Disappearing collagen antibodies in rheumatoid arthritis.
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Animals↗
Biomedical subjects
K I Welsh
Publications and source records attributed to K I Welsh.
Differentiation between allograft rejection and cyclosporin nephrotoxicity in renal-transplant recipients.
In a retrospective study of 60 renal-transplant patients immunosuppressed with cyclosporin no specific clinical features differentiated allograft dysfunction responsive to anti-rejection therapy from dysfunction responsive to reduction in cyclosporin dosage. Histologically, allograft dysfunction responsive to anti-rejection therapy was strongly associated with diffuse interstitial infiltration by mononuclear cells, oedema, and haemorrhage, vascular endothelial-cell proliferation, and infiltration of arterial walls by mononuclear cells. Arteriolar medial hypertrophy and hyalinosis were more commonly found in biopsy specimens from allografts with dysfunction responsive to reduction in cyclosporin dose than in those with dysfunction responsive to anti-rejection therapy and those with stable or improving function. Whole-blood cyclosporin concentrations were significantly lower in patients with dysfunction reversed by anti-rejection therapy than in those with dysfunction reversed by reduction in cyclosporin dose or in those with stable function. There was, however, considerable overlap between these groups, so that individual cyclosporin measurements were of little diagnostic value.
Adolescent↗
HLA associations in fibrotic disease.
HLA antigens have been associated with a wide variety of human diseases. In general these associations are not absolute in the way that classical genetic disorders are. Thus although the association between ankylosing spondylitis and HLA-B27 has been known for 11 years we are not able to define a closer genetic marker for the disease or indeed to define the mechanism by which B27 is involved with the disease process. This paper indicates the major disease associations with HLA antigens and compares them with those found in fibrotic disease. Some attempt is made to localize the position in the disease process where HLA might play a role. The aim of studies of HLA associations often includes the identification of at-risk groups in the hope of being able to apply selective preventive measures. Some progress along this path has been made and is outlined.
Arthritis, Rheumatoid↗
Immunoglobulin C mu gene restriction fragment length polymorphisms associated with chronic renal failure.
The DNA's of 41 patients with various forms of renal disease and of 52 controls were investigated for restriction fragment length polymorphisms (RFLP), using a probe recognising the immunoglobulin Cmu heavy chain gene. With the restriction endonuclease Sst 1, 50 of the controls and 12 of the patients had the expected single 4.3 kilobase (kb) fragment. The remaining 29 patients and 2 controls displayed two patterns of banding, 8 patients and 1 control had a 6.8 kb band in addition to the 4.3 kb, and 21 patients and 1 control had a single band of 5.1 kb. In addition, a significant association between high creatinine levels (greater than 150 mumol/l) and abnormal bands was found (21/25 patients with high levels had abnormal bands compared with only 5/16 patients with normal levels). These results are evidence for an association between the human immunoglobulin heavy chain region and renal disease and they apparently confirm an association already reported at the protein level. However, the new RFLP bands, although reproducible and restricted to renal patients, occur in an area where few polymorphisms would be expected. Further, the association with high creatinine suggests some subtle interaction between the creatinine pathway and this area of the human chromosome.
Creatinine↗
Increased frequency of IgG heavy chain marker Glm(2) and of HLA-B8 in Lambert-Eaton myasthenic syndrome with and without associated lung carcinoma.
In view of the evidence for an autoimmune pathogenesis of the Lambert-Eaton myasthenic syndrome, we have sought associations with IgG heavy chain allotypes (Gm) and HLA antigens in 30 patients, of whom 20 had evidence of lung carcinoma (histologically proven small ("oat") cell type in 17). A highly significant overall increase in frequency of Glm(2) (chi 2 = 10.95; p less than 0.001; n = 30) and of HLA-B8 (chi 2 = 19.07; p less than 0.001; n = 23) was observed. These two factors apparently occurred independently of each other. The Glm(2) frequency in 36 non-myasthenic small cell carcinoma cases was the same as in a control panel (n = 167). We conclude that Glm(2) and HLA-B8 both associate with increased susceptibility to the Lambert-Eaton myasthenic syndrome, and suggest that Glm(2) may be in linkage disequilibrium with a limited number of VH genes coding for antibodies to restricted antigenic determinants at the nerve terminals, which may be shared by the carcinoma cells.
Adult↗
Rheumatoid factors and HLA-DR4 in RA.
The levels of serum rheumatoid factors (RF) and the in vitro production of immunoglobulin were studied in 21 patients with rheumatoid arthritis (RA) and compared to the in vitro responses of 20 controls. In RA patients the levels of serum IgM RF and IgG RF were not significantly increased in patients possessing HLA-DR4 or any other DR antigen. Lymphocytes from seropositive RA patients released measurable quantities of IgM RF spontaneously, greatest in those possessing HLA-DR4. When lymphocytes were treated with either pokeweed mitogen or the T cell mitogen derived from Mycoplasma arthritidis the increased production of IgM RF was not related to HLA-DR4 status, either for RA patients or controls. Seronegative RA lymphocytes, while having similar IgM RF responses to controls, differed in having IgG RF in their serum.
