.53, not significant (NS]. The decrease of DPw3 was more marked in DR4- RA patients (RR = 0.33, P less than 0.05) than in DR4+ RA patients (RR = 0.69, NS). In FS patients, 96% of whom were DR4+, decreased DPw1 was very marked, whereas the frequency of DPw3 was unaltered compared to DR4+ normals. These alterations in frequencies were not caused by linkage disequilibria between HLA-DR and -DP alleles. Thus, taken together, these data suggest that, in the presence of the major DR4-associated "susceptibility" gene(s) for RA, DPw1 may have "protective" effects, whereas in the absence of DR4, the presence of DPw3 has significant "protective" activity.

Effect of thymectomy on myasthenia gravis and autoimmune thrombocytopenic purpura in a 13-year-old girl.

We report the association of myasthenia gravis (MG) and autoimmune thrombocytopenic purpura (AITP) in a 13-year-old girl. The co-existence of these autoimmune diseases is rare in adults and, to our knowledge, never described in children. In our patient thymectomy had a therapeutic effect on both MG and AITP, suggesting a altered T-cell function as a pathogenic factor of major importance in both affections.

Remarkably similar response to gold therapy in HLA identical sibs with rheumatoid arthritis.

Two pairs of sibs with definite rheumatoid arthritis responded in a remarkably similar way to parenteral gold therapy, in terms of both toxicity and efficacy. Both pairs proved to be HLA identical. One of the pairs possessed the HLA antigens B8 and DR3, which have been associated with both drug toxicity and excellent clinical response. The other pair did not possess either of these antigens, suggesting that the reaction to gold therapy in patients with rheumatoid arthritis may be determined by other HLA or genetic factors coded for by chromosome 6, or both.

HLA-B POT: a new HLA-antigen within the B7-cross reactive group.

In this report, a new HLA-B locus antigen is described (tentatively called POT). The antigen has been identified with antisera against the antigens that belong to the B7-cross reacting group. In a collaborative study, based on exchange of cells and sera, it was confirmed by population and family studies that the antigen is distinct from B7, Bw42 or Bw73 and is associated with Bw6. In absorption experiments with EBV-transformed cell lines, the POT-antigens removes preferentially anti-B7, Bw42 and Bw73 activity and to a lesser extent antibodies reactive with the B40 CREG-antigens.

The influence of HLA phenotypes on the response to parenteral gold in rheumatoid arthritis.

One hundred and ten patients with rheumatoid arthritis (RA) were studied for a possible influence of HLA phenotypes on the reaction to parenteral gold in the first 6 months of treatment, in terms of both clinical response and toxicity. Frequencies of HLA-B8 and -DR3 were significantly increased in patients who responded excellently to gold treatment as compared with non-responders (p = 0.04 for both antigens). On the other hand, for HLA-DR7 there was a tendency for increased frequency in non-responders versus excellent and moderate responders (p less than 0.03; Pc = n.s.). Drug toxicity was higher in excellent than in non-responders (p less than 0.04), being exceptionally high in male excellent responders (85% versus 33% in females, p less than 0.01), probably due to the increased frequency in B8 and DR3 in the excellent responder group as a whole and in the excellent responder males in particular. We conclude that HLA antigens B8 and DR3 co-determine both toxicity and excellent clinical response to parenteral gold, whereas the presence of DR7 is possibly associated with non-response. In addition, we found sex differences in reaction to parenteral gold, which may be related to an increased frequency of HLA-B8 and -DR3 in male RA patients.

Adult-onset Still's disease. Disease course and HLA associations.

Disease course and HLA antigens were determined in 29 patients with definite and 13 patients with probable adult-onset Still's disease (AOSD). Twenty-six patients had persistent disease with continuous disease activity for at least 1 year. Radiographic examination revealed evidence of joint destruction in 26 patients. In 15 patients, at least 1 root joint was impaired. The frequency of DR4 was increased in the total group of patients (35%, P = 0.03) and in the 29 patients with definite AOSD (41%, P = 0.02) compared with the frequency in normal controls (20%). None of the patients was positive for DR1, and only 1 was positive for Bw35. The frequency of DRw6 was increased in the patients with involvement of at least 1 root joint (40%, P = 0.03) compared with the patients without involvement of these joints (11%).

HLA associations in aurothioglucose- and D-penicillamine-induced haematotoxic reactions in rheumatoid arthritis.

HLA phenotype frequencies were studied in 21 rheumatoid arthritis (RA) patients with haematotoxic reactions to aurothioglucose (AuTG) or D-penicillamine (DP), 65 matched RA controls and 277 healthy controls. Antigens B8 and DR3 were significantly increased in the toxic RA patient group as compared to both RA controls and healthy controls. These contrasts were strongest in the patients with AuTG-induced thrombocytopenia or leucopenia: all patients developing either reaction to this drug were B8- and/or DR3-positive (p less than 0.001), 7 (78%) being positive for both antigens. In the patient group with DP-induced reactions these antigens were also increased but these differences were not significant. In the latter group the prevalence of antigen DR4 was high, especially in the patient group with DP-induced thrombocytopenia, all 12 patients with this type of reaction being DR4 positive. Our data suggest that haematotoxic reactions to AuTG and DP develop primarily (or even exclusively) in genetically predisposed RA patients. Furthermore, the HLA phenotype contributing to an increased risk seems not to be the same for the two anti-rheumatic drugs studied.

Improved patient and graft survival after treatment of acute rejections of cadaveric renal allografts with rabbit antithymocyte globulin.

In a prospective randomized trial, we compared the effectiveness of rabbit antithymocyte globulin (RATG) in the treatment of acute renal allograft rejection with the results of treatment by high oral doses of prednisone. Fifty recipients of cadaveric kidneys were included in each group. In the RATG group, the prednisone dose was not increased and a dose-by-rosette protocol was used to keep T cell levels between 50 and 150/mm. The three-month and one-year graft survival rates in the RATG group were 84% and 78%, and were significantly higher than those in the prednisone group (64% and 50%). A significant difference in patient survival could also be detected. In the RATG group the three-months and one-year patient survival rates were 100% and 98%, and patient survival rates in the prednisone group were 91% and 84%, respectively. The percentage of second rejections was higher in the prednisone group and 70% of these patients showed a good response to subsequent RATG treatment. Renal function after six months was similar in both groups. No serious side effects were encountered in the RATG group. The incidence of infections was the same in both groups. Treatment of acute rejections with RATG is preferable to prednisone treatment. It improves long-term graft and patient survival and is steroid-sparing.

Influence of HLA-DRW6 in the recipient on occurrence of acute rejection of first renal allografts: beneficial influence of antithymocyte globulin as antirejection treatment.

In a retrospective analysis of 232 recipients of first cadaveric kidney grafts the percentage of patients without an acute rejection was significantly higher in DRW6-negative than in DRW6-positive patients. This was not reflected in a better graft survival rate. This discrepancy was probably caused by the kind of antirejection treatment used. In DRW6-positive patients who had received RATG as the initial treatment for rejection, graft survival was significantly better than in DRW6-positive recipients treated with high doses of prednisone. In the DRW6-negative patients RATG treatment gave also better results, but here the difference was not significant. These findings show that the negative influence of the DRW6 antigen present in the recipients was counterbalanced by the beneficial effect of RATG-treatment for first rejection episodes. No influence of DR matching could be detected.

Exocrine pancreatic insufficiency and idiopathic haemochromatosis.

The case history of a 34-year-old patient with precirrhotic idiopathic haemochromatosis and severe chronic steatorrhoea is presented. The pancreas had a normal appearance on ultrasonography and endoscopic retrograde pancreaticography. However, pancreatic function tests revealed significant abnormalities. The pancreatic output of trypsin, amylase, lipase and bicarbonate was deficient and basal and stimulated serum pancreatic polypeptide levels were subnormal. In contrast, the oral glucose tolerance test was unimpaired. The pancreatic insufficiency had started suddenly during a summer vacation and may have had a viral aetiology. The hypothesis is advanced that in haemochromatosis the iron-laden pancreatic acinar and PP-producing cells are more susceptible to damage by viruses than normal pancreatic cells.