Adult↗
Relationship of HLA-DR4 to defective cellular immunity in rheumatoid arthritis using PPD, and mycoplasma and lectin mitogens.
The disordered cellular immunity of rheumatoid arthritis (RA) was studied in vitro by assessing the stimulatory effect of tuberculin PPD, a mycoplasma product with major histocompatility complex restricted properties in mice (MAS) and concanavalin A (Con A) on RA and control cells of known tissue type. PPD provided the best discrimination between RA and controls (RA responses 34% of latter). The only significant association with HLA-DR type was that patients with RA who exhibited poor responsiveness to MAS had a significantly increased frequency of HLA-DR4.
Arthritis, Rheumatoid↗
Genetic markers in narcolepsy.
Narcolepsy has long been known to have a hereditary familial basis. All of 37 patients with narcolepsy expressed the major histocompatibility complex antigen HLA DR2 compared with 21.5% of 200 normal controls. This finding confirms the genetic basis for the disease, and furthermore links it with the short arm of chromosome 6. If the sleep disturbance in narcolepsy is due to a gene-determined defect in a neurotransmitter or receptor factor, the responsible agent may be DR2 itself or an enzyme determinant linked to DR2. This is the strongest HLA-disease association so far discovered.
Adolescent↗
Renal transplantation after removal and prevention of resynthesis of HLA antibodies.
Plasma exchange and immunosuppression with prednisolone and cyclophosphamide were used to remove HLA antibodies and prevent their resynthesis in five patients awaiting renal transplantation. After treatment HLA antibody titres and reactivities against a panel of donor lymphocytes were considerably reduced and, as a result, these patients received transplants. Four of these patients have successfully functioning transplants; the other patient died as a result of septicaemia with a poorly functioning allograft.
Adolescent↗
Polymyalgia rheumatica and rheumatoid arthritis: similarity of HLA antigen frequencies.
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Arthritis, Rheumatoid↗
Association of immunoglobulin Gm allotypes with antiglomerular basement membrane antibodies and their titer.
We studied the immunoglobulin Gm allotypes in 41 patients with glomerular nephritis caused by autoantibodies to glomerular basement membrane (GBM). Gm phenotypes of all 41 patients were attributable to combinations of the 3 Gm haplotypes commonly found in Caucasoid populations; identified by the allotypes Gm 1,21 (ag), Gm 1,2,21 (axg), and Gm 3,5,11 (fb). The incidence of the putative haplotype Gm 1,2,21 (axg) was greatly increased in the patients being present in 22 of 41 (56%) of patients compared to 28 of 167 controls. (Pcor = 1.5 X 10(-5]. The increase in Gm 1,2,21 (axg) was attributable entirely to presumed heterozygotes with the phenotype Gm 1,2,21;3,5,11 (axg;fb), with concomitant decreases in the frequencies of patients with the phenotypes Gm 1,21 (ax) and with Gm 3,5,11 (fb). Heterozygotes at Gm loci had higher titers of anti-GBM antibodies irrespective of the presence of Gm 1,2,21 (axg). Thus genes within or closely linked to the Gm complex in addition to HLA linked genes influence susceptibility to or clinical expression of anti-GBM disease.
Autoantibodies↗
The influence of HLA-linked genes on the severity of anti-GBM antibody-mediated nephritis.
Thirty-nine Caucasian patients with glomerulonephritis caused by autoantibodies to glomerular basement membrane (GBM) were studied. They were segregated into three groups depending on presentation: Group 1 (19 patients) were anuric or oliguric, group 2 (13 patients) had rapidly deteriorating renal function but were not oliguric, and group 3 (seven patients) had stable renal function. The incidence of HLA-DR2 was greatly increased; it was present in 34 of 38 patients in whom DR antigens were identified compared to 43 of 154 controls (Pc = 0.63 X 10(-8), relative risk 36, etiological fraction 0.86). The incidence of HLA-B7 was also increased; present in 23 of 39 patients and 43 of 193 controls (Pc = 0.26 X 10(-4), relative risk 5.0, etiological fraction 0.43). These data were analyzed for a third order association between HLA-DR2, HLA-B7, and anti-GBM disease. Such an association was probable for patients in group 1 (P = 0.27 X 10(-6), likely for those in group 2 (P = 0.024) but unlikely for patients in group 3 (P = 0.62) suggesting HLA-B7-associated genes influence severity. Clinical results from a subset of the patients referred directly on presentation showed that patients who inherited HLA-B7 together with DR2 had significantly higher plasma creatinines, a greater proportion of glomeruli surrounded by crescents and a worse prognosis. Despite this there was little difference in severity of their lung disease.
Adolescent↗
HLA antigens, autoantibodies and clinical subsets in scleroderma.
The HLA antigens were determined in 54 Caucasoid patients with scleroderma (ARA criteria). All were assessed for extent of skin and organ involvement, anticentromere (ACA), and scleroderma 70 (Scl 70) antibodies. The antigens DR1, DR3 and DR5 were raised in the patient group, and DR2 was lowered. Of these only the increase in DR5 was significant (chi 2 = 5.2; p = 0.02). The increased frequency of DR3 was attributable to a rise in the A1, B8, DR3 haplotype (chi 2 = 3.9; p = 0.05). Patients with non-diffuse disease showed a significant increase in the DR1 and DR5 antigens (chi 2 = 3.7, p = 0.05; chi 2 = 8.0, p = 0.01). No association was found between the HLA antigens and specific organ involvement. Anticentromere antibodies were present in 15 of the HLA-DR typed patients. Thirteen of these 15 patients were either DR1 or DR5. No relationship was found between the frequencies of HLA antigens and anti-Scl 70 antibodies.
Adult↗
Successful removal and prevention of resynthesis of anti-HLA antibody.
The successful removal and prevention of the resynthesis of an anti-HLA antibody by plasma exchange and immunosuppression in a patient awaiting renal transplantation is described. Before treatment, the patient's serum contained a high titer (greater than 1/50) anti-HLA antibody that reacted with 94% of our lymphocyte donor panel and produced positive cross matches with the lymphocytes from 40 cadaver kidneys. Following treatment, her anti-HLA titers fell to less than 1/10 and her sera reacted with 43% of our lymphocyte donor panel and produced negative crossmatches with lymphocytes from the first two cadaver kidney donors she was tested against. She was successfully transplanted with the second of these kidneys and is now well eight months later, with good graft function.
Adult↗
Immunoglobulin (Gm) allotype frequencies in idiopathic membranous nephropathy and minimal change nephropathy.
40 Caucasoid patients with idiopathic membranous nephropathy (IMN) and 49 Caucasoid patients with minimal change nephropathy (MCN) were immunoglobulin allotyped for the Gm markers G1m (1, 2, 3) and G3m (5, 11, 21). Compared with normal controls the IMN group had a significantly decreased incidence of the G1m (3); G3m (5, 11) phenotype (P = less than 0.005). This decrease was accompanied by concommitant increase in both the G1m (1, 3); G3m (5, 11, 21) and the G1m (1, 2, 3); G3m (5, 11, 21) phenotypes. The result was most pronounced in IMN patients with deteriorating renal function. In contrast no significant differences were observed between the Gm phenotype frequencies of the MCN patients and controls.
Adolescent↗
D-Penicillamine induced toxicity in rheumatoid arthritis: the role of sulphoxidation status and HLA-DR3.
Sulphoxidation of carbocysteine, a drug structurally similar to D-penicillamine, displays a skewed distribution within a population. In 66 patients with rheumatoid arthritis (RA) a significant association between impaired sulphoxidation and toxicity (p less than 0.001) was found; HLA-DR3, although associated with toxicity (p less than 0.05), appeared to be an independent risk factor of most importance in the group with extensive sulphoxidation. The relative risk of toxicity in a patient possessing either DR3 or impaired sulphoxidation was 25. The prevalence of poor sulphoxidizers within this group of RA patients was increased compared to that in a previous population study and requires further investigation. Our findings explain a number of the toxic phenomena associated with D-penicillamine administration in RA.
Adult↗
Immunoglobulin allotypes in psoriasis, psoriatic arthropathy and ankylosing spondylitis.
Immunoglobulin allotyping carried out on patients with ankylosing spondylitis, psoriatic arthritis and psoriasis alone showed increase in the phenotype G1m(1,2,3);G3m(5,11,21) in the psoriasis patients in general (p less than 0.05). In patients with psoriasis alone this increase was of greater significance (p less than 0.01). No significant deviation from the normal controls was found in ankylosing spondylitis.
Arthritis, Psoriatic↗
Genetic susceptibility to scleroderma-like syndrome induced by vinyl chloride.
Vinyl chloride (VC) monomer can induce a scleroderma-like syndrome in a proportion of workers exposed to it during production of polyvinyl chloride. As part of a 5-year follow-up study HLA A, B, and DR antigens and anti-centromere and anti-scleroderma-70 antibodies were determined in 44 such workers. 21 of these had severe and 23 mild forms of vinyl-chloride disease. 50 patients with "classical" scleroderma and 148 healthy hospital workers acted as controls. 11 of the 21 patients classified as having severe VC disease were DR3 positive, and 8 of these had both B8 and DR3 antigens. None of the 23 patients with mild disease carried either antigen. The HLA-antigen frequencies in VC disease mirrored those found in scleroderma (raised DR5 frequency and increased linkage disequilibrium between B8 and DR3). There were, however, significant differences in the frequency of autoantibodies in the two conditions.
Autoantibodies↗